PubAnnotation

Id	Subject	Object	Predicate	Lexical cue
T1	0-24	Sentence	denotes	COVID-19 and the Kidney:
T2	25-63	Sentence	denotes	From Epidemiology to Clinical Practice
T3	65-73	Sentence	denotes	Abstract
T4	74-397	Sentence	denotes	The new respiratory infectious disease coronavirus disease 2019 (COVID-19) that originated in Wuhan, China, in December 2019 and caused by a new strain of zoonotic coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), to date has killed over 630,000 people and infected over 15,000,000 worldwide.
T5	398-502	Sentence	denotes	Most of the deceased patients had pre-existing comorbidities; over 20% had chronic kidney disease (CKD).
T6	503-698	Sentence	denotes	Furthermore, although SARS-CoV-2 infection is characterized mainly by diffuse alveolar damage and acute respiratory failure, acute kidney injury (AKI) has developed in a high percentage of cases.
T7	699-838	Sentence	denotes	As AKI has been shown to be associated with worse prognosis, we believe that the impact of SARS-CoV-2 on the kidney should be investigated.
T8	839-997	Sentence	denotes	This review sets out to describe the main renal aspects of SARS-CoV-2 infection and the role of the virus in the development and progression of kidney damage.
T9	998-1282	Sentence	denotes	In this article, attention is focused on the epidemiology, etiology and pathophysiological mechanisms of kidney damage, histopathology, clinical features in nephropathic patients (CKD, hemodialysis, peritoneal dialysis, AKI, transplantation) and prevention and containment strategies.
T10	1283-1473	Sentence	denotes	Although there remains much more to be learned with regards to this disease, nonetheless it is our hope that this review will aid in the understanding and management of SARS-CoV-2 infection.
T11	1475-1477	Sentence	denotes	1.
T12	1478-1490	Sentence	denotes	Introduction
T13	1491-1618	Sentence	denotes	By December 2019, unusual cases of pneumonia had been reported in the city of Wuhan, located in central China’s Hubei province.
T14	1619-1967	Sentence	denotes	On January 12th 2020, the World Health Organization (WHO) stated that the disease was caused by a novel coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), belonging to the β-coronavirus cluster, which also includes the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses [1,2].
T15	1968-2236	Sentence	denotes	The resulting SARS-CoV-2 related disease was defined as the novel coronavirus disease 2019, or COVID-19, that rapidly spread throughout China, followed by an increasing number of cases in all continents with the exception of Antarctica, resulting in a global pandemic.
T16	2237-2294	Sentence	denotes	The data of the global burden of COVID-19 are impressive.
T17	2295-2505	Sentence	denotes	Indeed, currently (available data up to 23 July 2020) the coronavirus is affecting 212 countries and territories around the world, with over 15 million cases and over 630,000 confirmed deaths (global mortality:
T18	2506-2518	Sentence	denotes	5.4%) [3,4].
T19	2519-2589	Sentence	denotes	The Americas and Europe are the most affected continents in the world.
T20	2590-2691	Sentence	denotes	In the United States of America (U.S.A.), 4,103,674 cases and over 146,000 deaths have been reported.
T21	2692-2820	Sentence	denotes	In Europe, many outbreaks are steadily rising in Russia, Spain, UK and Italy, with over 200,000 overall deaths in the continent.
T22	2821-2919	Sentence	denotes	However, in China the rate of new cases has progressively decreased substantially since March [3].
T23	2920-2971	Sentence	denotes	The pandemic has also had a severe economic impact.
T24	2972-3236	Sentence	denotes	In fact, to help improve the clinical management of patients infected with the virus, Europe has mobilized more than 10 million euros from research funding and the United Kingdom has also invested £20,000,000 to allow for the development of a COVID-19 vaccine [5].
T25	3237-3850	Sentence	denotes	It has also been estimated that in the U.S.A., the health care costs for a single infected patient is over $3000, resulting in an overall predicted expenditure of $654.0 billion over the entire period of the pandemic [6,7].A flu-like syndrome of mild severity has been observed in most cases (80%) of COVID-19 [8,9], but in 20% of cases there have been other complications such as interstitial pneumonia with a variable degree of respiratory failure [10] as well as thromboembolic complications, including venous thromboembolism (VTE), ischemic stroke and acute coronary syndrome (ACS)/myocardial infarction [11].
T26	3851-4099	Sentence	denotes	Although the principal features associated with COVID-19 are diffuse alveolar damage and acute respiratory failure, kidney impairment has also often developed, with the frequent onset of acute kidney injury (AKI) in patients infected by SARS-CoV-2.
T27	4100-4199	Sentence	denotes	In addition, more than 20% of deceased patients were affected by chronic kidney disease (CKD) [11].
T28	4200-4276	Sentence	denotes	For this reason, the kidney’s role in COVID-19 needs to be investigated [8].
T29	4277-4523	Sentence	denotes	The aim of this review is to describe the main aspects of COVID-19 infection, namely the epidemiology and pathophysiology, together with prevention strategies and the contribution of kidney diseases to the prognosis of COVID-19 affected patients.
T30	4525-4527	Sentence	denotes	2.
T31	4528-4540	Sentence	denotes	Epidemiology
T32	4541-4641	Sentence	denotes	Globally, over 15 million confirmed cases of COVID-19 have been reported to date (23 July 2020) [4].
T33	4642-4745	Sentence	denotes	Such a large number of affected patients have been caused by the way in which the virus is transmitted.
T34	4746-4904	Sentence	denotes	COVID-19 is more contagious when compared to MERS and SARS since the virus spreads by human-to-human transmission via direct or fecal contact or droplets [7].
T35	4905-5105	Sentence	denotes	Furthermore, the possibility that the virus may be transmitted by asymptomatic individuals or by individuals within the incubation period, may also explain the high contagiousness of the disease [12].
T36	5106-5271	Sentence	denotes	COVID-19 infection is thought to have an incubation period up to 14 days following exposure, with most symptoms showing around four to five days after exposure [13].
T37	5272-5370	Sentence	denotes	However, case reports with longer incubation periods (up to 27 days) have also been reported [11].
T38	5371-5474	Sentence	denotes	An updated publication confirmed these findings, with the incubation lasting as long as 24 days (range:
T39	5475-5493	Sentence	denotes	0–24 days; median:
T40	5494-5508	Sentence	denotes	3.0 days) [7].
T41	5509-5673	Sentence	denotes	Nonetheless, the onset of symptoms is variable amongst infected patients, and the interval during which an individual with COVID-19 is contagious remains uncertain.
T42	5674-5799	Sentence	denotes	It appears that SARS-CoV-2 can be transmitted prior to the development of symptoms and throughout the course of illness [14].
T43	5800-6037	Sentence	denotes	The infection can involve all age groups, including children, and, moreover, males suffer a disproportionately higher number of deaths than females according to data from cohorts of patients in China, Italy and the United States [15,16].
T44	6038-6455	Sentence	denotes	Patients admitted at the Tongji Hospital, the major endemic area, and positive for COVID-19, showed a median age of over 60-years and a large part (up to 42%) were affected by 1 or more comorbidities, including diabetes mellitus, cardiovascular disease, hypertension, chronic lung disease, cancer, chronic kidney disease, immunocompromising conditions, severe obesity (body mass index ≥ 40) and liver disease [17,18].
T45	6456-6613	Sentence	denotes	Similar evidence was derived from a cohort of 5700 hospitalized patients on the other side of the world, namely in the New York city area in the U.S.A. [15].
T46	6614-6714	Sentence	denotes	Moreover, the data of 333 children with confirmed SARS-CoV-2 from 11 case series were analyzed [19].
T47	6715-6918	Sentence	denotes	Intriguingly, despite the recent evidence that children have the same risk for infection than adults, few cases have been admitted to intensive care units (3%) and only a few deaths have been registered.
T48	6919-7145	Sentence	denotes	The less-severe infection has been principally related to the fact that children have a stronger innate immune response and a minor prevalence of comorbidities (arterial hypertension, cardiovascular diseases) than adults [20].
T49	7146-7310	Sentence	denotes	Most patients also showed an inflammatory status and coagulopathies with elevated levels of high-sensitivity C-reactive protein and serum lactose dehydrogenase [8].
T50	7311-7554	Sentence	denotes	Interestingly, up to 15% of the hospitalized COVID-19 patients had at least one kidney abnormality represented by increased blood urea nitrogen or reduced estimated glomerular filtration rate (eGFR) which is the best marker of kidney function.
T51	7555-7821	Sentence	denotes	Moreover, findings from different cohorts of hospitalized patients showed that 26–63% of patients presented proteinuria at admission or developed proteinuria during their stay in hospital, proteinuria being considered the most recognized sign of kidney damage [7,8].
T52	7822-8060	Sentence	denotes	An individual risk profile also found that COVID-19 patients with kidney abnormalities, compared with those with normal renal function at admission, were more likely to be males, with advanced age and with a worse coagulation profile [8].
T53	8061-8176	Sentence	denotes	In addition, a meta-analysis [21] has confirmed that CKD is associated with an enhanced risk of COVID-19 infection.
T54	8177-8371	Sentence	denotes	As previously mentioned, an urgent epidemiological effort has been undertaken to understand what risk factors are responsible for the principal outcome associated with COVID-19, i.e., mortality.
T55	8372-8742	Sentence	denotes	From Chinese studies, mortality rates were increasing along age categories (mortality rate of 1.3% in the 50–59 range, 3.6% in the 60–69 range, 8% in the 70–79 range and 14.8% in the ≥range 80 years), the presence of cardiovascular diseases (10.5%), diabetes (7.3%), chronic respiratory diseases (6.3%), arterial hypertension (6%) and neoplasms (mortality 5.6%) [22,23].
T56	8743-8974	Sentence	denotes	In Italy, data from ISS—i.e., the Italian Health Institute—indicates that 1% of the patients who died did not suffer from any other diseases, 26% had only one disease, 26% had 2 diseases and 47% had 3 or more pathologic conditions.
T57	8975-9354	Sentence	denotes	The most common chronic preexisting diseases in deceased patients were: arterial hypertension (70%), followed by diabetes mellitus (31.7%), chronic kidney disease CKD (23.1%), atrial fibrillation (22.5%), chronic obstructive pulmonary disease (COPD) (18.1%), the presence of an active cancer within the previous 5 years (16.8%), ischemic heart disease (16%) and obesity 10% [20].
T58	9355-9571	Sentence	denotes	It is very remarkable that CKD was present in more than 20% of the deceased patients due to COVID-19, also surpassing, in prevalence, those affected by COPD and/or those with an active cancer within the last 5 years.
T59	9572-9818	Sentence	denotes	In addition to the presence of CKD, it also has been demonstrated that COVID-19 patients are at increased risk of developing acute kidney injury (AKI), a clinical condition that is associated with unfavorable outcomes, including mortality [8,24].
T60	9819-9903	Sentence	denotes	The incidence of AKI in COVID-19 patients is similar to that found in SARS patients.
T61	9904-10158	Sentence	denotes	This sudden loss of kidney function is strongly associated with increased mortality and morbidity and is a complication that can occur during the progression of COVID-19 in patients suffering from kidney disease as well as in those who are not [8,23,25].
T62	10159-10325	Sentence	denotes	From the analysis of several studies, this incidence varies from 0.5% to 23%, with an interval from baseline visit to the onset of AKI of 7–15 days in median [25,26].
T63	10326-10545	Sentence	denotes	Patients who developed AKI had a more critical prognosis, in terms of mortality rate compared with those who only had chronic illness as comorbidity (AKI increased the risk of death by 5.3 times in these patients) [27].
T64	10546-10768	Sentence	denotes	All these observations suggest that AKI could be one of the risk factors for mortality in COVID-19 patients, and a recent meta-analysis of 26 studies suggested that mortality from AKI may, in fact, be 13 times higher [28].
T65	10769-10964	Sentence	denotes	Overall, either the presence of CKD at hospital admission or the development of AKI during the COVID-19 infection have been both recognized as two independent risk factors of mortality [8,29,30].
T66	10965-11039	Sentence	denotes	COVID-19 has also affected patients on renal replacement treatments (RRT).
T67	11040-11300	Sentence	denotes	The Italian Society of Nephrology (S.I.N.) report found 521 patients (2.8%) positive for SARS-CoV-2 in a population of 17,848 patients undergoing hemodialysis, 18 patients (0.65%) were positive in a population of 2252 patients treated with peritoneal dialysis.
T68	11301-11480	Sentence	denotes	In positive RRT patients, 54% were dialyzed at their own dialysis center, 18% required hospitalization in sub-intensive care unit and 4.7% were dialyzed in an intensive care unit.
T69	11481-11546	Sentence	denotes	Death occurred in a non-trivial proportion of cases (25.8%) [31].
T70	11547-11856	Sentence	denotes	Indeed, data from the Dialysis Units of Piedmont and Aosta Valley (two Italian Northern West regions) found that absolute mortality risk was higher in males than in females (31.1% vs. 4%, respectively) and in presence of cardiovascular disease (29.9% vs. 10.7%) whereas it was not related to dialysis vintage.
T71	11857-11927	Sentence	denotes	Diabetes was a risk factor in transplanted patients (66.7% vs. 13.6%).
T72	11928-12024	Sentence	denotes	A history of neoplasia was also associated with an increase in risk of death (40% vs. 19%) [32].
T73	12025-12125	Sentence	denotes	These data demonstrate how hemodialysis patients are particularly susceptible to COVID-19 infection.
T74	12127-12129	Sentence	denotes	3.
T75	12130-12138	Sentence	denotes	Etiology
T76	12139-12272	Sentence	denotes	Coronaviruses are a group of single-stranded RNA viruses (ssRNAs) with positive polarity, belonging to the Coronaviridae family [33].
T77	12273-12355	Sentence	denotes	Until 2019, six coronavirus strains, which were able to infect humans, were known.
T78	12356-12452	Sentence	denotes	Four strains usually circulate in the human population causing mild respiratory infections [34].
T79	12453-12581	Sentence	denotes	In 2003 and 2012, the first two zoonotic strains of coronaviruses capable of infecting humans through an animal were identified.
T80	12582-12674	Sentence	denotes	These have caused severe lung syndromes in recent times: SARS in 2003 and MERS in 2012 [34].
T81	12675-12901	Sentence	denotes	Studies carried out on these strains showed that zoonotic coronaviruses use the bat as the primary host and are transmitted to humans through an intermediate host, represented by the civet for SARS and the camel for MERS [35].
T82	12902-13047	Sentence	denotes	However, some bat coronaviruses have been recently identified as being able to infect human cells without the need for an intermediate host [35].
T83	13048-13371	Sentence	denotes	The new respiratory infection originating from Wuhan (Hubei Province) in China that spread rapidly to the rest of the country, was initially traced back to Huanan Seafood Wholesale Market [13]; but only in January 2020 was a strain of coronavirus, which was unknown, identified as the responsible pathogen of the infection.
T84	13372-13480	Sentence	denotes	It was named as SARS-CoV-2 and belongs to the β-coronavirus cluster that includes SARS-CoV and MERS-CoV [2].
T85	13481-13558	Sentence	denotes	SARS-CoV-2 is the third strain of zoonotic coronaviruses currently known [1].
T86	13559-13730	Sentence	denotes	Subsequently, it was documented that SARS-CoV-2 is a chimaeric virus resulting from pre-existing viruses: a bat coronavirus and another coronavirus of unknown origin [36].
T87	13731-14038	Sentence	denotes	Its genomic sequence corresponds to the bat coronavirus with an 88% identity [37] and the pangolin coronavirus with a 99% identity [38], although the genetic analysis performed on the pangolin coronavirus did not involve the whole viral genome, but a specific site known as the receptor binding domain [37].
T88	14039-14159	Sentence	denotes	However, it emerged that SARS-CoV-2 and the pangolin coronavirus did not share the same structural characteristics [39].
T89	14160-14324	Sentence	denotes	Therefore, pangolin was identified as the intermediate species of transition from bat to humans rather than directly responsible for the SARS-CoV-2 pandemic [3,11].
T90	14326-14328	Sentence	denotes	4.
T91	14329-14344	Sentence	denotes	Pathophysiology
T92	14345-14503	Sentence	denotes	To understand the pathophysiological mechanism of SARS-CoV-2, its genomic sequence was compared to the other two similar coronaviruses, SARS-CoV and MERS-CoV.
T93	14504-14615	Sentence	denotes	In fact, it emerged that SARS-CoV-2 has a sequence identity of 79% with SARS-CoV and 50% with MERS-CoV [37,40].
T94	14616-14864	Sentence	denotes	Upon analysis of certain proteins, such as the coronavirus main proteinase (3CLpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), it was observed that the sequence identity value between SARS-CoV and SARS-CoV-2 is 96% [41].
T95	14865-14983	Sentence	denotes	Therefore, an analogy between the physiopathological mechanisms of SARS-CoV and SARS-CoV-2 has been hypothesized [42].
T96	14984-15116	Sentence	denotes	Many studies reported that SARS-CoV-2, like SARS-CoV, uses Angiotensin converting enzyme 2 (ACE-2) to enter target cells [43,44,45].
T97	15117-15424	Sentence	denotes	ACE-2 is a carboxypeptidase expressed on the cell surface which cleaves Angiotensin I (Ang I) into Angiotensin 1–9 and Angiotensin II (Ang II) into Angiotensin 1–7, counteracting the vasoconstrictor, proliferative and fibrotic effects of Angiotensin II generated by Angiotensin converting enzyme (ACE) [46].
T98	15425-15590	Sentence	denotes	Single-cell RNA sequencing analysis demonstrated a wide distribution of ACE-2 in different tissues [12,47] and histochemical staining then confirmed these data [48].
T99	15591-15856	Sentence	denotes	However, since low levels of ACE-2 expression were found on several cells types [47], it was supposed that cellular interaction and internalization by SARS-CoV-2did not depend only on ACE-2, but depended also on other auxiliary cell membrane receptors and proteins.
T100	15857-15939	Sentence	denotes	In fact, it is recognized that ssRNA viruses tend to have multiple receptors [49].
T101	15940-16117	Sentence	denotes	Qi et al. analyzed the expression of ACE-2 on 119 cell types from 13 human tissues and the coexpression characteristics of the ssRNA human viral receptors and membrane proteins.
T102	16118-16244	Sentence	denotes	Pearson correlation analysis of gene expression matrices showed 94 genes were found to be significantly correlated with ACE-2.
T103	16245-16437	Sentence	denotes	Among these, the coding genes of the peptidases alanylaminopeptidase (ANPEP), glutamyl aminopeptidase (ENPEP) and dipeptidyl peptidase 4 (DPP 4) showed the highest correlation with ACE-2 [12].
T104	16438-16731	Sentence	denotes	While both ANPEP and DPP4 are already known as a target receptors for other coronaviruses (human coronavirus 229E, swine epidemic diarrhea virus, canine coronavirus, feline coronavirus, for ANPEP and MERS-CoV for DPP4), the relationship between ENPEP and viral infection is not yet known [12].
T105	16732-16862	Sentence	denotes	ENPEP is a member of the M1 family of endopeptidases which are mammalian type II integral membrane zinc-containing endopeptidases.
T106	16863-17093	Sentence	denotes	It is mainly expressed in the terminal ileum and in the renal cortex and plays a role in the catabolic pathway of the Renin-Angiotensin system (RAAS), in the regulation of blood pressure and in the formation of blood vessels [50].
T107	17094-17228	Sentence	denotes	While the observations of Qi et al. suggest ENPEP may be a coronavirus receptor, further investigation is needed to confirm this [12].
T108	17229-17341	Sentence	denotes	However, the low expression of ACE-2 on the cell surface could also be interpreted as a viral defense mechanism.
T109	17342-17514	Sentence	denotes	In the past, the down regulation of ACE-2 had been correlated with faster cell-cell spread of human coronaviruses [51] and with more severe clinical manifestations [52,53].
T110	17515-17704	Sentence	denotes	Guzzi et al., in a recent study, hypothesized that even for COVID-19 the down regulation of ACE-2 could be a mechanism induced by SARS-CoV-2 to obtain a faster intercellular diffusion [54].
T111	17705-17938	Sentence	denotes	Studies carried out to understand the effect of angiotensin receptor blocker (ARB) drugs in patients with COVID-19, have suggested mechanisms through which the upregulation of ACE-2 may be protective during SARS-CoV-2 infection [55].
T112	17939-18009	Sentence	denotes	ARBs, in fact, greatly increase the cellular expression of ACE-2 [56].
T113	18010-18348	Sentence	denotes	However, since SARS-CoV-2-ACE-2 interaction represents the first step of a chain of events, if the upregulation of ACE-2 is not followed by the increase of certain cell proteases essential for internalization and viral activation, it would only result in the sequestration of SARS-CoV-2 on the cell membrane limiting viral infection [35].
T114	18349-18480	Sentence	denotes	Furthermore, the metalloproteinase ADAM17 can act upon the membrane-bound ACE-2, leading to the release of a soluble form of ACE-2.
T115	18481-18661	Sentence	denotes	If the increased expression of ACE-2 correlates with an increase in soluble ACE-2, this might act as a decoy receptor for SARS-CoV-2 by limiting viral entry into target cells [35].
T116	18662-18859	Sentence	denotes	Upon analysis of the SARS-CoV-2-ACE-2 interaction, there was confirmation that this occurs through the spike glycoprotein expressed on the viral envelope, being the same for all coronaviruses [35].
T117	18860-19113	Sentence	denotes	The coronavirus spike protein is composed of an intracellular segment, a transmembrane segment and a large ectodomain formed by an S1 subunit for interaction with the target receptor and an S2 subunit for fusion between the viral and cell membrane [57].
T118	19114-19230	Sentence	denotes	Subunit S1 consists of four domains, one N terminal domain (NTD) and three C-terminal domains (CTD1, CTD2 and CTD3).
T119	19231-19375	Sentence	denotes	The cell receptor and the viral protein bind through the receptor-binding domain (RBD), located in the CTD1 domain in the case of SARS-CoV [58].
T120	19376-19590	Sentence	denotes	Experiments undertaken to investigate virus-receptor interaction with resolution at the atomic level showed that SARS-CoV and SARS-CoV-2 had a high sequence similarity (89.2%) and sequence identity (73.7%) [14,22].
T121	19591-19758	Sentence	denotes	However, a more targeted evaluation of SARS-CoV-2 RBD revealed peculiar characteristics that are probably responsible for the greater diffusion compared with SARS-CoV.
T122	19759-19873	Sentence	denotes	Wan et al. found that the SARS-CoV-2 RBD has a single mutation that improves its binding affinity with ACE-2 [59].
T123	19874-20088	Sentence	denotes	Heet al. have shown that the characteristics of SARS-CoV-2 RBD make the virus more soluble, therefore capable of binding ACE-2 more easily, but also more stable, therefore able to survive at high temperatures [42].
T124	20089-20206	Sentence	denotes	At the same time, the SARS-CoV-2 RBD has greater flexibility than the SARS-CoV RBD, especially near the binding site.
T125	20207-20401	Sentence	denotes	For this reason, SARS-CoV-2 is much more sensitive to temperature than SARS-CoV in terms of the RBD-ACE-2 bond and this would cause the decrease in infectivity with increasing temperatures [42].
T126	20402-20552	Sentence	denotes	The SARS-CoV RBD-ACE-2 binding induces conformational changes in the S2 subunit, such as to induce the fusion between the viral membrane and the cell.
T127	20553-20671	Sentence	denotes	A low pH and pH-dependent endosomal cysteine proteases called cathepsins facilitate endosomal cell entry of the virus.
T128	20672-20884	Sentence	denotes	Furthermore, the S protein is cleaved into the S1 and S2 subunits by the host transmembrane cell proteases [60], which are necessary for the entry of the virus through the cell surface non-endosomal pathway [61].
T129	20885-21044	Sentence	denotes	Hoffmann et al. have shown that in particular SARS-CoV-2 S protein depends on the cellular protease Transmembrane Serine Protease 2 (TMPRSS2) for priming [62].
T130	21045-21171	Sentence	denotes	Therefore, the coexpression of ACE-2 and TMPRSS2 is a determining factor for the entry of SARS-CoV-2 into the host cells [63].
T131	21172-21317	Sentence	denotes	After entering the cell and becoming activated, SARS-CoV-2 uses the endogenous transcription mechanism of the cells to replicate and spread [60].
T132	21318-21445	Sentence	denotes	Cells infected by SARS-CoV-2 can recruit and modulate immune cells through the secretion of chemokines or other cytokines [12].
T133	21446-21492	Sentence	denotes	The role of macrophages remains to be defined.
T134	21493-21658	Sentence	denotes	In fact, the interaction between macrophages and cells expressing ACE-2 is known, suggesting a primary role of macrophages as a sentinel during viral infection [12].
T135	21659-21768	Sentence	denotes	A recent study, however, has shown a down regulation of mitochondrial proteins that interact with SARS-CoV-2.
T136	21769-21890	Sentence	denotes	This mechanism could be interpreted as a process through which the virus prevents apoptosis induced by mitochondria [54].
T137	21892-21894	Sentence	denotes	5.
T138	21895-21949	Sentence	denotes	Pathophysiology of Kidney Damage Induced by SARS-CoV-2
T139	21950-22082	Sentence	denotes	The expression of ACE-2 has been shown not only in the lung but also in the liver, stomach, ileum, colon, esophagus and kidney [47].
T140	22083-22352	Sentence	denotes	These data associated with the evidence that AKI (7%), myocardial dysfunction with acute cardiovascular events (12%) and gastrointestinal disorders are among the most frequent clinical manifestations of COVID-19 [23], suggesting that SARS-CoV-2 can infect these organs.
T141	22353-22512	Sentence	denotes	However, whether SARS-CoV-2 replication occurs in these organs causing functional damage and contributing to the systemic spread of the virus is not yet clear.
T142	22513-22693	Sentence	denotes	Zou et al. [47], stratifying the human organs in high and low risk according to the level of ACE-2 expression, have shown that the kidney is very vulnerable to SARS-CoV-2infection.
T143	22694-23042	Sentence	denotes	Qi et al. [12], through single cell RNA sequencing studies, have shown that ACE-2 in the kidney is expressed primarily by renal proximal tubular cells (~82%) and also to a lesser extent by cells of the intercalated duct, main cells of the collecting duct, renal distal tubular cells, glomerular parietal epithelium cells and immune cells (8%) [12].
T144	23043-23203	Sentence	denotes	Pan et al. [63], using single cell transcriptome analysis, confirmed the cellular co-expression of ACE-2and TMPRRS genes in proximal tubule cells and podocytes.
T145	23204-23379	Sentence	denotes	Batlle et al. have also suggested whether the expression of other cellular TMPRSSs other than TMPRSS2 (such as TMPRSS 4, 5 or 9) may also play a role in the priming step [64].
T146	23380-23644	Sentence	denotes	Studies showed that the co-expression of the ACE-2 receptor and TMPRSS genes in kidney epithelial cells was as significant as in the lung, esophagus, small intestine and colon, suggesting that the kidney might also be an important target organ for SARS-CoV-2 [63].
T147	23645-23774	Sentence	denotes	In particular, a high co-expression of ACE-2 and TMPRSS genes was found in podocytes and proximal rectangular tubular cells [63].
T148	23775-24005	Sentence	denotes	Other noteworthy observations include the presence ofSARS-CoV-2 nucleocapsid protein in renal tubular structures and virus-like particles in podocytes and renal tubular epithelial cells, as observed by electron microscopy [65,66].
T149	24006-24117	Sentence	denotes	Together these observations suggest the virus may cause AKI through a direct cytopathic effect on kidney cells.
T150	24118-24336	Sentence	denotes	In particular, it is conceivable that the virus may enter the kidney by invading the podocytes first, thereby gaining access to the tubular fluid and thence to the proximal tubule cells where it may bind to ACE-2 [64].
T151	24337-24499	Sentence	denotes	The viral replication in podocytes and the resulting damage could explain the proteinuria and hematuria reported in a high percentage of COVID-19 patients [8,27].
T152	24500-24686	Sentence	denotes	However, if the renal dysfunction is caused only by direct damage of SARS-CoV-2 or is secondary also to other systemic processes triggered by the virus, it has not been well defined yet.
T153	24687-24938	Sentence	denotes	Diao et al. [65] observed that kidney damage associated with COVID-19 is an acute tubular necrosis induced directly by SARS-CoV-2 during infection and replication, but also indirectly through the complex immune mechanisms triggered by cellular damage.
T154	24939-25315	Sentence	denotes	In fact, the histopathological examination performed on kidney specimens, obtained from autopsy of COVID-19 patients with renal function impairment, showed viral antigens in the cytoplasm of the tubular cells, but also a strong presence of CD68+ macrophages in the tubulo-interstitium and strong C5b-9 depositions on the apical brush border of tubular epithelial cells (TECs).
T155	25316-25538	Sentence	denotes	This suggested that proinflammatory cytokines derived from macrophages in the tubulo-interstitium and complement-mediated mechanisms resulting from cell damage participate in the pathogenesis of tubulo-interstitial damage.
T156	25539-25787	Sentence	denotes	In fact, despite the infiltration of infected tissue by host immune cells in order to contain viral replication, the hyperactivation of these immune cells may lead to fibrosis, epithelial cell apoptosis and cause microvasculature damage [67,68,69].
T157	25788-25999	Sentence	denotes	Studies performed on SARS-CoV suggested that AKI in SARS patients was the result of specific pathogenic conditions, such as the cytokine release syndrome [70], rather than active viral replication in the kidney.
T158	26000-26200	Sentence	denotes	In consideration of the analogy between SARS-CoV and SARS-CoV-2, flow cytometry was used to study the immune phenotype and the function of peripheral blood mononuclear cells in COVID-19 patients [71].
T159	26201-26466	Sentence	denotes	Studies showed that patients infected by SARS-CoV-2 showed lymphopenia, mainly related to the significant reduction in absolute T cell counts, particularly cytotoxic T lymphocytes (CD8+), increased neutrophil counts and elevated levels of proinflammatory cytokines.
T160	26467-26566	Sentence	denotes	In particular, high levels of interleukin (IL)-2, IL-6, IL-10 and interferon (IFN)-γ were observed.
T161	26567-26702	Sentence	denotes	Therefore, it has been speculated that a loss of T cells during the viral infection may result in enhanced inflammatory responses [72].
T162	26703-26828	Sentence	denotes	In fact, it is known that T cells are important for dampening overactive innate immune responses during viral infection [73].
T163	26829-27035	Sentence	denotes	In accordance with this hypothesis, it has been observed that when the T cell count drops the serum levels of IL-2, IL-4, IL-10, tumour necrosis factor (TNF)-α and interferon (IFN)-γ reach their peaks [72].
T164	27036-27202	Sentence	denotes	Another important finding is that COVID-19 patients with more severe clinical manifestations have higher serum concentrations of IL-6 and lower IFN-γ than mild forms.
T165	27203-27276	Sentence	denotes	This is mainly due to the decrease in CD4+, CD8+ and NK lymphocytes [74].
T166	27277-27406	Sentence	denotes	Interferons (IFN) are a family of cytokines that play a central role in innate immunity to viruses and other microbial pathogens.
T167	27407-27579	Sentence	denotes	The IFN-receptor binding induces a cascade of signals with activation of genes coding for proteins with antiviral, antiproliferative or immunomodulatory properties [70,75].
T168	27580-27866	Sentence	denotes	Normally the interaction between the IFN-γ and IL-6/sIL-6R signals contributes to the recruitment and subsequent clearance of neutrophils, thereby controlling infection and resolution of acute inflammation as well as influencing the transition between innate and adaptive immunity [76].
T169	27867-27979	Sentence	denotes	In patients infected by SARS-CoV-2, a higher IL-6/IFN-γ ratio may be related to an enhanced cytokine storm [74].
T170	27980-28133	Sentence	denotes	These observations suggest that in both SARS patients, and in patients with COVID-19, AKI may have an inflammatory etiology mediated by a cytokine storm.
T171	28134-28269	Sentence	denotes	The cytokine storm is associated with an inflammatory process that originates in a local site and spreads via the systemic circulation.
T172	28270-28451	Sentence	denotes	The inflammatory process can cause dysfunction in organs, particularly when tissue edema causes an increase in extravascular pressures and a consequent decrease in tissue perfusion.
T173	28452-28611	Sentence	denotes	Compensatory repair processes arise soon after the beginning of inflammation, and in a lot of cases they can completely re-establish tissue and organ function.
T174	28612-28770	Sentence	denotes	However, when a severe inflammation condition injures local tissue structures, healing occurs with fibrosis, which can cause permanent organ dysfunction [70].
T175	28771-28933	Sentence	denotes	In fact, when a cytokine storm occurs, the immune system may not be able to kill SARS-CoV-2, but it can kill large numbers of normal cells and damage organs [63].
T176	28934-29156	Sentence	denotes	In support of the hypothesis that AKI in COVID-19 patients may be the consequence of inflammatory damage, a cohort study found that the CT scan of kidneys showed a reduced density, indicative of inflammation and edema [8].
T177	29157-29292	Sentence	denotes	In addition to being frequently associated with the cytokine storm, severe lung infections often require prolonged ventilatory support.
T178	29293-29428	Sentence	denotes	This predisposes to the development of sepsis, classically defined by marked hypotension which requires treatment with inotropic drugs.
T179	29429-29698	Sentence	denotes	Therefore, in patients with COVID-19 or acute respiratory distress syndrome (ARDS), it is plausible that persistent hypotension and vasoconstriction induced by inotropics can participate in the fall of the glomerular filtrate and consequent acute tubular necrosis [77].
T180	29699-29812	Sentence	denotes	In the most recent studies, the hypothesis of a multifactorial etiology of renal damage in COVID-19 is confirmed.
T181	29813-29983	Sentence	denotes	Su et al. [66] in a study performed by analyzing autopsy kidney samples showed pigmented casts with high levels of creatine phosphokinase, attributable to rhabdomyolysis.
T182	29984-30085	Sentence	denotes	In rhabdomyolysis the massive release of myoglobin due to muscle damage can cause kidney dysfunction.
T183	30086-30348	Sentence	denotes	Myoglobin, in fact, shows its renal toxicity through various mechanisms: renal vasoconstriction related to the hyperactivation of RASS by hypoperfusion and the reduction of nitric oxide levels; intratubular cast formation; direct toxicity on renal tubular cells.
T184	30349-30403	Sentence	denotes	These processes result in acute tubular necrosis [78].
T185	30404-30473	Sentence	denotes	Rhabdomyolysis in COVID-19 patients is hypothetically multifactorial.
T186	30474-30636	Sentence	denotes	In fact, it may be secondary to a direct cytotoxic effect of SARS-CoV-2 on the muscle, tissue hypoxia due to hyperventilation or also to drug-induced damage [66].
T187	30637-30744	Sentence	denotes	Presumably, in COVID-19 patients who develop rhabdomyolysis, it may participate in the pathogenesis of AKI.
T188	30745-30948	Sentence	denotes	Su et al. [66] demonstrated the presence of erythrocyte aggregates, without platelets or fibrinoid fragments, which obstructs the lumen of the peritubular and glomerular capillaries in COVID-19 patients.
T189	30949-31193	Sentence	denotes	Erythrocyte aggregation, presumably induced by inflammation (reflected by a high rate of erythrocyte sedimentation) and hypotension, can potentiate oxidative stress, inflammation and complement activation, aggravating microvascular damage [64].
T190	31194-31320	Sentence	denotes	Furthermore, occlusion of microvascular lumens by erythrocytes has been associated with a variety of endothelial lesions [66].
T191	31321-31419	Sentence	denotes	Normally, in endothelial cells of the kidney, only ACE is expressed without detectable ACE-2 [79].
T192	31420-31495	Sentence	denotes	Therefore, the renal endothelium cannot be infected directly by SARS-CoV-2.
T193	31496-31614	Sentence	denotes	However, this cannot be totally excluded, since ACE-2expressioncan be changed in pathological states or by drugs [66].
T194	31615-31810	Sentence	denotes	Varga et al. recently concluded that SARS-CoV-2 infection induces endothelitis in various organs, directly and indirectly, and that could explain the systemic impairment of microcirculation [80].
T195	31811-31903	Sentence	denotes	Further studies are necessary to better understand the genesis of renal endothelial lesions.
T196	31904-32151	Sentence	denotes	Of note, a recent study has proposed a new route for SARS-CoV-2 invasion of host cells via an alternative cell receptor known as CD147 (and also called basigin), which is a transmembrane glycoprotein and is expressed on all endothelial cells [81].
T197	32152-32304	Sentence	denotes	Recently, the high incidence of thromboembolic events in COVID-19 patients suggests that SARS-CoV-2 may play an important role in inducing coagulopathy.
T198	32305-32401	Sentence	denotes	Analyzing the hematological profile of COVID-19 patients, a state of hypercoagulability emerged.
T199	32402-32558	Sentence	denotes	In fact, high plasma levels of reactive protein C, fibrinogen, D-dimer and ferritin, associated with thrombocytopenia, were found in these patients [71,82].
T200	32559-32771	Sentence	denotes	Recently, clinical and autopsy reports from China and the U.S. confirm the development of disseminated intravascular coagulation following SARS-CoV-2 infection, with evidence of microangiopathy in several organs.
T201	32772-33030	Sentence	denotes	In fact, the activation of macrophages associated with COVID-19, the storm of cytokines and the molecular proteins associated with the damage can cause both tissue factors’ release and the activation of coagulation factors predisposing to hypercoagulability.
T202	33031-33215	Sentence	denotes	In some cases, this state of hypercoagulability could favor the evolution of acute tubular necrosis into cortical necrosis and, therefore, the development of irreversible renal damage.
T203	33216-33372	Sentence	denotes	These observations suggest that low back pain and microhematuria observed in some positive COVID-19 patients may be manifestations of renal infarction [64].
T204	33373-33505	Sentence	denotes	The SARS-CoV-2 contribution to the development of CKD could involve pathways similar to those described for the acute kidney injury.
T205	33506-33641	Sentence	denotes	Indeed, it has been observed that a non-trivial portion of patients develop signs of tubular or glomerular damage during the infection.
T206	33642-33820	Sentence	denotes	The direct tubule-glomerular cellular injury, due to the virus, often manifests with proteinuria and hematuria that, in turn, could start a chronic, non-reversible, process [83].
T207	33821-33954	Sentence	denotes	It has been shown that proteinuria exerts a direct toxic effect on renal tubular cells and promotes renal fibrosis over time [84,85].
T208	33955-34166	Sentence	denotes	In conclusion, the renal damage observed in COVID-19 patients is the result of complex mechanisms induced directly and indirectly by SARS-CoV-2 that predispose to the development of renal dysfunction (Figure 1).
T209	34167-34399	Sentence	denotes	Further studies are needed to better understand the pathophysiological mechanisms of kidney injury, to develop new therapeutic strategies able to limit and/or prevent kidney damage, and to improve the prognosis of COVID-19 patients.
T210	34401-34403	Sentence	denotes	6.
T211	34404-34418	Sentence	denotes	Histopathology
T212	34419-34684	Sentence	denotes	As mentioned before, the virus gains access to the kidney via the ACE-2receptor for which it uses to enter entrance to target cells [62,86,87] and it has been shown that the ACE-2 receptor of SARS-CoV-2 is highly expressed in renal proximal tubule cells [63,88,89].
T213	34685-34789	Sentence	denotes	Possible mechanisms for kidney injury in COVID-19 include direct infection of the renal parenchyma [47].
T214	34790-35007	Sentence	denotes	Diao et al. [65] retrospectively analyzed the clinical data on renal function from 85 cases of COVID-19; a similar analysis on kidney abnormalities in 26 autopsies of COVID-19 patients was conducted by Su et al. [66].
T215	35008-35148	Sentence	denotes	Using light microscopy, ultrastructural observation and immunostaining have been very informative to understand the extent of kidney injury.
T216	35149-35384	Sentence	denotes	Light microscopy examination using Hematoxylin and Eosin staining may show the extent of tubular atrophy and interstitial disease, these are strong histological markers of renal damage and may also predict progression of renal failure.
T217	35385-35692	Sentence	denotes	Using light microscopy, proximal tubule injurywas observed with the loss of brush border and vacuolar degeneration with necrosis and detachment of the epithelium observed in the lumen of the tubules; dilatation of the tubular lumen was also noted together with cellular debris resulting from necrosed cells.
T218	35693-36023	Sentence	denotes	Erythrocyte aggregates were also observed, causing obstruction of peritubular and glomerular capillary loops, with no obvious erythrocyte or platelet fragmentation or any fibrin thrombi, and less erythrocyte aggregation was observed in peritubular capillaries in those cases with predominantly glomerular loop obstruction [65,66].
T219	36024-36264	Sentence	denotes	Hemosiderin granules were identified in the renal tubular epithelium of a few patients, while pigmented casts were found in a small number of patients who had high levels of creatine phosphokinase, indicating the presence of rhabdomyolysis.
T220	36265-36452	Sentence	denotes	Su et al. noted some cellular swelling of the renal distal tubules and collecting ducts, with some edematous expansion of the interstitial space, but without any significant inflammation.
T221	36453-36558	Sentence	denotes	They also noted infiltration of lymphocytesin areas of nonspecific fibrosis, including subcapsular areas.
T222	36559-37049	Sentence	denotes	Glomeruli were intact, with various degrees of morphologic changes: nodular mesangial expansion and arteriolar hyalinosis; endothelial cell swelling and degeneration was observed in a small number of COVID-19 patients but these were older individuals with a history of diabetes and hypertension; in other cases podocyte vacuolation and detachment from the glomerular basement membrane was seen; in 2 patients with proteinuria and diabetes, focal segmental glomerulosclerosis was also noted.
T223	37050-37360	Sentence	denotes	Immunohis to chemical studies utilizing an anti-SARS-CoV nucleoprotein antibody against the viral nucleocapsid protein (NP) and indirect fluorescence microscopy, showed the NP antigen was present in the renal tubular cells of the infected tissues, suggesting that SARS-CoV-2 can directly infect kidney tubules.
T224	37361-37653	Sentence	denotes	Moreover, Diao et al. observed that the presence ofSARS-CoV-2 virus resulted in the infiltration of high levels of CD68+ macrophages into the tubulo-interstitium, and it is feasible that these macrophages could release proinflammatory cytokines which in turn would cause renal tubular damage.
T225	37654-37817	Sentence	denotes	In contrast, CD8+ T cells were observed only in moderate numbers in the examined tissues, while CD4+ T cells and CD56+ natural killer (NK) cells were seldom found.
T226	37818-38065	Sentence	denotes	Diao et al. also observed the deposition of the C5b-9 complement complex (also known as the membrane attack complex pathway) on the apical brush border of renal tubular epithelial cells, whereas C5b-9 expression was absent in normal kidney tissue.
T227	38066-38215	Sentence	denotes	The complex may cause cell death and therefore renal injury and may be an important factor in the pathogenesis of tubulo-interstitial damage [90,91].
T228	38216-38377	Sentence	denotes	All these findings suggest that SARS-CoV-2 infection causes acute tubular necrosis not only through direct cytotoxicity, but also via immune mediated mechanisms.
T229	38378-38679	Sentence	denotes	Observations using transmission electron microscopy (EM) of kidney tissue from autopsies of COVID-19 cases has shown the presence of coronavirus-like particles in the cytoplasm of proximal and distal tubular cells; as well as in podocytes, podocyte foot processes and the glomerular basement membrane.
T230	38680-38921	Sentence	denotes	In two autopsy specimens observed by Diao et al., it was noted that the cells in infected kidney tissue were swollen, with enlargement of mitochondria and lysosomes, and viral particles were observed in the broken lysosomes in the cytoplasm.
T231	38922-39069	Sentence	denotes	These findings demonstrate SARS-CoV-2 can directly infect kidneys and why patients with COVID-19 often present with proteinuria, hematuria and AKI.
T232	39070-39243	Sentence	denotes	As has already been mentioned with the light microscopy observations, EM also showed erythrocytic obstruction of peritubular capillary lumens with injury of the endothelium.
T233	39244-39363	Sentence	denotes	Aggregation of erythrocytes in segmental glomerular capillary loops was frequent, but without inflammation or necrosis.
T234	39364-39684	Sentence	denotes	Intriguingly, according to a recent study [14] about endothelial cell infection and endothelitis in COVID-19, endothelial dysfunction is probably one of the main causes of microvascular dysfunction by causing vasoconstriction leading to organ ischemia, inflammation with associated tissue edema and a procoagulant state.
T235	39685-39777	Sentence	denotes	The principal findings of light microscopy, immunofluorescence and EM are shown in Figure 2.
T236	39779-39781	Sentence	denotes	7.
T237	39782-39799	Sentence	denotes	Clinical Features
T238	39800-39901	Sentence	denotes	Most COVID-19 infections are not severe, with the spectrum of symptoms ranging from mild to critical.
T239	39902-40050	Sentence	denotes	Based on all confirmed, suspected and asymptomatic cases of COVID-19 in the world on 23 July, the ISS—i.e., Italian Health Institute, reported that:
T240	40051-40482	Sentence	denotes	80% of infections are mild(asymptomatic 29% or with flu-like symptoms paucisymptomatic 12%, mild 35%), and those with these symptoms being able to recover at home; 10% are severe, developing severe diseases including pneumonia and dispnea; and 2% are critical and include: respiratory failure, septic shock and multi-organ failure requiring intensive care assistance; in about 2% of overall reported cases, the virus is fatal [92].
T241	40483-40794	Sentence	denotes	Comorbidities which have been associated with illness severity and mortality include the following ones: diabetes mellitus, cardiovascular disease, hypertension, chronic lung disease, cancer, chronic kidney disease, immunocompromising conditions, severe obesity (body mass index ≥ 40) and liver disease [90,91].
T242	40795-40898	Sentence	denotes	COVID-19 infection is frequently severe among patients of advanced age and other medical comorbidities.
T243	40899-41070	Sentence	denotes	Males, compared with females, suffer a disproportionately higher number of deaths according to data from cohorts of patients in China, Italy and the United States [15,92].
T244	41071-41355	Sentence	denotes	The most frequent serious clinical manifestation of infection appears to be pneumonia, which is primarily characterized by fever (which can even be absent), dry cough, fatigue, anorexia, myalgias, dyspnea, sputum production, and the presence of bilateral infiltrates on chest imaging.
T245	41356-41465	Sentence	denotes	Other reported symptoms can include the following: headache, sore throat, rhinorrhea and conjunctivitis [93].
T246	41466-41704	Sentence	denotes	However, no specific clinical features that can reliably distinguish COVID-19 from other viral respiratory infections have been reported, although development of dyspnea several days after the onset of initial symptoms is suggestive [25].
T247	41705-41828	Sentence	denotes	However, common symptoms in patients infected by COVID-19 are smell and taste disorders (e.g., anosmia and dysgeusia) [93].
T248	41829-41939	Sentence	denotes	Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain and diarrhea) have also been described [94].
T249	41940-42094	Sentence	denotes	There have been rare dermatological reports of erythematous rash, widespread urticaria and chickenpox-like vesicles and transient livedo reticularis [11].
T250	42095-42284	Sentence	denotes	Reddish-purple nodules on the distal digits similar in appearance to pernio (chilblains) have also been anecdotally described in children and young adults with suspected COVID-19 infection.
T251	42285-42424	Sentence	denotes	As mentioned previously, epidemiological data from many countries report that children make up a small minority of those who test positive.
T252	42425-42610	Sentence	denotes	Children account for 1–5% of patients and are less likely to become severely ill compared with adults, though preschool children and infants might have severe clinical features [95,96].
T253	42611-42927	Sentence	denotes	The small rate of COVID-19 infection for children has also been confirmed by another study which showed that children younger than 18 years made up less than 2% of national cases in different countries [97], so that, also in this case, that proportion reflects lower susceptibility among children versus adults [98].
T254	42928-43068	Sentence	denotes	The emergence of a severe Kawasaki-like disease in children related to COVID-19 has now shifted focus on the vulnerability of children [99].
T255	43069-43185	Sentence	denotes	It is a rare acute pediatric vasculitis, with the development of coronary artery aneurysms as its main complication.
T256	43186-43351	Sentence	denotes	Diagnosis of this disease is based on the presence of persistent fever, lymphadenopathy, conjunctival injection exanthema and changes to the mucosae and extremities.
T257	43352-43602	Sentence	denotes	Pediatricians in the United Kingdom identified a small group of children presenting with shock and a multisystem inflammation, some of whom had coronary artery aneurysms, and a further group of less severely ill children with a Kawasaki-like disease.
T258	43603-43915	Sentence	denotes	Based on the review of clinical and laboratory features, a case definition of the syndrome named “pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)” was formulated by experts in the United Kingdom and published by the Royal College of Paediatrics and Child Health [100].
T259	43916-44159	Sentence	denotes	Some COVID-19 patients who at first do not show anysevere symptoms may nonetheless do so over the course of a week, with acute respiratory distress syndrome (ARDS) manifesting shortly after the onset of dyspnea in patients with severe disease.
T260	44160-44247	Sentence	denotes	Other reported complications are acute cardiac injury, arrhythmias, AKI and shock [25].
T261	44248-44355	Sentence	denotes	Thromboembolic complications, including pulmonary embolism and acute stroke, have also been reported [101].
T262	44357-44361	Sentence	denotes	7.1.
T263	44362-44425	Sentence	denotes	Clinical Features in Patients with Chronic Kidney Disease (CKD)
T264	44426-44540	Sentence	denotes	Chronic kidney disease (CKD) seems to be associated with enhanced risk of severe COVID-19 infection and mortality.
T265	44541-44663	Sentence	denotes	Cheng et al. evaluated the association between markers of renal impairment and death in a cohort of 701 COVID-19 patients.
T266	44664-44862	Sentence	denotes	They found that 43.9% of patients admitted had proteinuria and 26.7% had hematuria, serum creatinine and blood urea nitrogen (BUN) levels were increased in 14.4% and 13.1% of patients, respectively.
T267	44863-44958	Sentence	denotes	Estimated glomerular filtration rate < 60 mL/min per 1.73 m2was found in 13.1% of patients [8].
T268	44959-45241	Sentence	denotes	In particular, the authors have shown that, at univariate analysis the presence of proteinuria was associated with a 4 up to 11-fold increased risk of in-hospital death compared with COVID-19 patients without kidney damage, whereas hematuria increased the risk of death by 12 times.
T269	45242-45321	Sentence	denotes	These hazard ratios (HR)were higher than risk factors such as advanced age (HR:
T270	45322-45348	Sentence	denotes	2.43), severe disease (HR:
T271	45349-45665	Sentence	denotes	6.10) and remained significantly associated with mortality even after adjustment (therefore to multivariate analysis) by age, gender, disease severity, lymphocyte count, comorbidity, thus demonstrating that measures of kidney damage play a very important role in assessing prognosis of COVID-19 patients [8,102,103].
T272	45666-45786	Sentence	denotes	This significant association of CKD with severe COVID-19 infection was observed also in the meta-analysis by Lippi [21].
T273	45787-45925	Sentence	denotes	This can be explained by the pro-inflammatory state and by the alterations of the innate and adaptive immune response associated with CKD.
T274	45926-45995	Sentence	denotes	This immune profile increases susceptibility to all infections [104].
T275	45996-46287	Sentence	denotes	These findings suggest that COVID-19 patients with high baseline serum levels of creatinine are more likely to be led to intensive care unit treatment and to undergo mechanical ventilation, because the presence of a renal disease on admission constitutes a higher risk of negative prognosis.
T276	46288-46450	Sentence	denotes	It has been recently shown that a large part of COVID-19 patients suffer from other comorbidities and most of these patients are also elderly and males [102,103].
T277	46451-46565	Sentence	denotes	Among these comorbidities, the presence of chronic kidney disease is an independent risk factor of poor prognosis.
T278	46566-46842	Sentence	denotes	It is also true, on the contrary, that nephropathic patients are mainly affected by hypertension and cardiovascular disease per se and this can lead to a higher risk of COVID-19 infection when compared with the general population or with patients without kidney disease [105].
T279	46843-47023	Sentence	denotes	Nephropathic patients are also patients with cardiovascular disease which is currently considered a biomarker of increased risk for COVID 19 infection and for poor prognosis [105].
T280	47024-47239	Sentence	denotes	However, an increased risk of death, about 3–8 times, was found in patients infected with other viruses such as H1N1 flu virus and who developed kidney injury during infection as compared to those who had not [106].
T281	47240-47488	Sentence	denotes	Moreover, patients who enter the hospital with elevated serum creatinine levels were predominantly male and older (median age was 73 years) and were more severely ill compared with patients who had normal serum creatinine (median age was 61 years).
T282	47489-47700	Sentence	denotes	In addition, patients with increased baseline serum creatinine levels show an alteration of leukocyte count with an increase in the absolute number of leukocytes and a decrease in lymphocyte and platelet counts.
T283	47701-47899	Sentence	denotes	Coagulation pathway abnormalities, which include prolonged activated partial thromboplastin time and higher D-dimer, are more frequent in patients with increased baseline serum levels of creatinine.
T284	47900-48095	Sentence	denotes	The rate of patients with increased procalcitonin, and the plasma levels of aspartate aminotransferase and LDH are also higher in patients with CKD compared with those with normal renal function.
T285	48096-48260	Sentence	denotes	The incidence of in-hospital death in patients with CKD was found to be significantly higher than in those patients with normal baseline serum levels of creatinine.
T286	48262-48266	Sentence	denotes	7.2.
T287	48267-48327	Sentence	denotes	Clinical Features in Patients with Acute Kidney Injury (AKI)
T288	48328-48521	Sentence	denotes	It is not the first time that a virus mainly involving the respiratory tract can also involve the kidney, as it has been already reported during the course of the SARS epidemic in 2003 [8,107].
T289	48522-48611	Sentence	denotes	AKI represents a life-threatening complication, often leading to increased risk of death.
T290	48612-48780	Sentence	denotes	One possible explanation of the high prevalence of kidney involvement at hospital admission is that some of the COVID-19 patients may already have had a history of CKD.
T291	48781-48963	Sentence	denotes	Such patients tend to have a pro-inflammatory state with functional defects in their immune system [108] and are at a higher risk for upper respiratory tract infection and pneumonia.
T292	48964-49111	Sentence	denotes	Cheng et al. [8], as mentioned before, in their study of a cohort of 701 patients found that 5.1% of patients developed AKI during hospitalization.
T293	49112-49258	Sentence	denotes	Patients with increased baseline serum creatinine levels were more likely to develop AKI (11.9%) than patients with normal baseline values (4.0%).
T294	49259-49539	Sentence	denotes	This means that, while renal complications are more likely in patients with pre-existing chronic impairment of kidney function, moderate-to-severe AKI can also be found in patients with normal serum creatinine levels these may represent a higher-risk subset of patients with ARDS.
T295	49540-49769	Sentence	denotes	Wilson et al. [109] noted that similar observations have been reported for COVID-19-associated ARDS, which could develop into AKI on average 9 days after admission together with secondary infections and acute cardiac damage [26].
T296	49770-49887	Sentence	denotes	In ARDS, patients age, severity of illness and the presence of diabetes are all risk factors for acute kidney injury.
T297	49888-50015	Sentence	denotes	Furthermore, the patient’s BMI value and any previous history of heart failure may also be associated with the severity of AKI.
T298	50016-50096	Sentence	denotes	All these risk factors may count for the higher incidence of AKI in the elderly.
T299	50097-50381	Sentence	denotes	Hirsch et al. recently analyzed risk factors, clinical presentation and outcomes of AKI among hospitalized COVID-19 patients in the metropolitan New York area, encompassing twenty three hospitals within urban and suburban areas and including academic tertiary and community hospitals.
T300	50382-50500	Sentence	denotes	They found that among those with AKI, 694 died (35%), 519 (26%) were discharged and 780 (39%) were still hospitalized.
T301	50501-50730	Sentence	denotes	In addition to the known risk factors for AKI mentioned before, namely older age, cardiovascular disease, hypertension, diabetes mellitus and need for ventilation and of vasopressor drugs, black race was also included among them.
T302	50731-50920	Sentence	denotes	Indeed, individuals from minority communities, in particular African Americans and Hispanics have been disproportionately affected by and have had worse outcomes after SARS-CoV-2 infection.
T303	50921-51097	Sentence	denotes	Finally, they did not find that use of blockers of the Renin-Angiotensin and aldosterone system at hospital admission for COVID-19 disease was associated with greater AKI risk.
T304	51098-51334	Sentence	denotes	As expected, in their study involving different ethnicities in U.S.A., they confirmed that early AKI occurs frequently among COVID-19 patients and in temporal association with respiratory failure, with a consequent poor prognosis [110].
T305	51335-51502	Sentence	denotes	The standard assessment of AKI is still based on serum creatinine levels and daily urine output, but these represent only indicators of established renal damage [111].
T306	51503-51673	Sentence	denotes	Recently, Richardson et al. enrolled in the New York City Area (U.S.A.), the largest number of cases of sequentially hospitalized patients with confirmed COVID-19 in USA.
T307	51674-51812	Sentence	denotes	Males and those with pre-existing hypertension and/or diabetes were highly prevalent among 5700 case series with a median age of 63 years.
T308	51813-51909	Sentence	denotes	In this study, AKI was observed among 8.4% discharged live patients and among 63% dead patients.
T309	51910-52029	Sentence	denotes	On hospital admission, a significant percentage of patients had renal impairment, presenting proteinuria and hematuria.
T310	52030-52095	Sentence	denotes	AKI incidence in the overall cohort was in the range of 4.7–7.5%.
T311	52096-52218	Sentence	denotes	A higher incidence of proteinuria and hematuria was reported in patients with severe or critically ill COVID-19 pneumonia.
T312	52219-52372	Sentence	denotes	Among all patients with renal impairment, the patients with AKI had a higher incidence rate of proteinuria and hematuria compared with the non-AKI group.
T313	52373-52509	Sentence	denotes	Almost 50% of the critically ill cases developed AKI during hospitalization, especially those who were in the intensive care unit (ICU).
T314	52510-52652	Sentence	denotes	Patients were followed up for a median duration of 12 days, during which time most of the COVID-19 patients showed remission of the pneumonia.
T315	52653-52773	Sentence	denotes	Urine dipstick testing in most of the patients with proteinuria and hematuria were reported as negative after follow-up.
T316	52774-52827	Sentence	denotes	The mean time for AKI recovery was seen to be 6 days.
T317	52828-52913	Sentence	denotes	The percentage of patients who developed AKI was increased in patients with diabetes.
T318	52914-53118	Sentence	denotes	In conclusion, despite the high morbidity of kidney impairment, the short-term renal prognosis of those patients is still good: in fact 50% achieved remission in 3 weeks after the onset of their symptoms.
T319	53119-53274	Sentence	denotes	However, adverse short-term outcomes of patients with kidney impairment are also associated with high rate of mortality in COVID-19 infected patients [15].
T320	53275-53457	Sentence	denotes	The pattern described by Richardson regarding AKI was similar to data reported from China: a study [112] of 138 patients with COVID-19 reported that ~4% of COVID-19 patients had AKI.
T321	53458-53611	Sentence	denotes	Huang et al. [23] reported that among 41 patients with COVID-19 infection, 10% had elevated serum creatinine levels on admission and 7% had suffered AKI.
T322	53612-53732	Sentence	denotes	In addition, both blood urea and serum creatinine levels progressively increased along the course of COVID-19 infection.
T323	53733-53926	Sentence	denotes	In comparison with patients with normal serum creatinine levels, those who entered the hospital with high serum creatinine levels were predominantly male and old and were more severely ill too.
T324	53927-54165	Sentence	denotes	Another study [27] involving 193 patients with COVID-19 infection has reported that, at hospital admission, 59% of the patients had proteinuria, 44% hematuria, 14% increase in BUN plasma levels and 10% increase in serum creatinine values.
T325	54166-54279	Sentence	denotes	The abdomen CT showed kidneys with reduced density, suggestive of inflammation and edema of the renal parenchyma.
T326	54280-54414	Sentence	denotes	Li et al. also observed that as many as 28% of COVID-19 patients developed AKI (9% of non-severe patients and 66% of severe patients).
T327	54415-54629	Sentence	denotes	During hospitalization with a median of 2 days, there was an increase in BUN plasma levels in 30% of patients and, with a median of about 5 days, there was an increase in serum creatinine levels in 22% of patients.
T328	54630-54739	Sentence	denotes	As already mentioned, COVID-19 patients with AKI have a higher mortality risk than those without AKI [27,28].
T329	54740-55043	Sentence	denotes	In contrast, patients with chronic illnesses (cardiovascular and cerebrovascular diseases, nervous system diseases, respiratory system diseases, digestive system diseases, urinary system diseases, reproductive system diseases and endocrine system diseases) had only on average ~1.5 times mortality risk.
T330	55044-55134	Sentence	denotes	Furthermore, one study reported a 100% mortality rate for patients with stage 3 AKI [113].
T331	55135-55264	Sentence	denotes	Therefore, the presence of a renal impairment in COVID-19 patients is an important negative prognostic factor for their survival.
T332	55265-55650	Sentence	denotes	However, dissimilar conclusions have been reported by Pei et al. who in a retrospective study, finding renal abnormalities in most of the patients with COVID-19 pneumonia, showed that renal complications in COVID-19 patients were associated with higher mortality, although proteinuria, hematuria and AKI often resolved in such patients within 3 weeks after the onset of symptoms [114].
T333	55651-55786	Sentence	denotes	If conservative treatments fail, RRT should be considered in patients with volume overload, especially those with refractory hypoxemia.
T334	55787-56002	Sentence	denotes	In patients with COVID-19 and AKI, early initiation of RRT and sequential extracorporeal organ support (ECOS) seem to provide adequate organ support and seem to prevent the worsening of the disease’s severity [115].
T335	56003-56432	Sentence	denotes	A high degree of AKI has been reported to require extracorporeal therapies, such as (RRT) in critically ill patients, preferentially utilizing CRRT (continuous renal replacement therapies) for patients in the ICU [115]; recently Nalesso et al. have reported to have designed a continuous veno-venous hemodialysis (CVVHD) with a high cut-off membrane (HCO) in regional citrate anticoagulation (RCA) named by them as RCA-HCO-CVVHD.
T336	56433-56827	Sentence	denotes	This treatment gives several advantages, when comparing it with an equivalent dose in continuous veno-venous hemofiltration, which include a lower effluent volume, fewer bag interventions (hence reducing nurses’ time for this), lower filtration fractions with a higher filter and circuit lifespan and fewer complications with blood flow as a result of central venous catheter malfunction [116].
T337	56828-57078	Sentence	denotes	Grasselli et al., in a study conducted in Italy and involving 1591 ICU patients with COVID-19, have reported that 27% of them required prone ventilation and that Extra Corporeal Membrane Oxygenation (ECMO) was performed in 1% of these patients [117].
T338	57080-57084	Sentence	denotes	7.3.
T339	57085-57135	Sentence	denotes	Clinical Features in Patients in Hemodialysis (HD)
T340	57136-57480	Sentence	denotes	The ERA-EDTA has created a European database that collects individual data of dialysis patients with COVID-19; in the last update dating back to 23rd July, 5596 cases of COVID-19 and 1331 deaths were reported among hemodialysis patients [118].Patients undergoing dialysis have impaired immune systems and have a high risk of infectious disease.
T341	57481-57756	Sentence	denotes	Kwan et al. [119] reported that dialysis patients had a higher rate of contracting SARS compared with an individual from the general population, but both the degree of disease severity and the mortality rate of the dialysis group were similar to the one of the control group.
T342	57757-57922	Sentence	denotes	Based on SARS-CoV-2′s sequence similarity with SARS, it is possible that COVID-19 could follow the same trend as the one of SARS in patients undergoing hemodialysis.
T343	57923-58136	Sentence	denotes	To understand the clinical features of COVID-19 infection, it is of interest to consider the first multicenter study focused on 7154 patients undergoing long term hemodialysis in 65 centers in Wuhan (China) [120].
T344	58137-58323	Sentence	denotes	Among all patients in HD, 154 had laboratory-confirmed COVID-19 tests with an incidence of COVID-19 infection in 2% of patients, which is much higher than that of the general population.
T345	58324-58587	Sentence	denotes	This may be explained with the advanced age of the dialysis population, to the altered immune systems because of their uremic condition and the significant comorbidities that accompany this group, like cardiovascular disease, diabetes and cerebrovascular disease.
T346	58588-58696	Sentence	denotes	Among 154 patients with COVID-19, 77% were mild/moderate patients, whilst 23% were severe/critical patients.
T347	58697-58841	Sentence	denotes	The primary causes of end stage kidney disease (ESKD) in patients with severe/critical disease were similar to those with mild/moderate disease.
T348	58842-59007	Sentence	denotes	The presence of cardiovascular disease was more likely to be present in patients with severe/critical infectious disease than among those with mild/moderate disease.
T349	59008-59238	Sentence	denotes	Moreover, there were no significant differences between severe/critical and mild/moderate COVID- 19 infection regarding age, gender, smoking status and complications like diabetes, chronic obstructive pulmonary disease and cancer.
T350	59239-59358	Sentence	denotes	The dialysis model, access, frequency of dialysis had no significant effect on the degree of COVID-19 disease severity.
T351	59359-59525	Sentence	denotes	The most common symptoms, especially in the severe/critical group, were: fever, cough, fatigue, sputum production, dyspnea, nausea/vomiting, diarrhea and sore throat.
T352	59526-59892	Sentence	denotes	An interesting case report of one of the first patients with COVID-19 in ESKD suffering from gastrointestinal (GI) problems highlights the importance of considering other clinical presentations of COVID-19 infection and not just focusing on the typical respiratory symptoms, in order to prevent exposure of potentially affected individuals to the general population.
T353	59893-60001	Sentence	denotes	GI symptoms are somewhat unusual and seem to be a delayed clinical presentation of COVID-19 infection [121].
T354	60002-60087	Sentence	denotes	However, some of those symptoms may be difficult to distinguish from uremic symptoms.
T355	60088-60148	Sentence	denotes	Diabetic patients showed more likely symptoms when infected.
T356	60149-60361	Sentence	denotes	The disease symptoms of hemodialysis patients were similar to those of the general population, but only 50% of them had fever and nearly 25% were asymptomatic over the whole clinical course of COVID-19 infection.
T357	60362-60488	Sentence	denotes	Since hemodialysis patients have disorders of B- and T-cell function [122], patients may show atypical clinical presentations.
T358	60489-60577	Sentence	denotes	The most common finding on chest computed tomography was ground-grass or patchy opacity.
T359	60578-60680	Sentence	denotes	These lesions often involved both the lungs; on the other hand, consolidation in lungs was not common.
T360	60681-60883	Sentence	denotes	These radiological findings were similar to those shown in the general population, but sometimes it was difficult to distinguish them from lung changes due to their uremia status or inadequate dialysis.
T361	60884-61151	Sentence	denotes	Data from laboratory tests showed that lymphocytopenia was common in patients described in other reports [26,120], and there was a trend for the decline of lymphocytesin the severe/critical group, which is consistent with the results of other recent clinical reports.
T362	61152-61327	Sentence	denotes	The uremic state of these patients is associated with a wide range of impairments in lymphocyte and granulocyte functions; lymphocytopenia is also common in dialysis patients.
T363	61328-61491	Sentence	denotes	Considering low lymphocyte counts in chronic hemodialysis patients [108], lymphopenia is unlikely to be helpful for identifying individuals infected by SARS-CoV-2.
T364	61492-61654	Sentence	denotes	Procalcitonin levels have similar limitations: in fact, its levels are chronically elevated in hemodialysis patients, even in the absence of severe acute illness.
T365	61655-61734	Sentence	denotes	In addition, the majority of patientshad normal white cell and platelet counts.
T366	61735-61819	Sentence	denotes	Serum albumin levels were also within the normal range for most of the patients too.
T367	61820-62058	Sentence	denotes	Conversely, considering these limitations and the high prevalence of comorbid conditions, COVID-19 pneumonia diagnosis in hemodialysis patients is based on clinical epidemiology, radiographic findings and viral nucleic acid testing [123].
T368	62059-62244	Sentence	denotes	Interestingly, diabetes, as a primary cause of ESKD or a coexisting disorder, was much more common in symptomatic patients affected by COVID-19 and lymphocytopenia was also more severe.
T369	62245-62391	Sentence	denotes	In total, about 40% of patients had at least one compromised organ, including cardiac injury, liver dysfunction, ARDS and a cerebrovascular event.
T370	62392-62589	Sentence	denotes	Most patients undergoing hemodialysis (HD), who were regularly monitored, showed stable clinical conditions in the course of treatment of COVID-19 and pulmonary inflammation was gradually absorbed.
T371	62591-62595	Sentence	denotes	7.4.
T372	62596-62650	Sentence	denotes	Clinical Features in Peritoneal Dialysis Patients (PD)
T373	62651-62864	Sentence	denotes	The Italian report created by SIN has collected individual data of peritoneal dialysis (PD) patients with COVID-19; in the last update dating back to May, 57 cases of COVID-19 and 28 deaths were reported in total.
T374	62865-62957	Sentence	denotes	This report shows a higher rate of mortality, almost 49%, than the general population [124].
T375	62958-63105	Sentence	denotes	Notably, SARS-CoV-2 positivity corresponded with peritoneal dialysis failure, suggesting a possible effect of the virus on the peritoneal membrane.
T376	63106-63275	Sentence	denotes	The first case in the literature which demonstrated SARS-CoV-2 in the peritoneal fluid, was described during an emergency surgical laparotomy in a COVID-19 sick patient.
T377	63276-63497	Sentence	denotes	During the procedure laparotomy, two swabs were obtained from peritoneal fluid and then sent for SARS-CoV-2 detection by specific real-time reverse transcriptase–polymerase chain reaction targeting three SARS-CoV-2 genes.
T378	63498-63605	Sentence	denotes	It was then detected in the peritoneal fluid at a higher concentration than in the respiratory tract [125].
T379	63606-63773	Sentence	denotes	Recently, an Italian study described for the first time the detection of SARS-CoV-2 in the peritoneal waste of a patient with COVID-19 and ESKD on peritoneal dialysis.
T380	63774-63894	Sentence	denotes	The patient showed the following common COVID-19 infection symptoms: fever, cough, myalgia, headache and mild hypoxemia.
T381	63895-64066	Sentence	denotes	Chest computed tomography reported bilateral multiple ground-glass opacities and laboratory tests showed mild lymphopenia, increased C-reactive protein and D-dimer levels.
T382	64067-64193	Sentence	denotes	The patient’s peritoneal dialysate was tested for SARS-CoV-2 by polymerase chain reaction, and was found to be positive [126].
T383	64194-64405	Sentence	denotes	According to the International Society Peritoneal Dialysis (ISPD) strategies regarding COVID-19 in peritoneal dialysis patients, the management of infection is the same for PD patients as for all other patients.
T384	64406-64545	Sentence	denotes	Mild or moderate patients on PD can continue PD treatment as usual, with prescription adjustment according to the usual general evaluation.
T385	64546-64785	Sentence	denotes	Those cases that aresevere or critically severe and requiring life support due to multiple organ dysfunction syndrome, can be temporarily transferred to automated peritoneal dialysis or bedside continuous kidney replacement therapy (CKRT).
T386	64786-64949	Sentence	denotes	As for patients on hemodialysis, it is advisable to keep patients in a ‘dry’ status, so that an increased ultrafiltration may be required if remaining on PD [127].
T387	64951-64955	Sentence	denotes	7.5.
T388	64956-65003	Sentence	denotes	Clinical Features in Kidney Transplant Patients
T389	65004-65242	Sentence	denotes	The European database created by ERA-EDTA [118] (collects individual data of dialysis patients and transplant patients with COVID-19; in the last update dating back to 23 July, 1403 cases of COVID-19 and 276 deaths were reported in total.
T390	65243-65369	Sentence	denotes	Similarly, the last Italian report of SIN observed 218 kidney transplant patients affected by COVID-19, of whom 54 died [124].
T391	65370-65470	Sentence	denotes	Both reports show a higher rate of mortality (ERA-EDTA 19% and SIN 25%) than the general population.
T392	65471-65689	Sentence	denotes	Moreover, as a population living with immunosuppression, the clinical manifestations, treatment and prognosis of COVID-19 pneumonia for renal transplant recipients may differ from those of the general population [128].
T393	65690-65874	Sentence	denotes	The immune response of renal transplant recipients, particularly the T-cell immune response, is significantly suppressed because of the long-term assumption of immunosuppressive drugs.
T394	65875-66146	Sentence	denotes	In the first reported renal transplant recipient with COVID-19 pneumonia described in Wuhan (China) [129], the clinical characteristics were similar to those of other non-transplanted adult patients with COVID-19 pneumonia; at the end, the patient successfully recovered.
T395	66147-66334	Sentence	denotes	However, kidney-transplant recipients appear to be at particularly high risk for critical COVID-19 illness because of both their chronic immunosuppression and coexisting conditions [130].
T396	66335-66642	Sentence	denotes	Recently, at Montefiore Medical Center, NY, 36 consecutive adult kidney-transplant recipients who were positive for COVID-19 were identified [131], and Columbia University Kidney transplant program enrolled 15 kidney transplant recipients who required hospitalization for confirmed COVID-19 infection [132].
T397	66643-66778	Sentence	denotes	Both reports described management, clinical course and outcomes of those patients living with a kidney transplant affected by COVID-19.
T398	66779-66844	Sentence	denotes	Patients were predominantly men, and the median age was 55 years.
T399	66845-66965	Sentence	denotes	The most common comorbidities were the following: hypertension, diabetes mellitus, history of smoking and heart disease.
T400	66966-67071	Sentence	denotes	Almost all patients were receiving tacrolimus, prednisone and mycophenolate mofetil or mycophenolic acid.
T401	67072-67162	Sentence	denotes	The patients reported symptom onset ranging from 1 day to nearly 3 weeks before admission.
T402	67163-67262	Sentence	denotes	The most common initial symptom was fever, but also cough, dyspnea, malaise, diarrhea and myalgias.
T403	67263-67365	Sentence	denotes	Over 50% of the patients had bilateral/multifocal opacities noted on initial chest x-ray radiographic.
T404	67366-67455	Sentence	denotes	Laboratory findings were lymphopenia, thrombocytopenia, low CD3, CD4 and CD8 cell counts.
T405	67456-67555	Sentence	denotes	As inflammatory markers, ferritin levels, C- reactive protein, procalcitonin and D-dimer were high.
T406	67556-67654	Sentence	denotes	Patients who were in a stable condition without major respiratory symptoms were monitored at home.
T407	67655-67966	Sentence	denotes	In another report, among 41 outpatient kidney transplant recipients with suspected or known COVID-19 infection, about one third required hospitalization by the end of their follow-up; there were no differences in demographics or medical comorbidities between those who were or were not admitted to the hospital.
T408	67967-68097	Sentence	denotes	These patients therefore required close clinical monitoring to prevent their organ deterioration until symptoms’ resolution [133].
T409	68098-68357	Sentence	denotes	As reported by Montefiore Medical Center and Columbia University, almost half of the patients had AKI, although none had a kidney biopsy performed to determine the cause, and required intubation and mechanical ventilation between 0 and 9 days after admission.
T410	68358-68526	Sentence	denotes	In particular, Columbia University’s report observed that 27% of their cases required intubation, a proportion that is similar for cases in New York City overall [132].
T411	68527-68599	Sentence	denotes	Among the patients who developed AKI, only 20% of patients required RRT.
T412	68600-68713	Sentence	denotes	At a median follow-up of 21 days, the mortality rate was about 28% of the kidney-transplant recipients [131,132].
T413	68714-68825	Sentence	denotes	Patients were managed with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin.
T414	68826-69051	Sentence	denotes	Therefore, among kidney transplant recipients, overall presentation was similar to the one reported for the general population and more than 50% of the patients were successfully discharged home by the end of follow-up [131].
T415	69052-69198	Sentence	denotes	Regarding treatment of transplant recipients, one challenge was adjusting immunosuppressive agents and at the same time protecting graft function.
T416	69199-69563	Sentence	denotes	When treating pneumonia due to opportunistic virus infections following kidney transplantation, a reduction (or even temporary) discontinuation of immunosuppressant drugs is a common therapeutic strategy, consequently allowing recipients the opportunity to reacquire anti-infection immunity within a short period, which is conducive to eliminating the virus [134].
T417	69564-69836	Sentence	denotes	The Columbia University Kidney Transplant Program’s clinical practice has suggested to delay reintroduction of these drugs for up to 2 weeks after discharge, recognizing that prolonged reduction of immunosuppression therapy increases the risk of allograft rejection [132].
T418	69837-70119	Sentence	denotes	Similarly, Alberici et al., in a single center observational study which was conducted in Italy, described a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in 20 kidney transplant recipients with SARS-CoV-2 pneumonia.
T419	70120-70304	Sentence	denotes	Thus, in this limited cohort of long-term renal transplant patients, SARS-CoV-2 induced pneumonia is characterized by a high risk of renal progression and a significant mortality rate.
T420	70305-70495	Sentence	denotes	Despite on average a relatively benign onset of the disease, a large rate of the patients showed worsening chest radiographs and consequently needed an escalation of the supplemental oxygen.
T421	70496-70645	Sentence	denotes	Of note, 25% of the patients died despite an aggressive approach to immunosuppression withdrawal and early administration of antiviral therapy [130].
T422	70647-70649	Sentence	denotes	8.
T423	70650-70688	Sentence	denotes	Management of the Nephropathic Patient
T424	70689-70864	Sentence	denotes	The patient with chronic kidney disease (CKD) is a fragile patient who in most cases suffers from several comorbidities that predispose to the development of infections [135].
T425	70865-71039	Sentence	denotes	For this reason, after the declaration of the pandemic state by the WHO, protective measures were developed for the patient with CKD without signs of ongoing acute pathology.
T426	71040-71183	Sentence	denotes	All nephrology units have been invited to establish a telemedicine system, through which the clinical progress of the patients may be followed.
T427	71184-71253	Sentence	denotes	In this way, hospital access was limited only for urgent cases [136].
T428	71254-71466	Sentence	denotes	For patients with the need to prepare arterial venous fistula for the initiation of hemodialysis treatment, the centers specializing in vascular access management organized screening of all patients for COVID-19.
T429	71467-71634	Sentence	denotes	Interventions for patients with confirmed or suspected infection needed to be carried out in designated premises with the necessary protection for medical staff [137].
T430	71635-71758	Sentence	denotes	In addition, for kidney transplants, it was necessary to develop preventive measures that could allow for their management.
T431	71759-71982	Sentence	denotes	In particular, each Transplant Center had to evaluate the possibility of performing a kidney transplant in relation to the availability of intensive care units and the risk of ICU admission for the individual patient [138].
T432	71983-72255	Sentence	denotes	In addition, during the course of the COVID-19 pandemic, organ donation and transplantation experienced significant changes: organ authorization decreased by 11%; the number of organs transplanted decreased by 18%; and organ recovery for transplantation fell by 17% [139].
T433	72256-72366	Sentence	denotes	Dialysis patients are even more prone to develop severe infectious diseases than the general population [135].
T434	72367-72535	Sentence	denotes	In fact, in previous epidemics or catastrophic situations, the case fatality rate has always been much higher in dialysis patients than in the general population [137].
T435	72536-72672	Sentence	denotes	In addition, for SARS-CoV-2 infection, patients on hemodialysis treatment have proved to be a population at risk of developing COVID-19.
T436	72673-72901	Sentence	denotes	In most cases, in fact, they are patients of advanced age and with many comorbidities (cardiovascular disease, high blood pressure, diabetes and lung disease) often associated with worse prognosis in COVID-19 patients [140,141].
T437	72902-73033	Sentence	denotes	The logistical aspects associated with dialysis treatment further increase the risk of contraction and transmission of the disease.
T438	73034-73189	Sentence	denotes	The patient on hemodialysis, in fact, must carry out the treatment generally three times a week and this implies the recurrent access to health structures.
T439	73190-73322	Sentence	denotes	Furthermore, the hemodialysis session is performed simultaneously by several patients who inevitably interact with each other [142].
T440	73323-73534	Sentence	denotes	These circumstances, associated with the possibility of non-specific clinical manifestations due to immune suppression related to uremia, cause a higher risk of diffusing the infection in the dialysis ward [83].
T441	73535-73705	Sentence	denotes	In some guidance documents, the possibility of performing home hemodialysis with telematic support of the patient and home visits when necessary was also considered [11].
T442	73706-73871	Sentence	denotes	In other papers, however, the reduction of hemodialysis sessions from 3 to 2 times a week has been indicated as an alternative in patients who tolerate this regimen.
T443	73872-74013	Sentence	denotes	This would reduce the risk of exposure to infections during transport and the probability of spreading to the dialysis unit or hospital [12].
T444	74014-74145	Sentence	denotes	Being prepared for a sudden and high amount of patients, suspected or confirmed, was crucial for the control of COVID-19 infection.
T445	74146-74348	Sentence	denotes	The Chinese Society of Nephrology [143], the Centers for Disease Control and Prevention, and also the various dialysis organizations developed guidelines for dialysis units during the COVID-19 epidemic.
T446	74349-74533	Sentence	denotes	In addition, the EUDIAL ERA-EDTA working group [137] provided recommendations for the prevention and containment of the emerging SARS-CoV-2 pandemic (COVID-19) in hemodialysis centers.
T447	74534-74651	Sentence	denotes	The first step in managing the COVID-19 pandemic in dialysis centers was to ensure training for all healthcare staff.
T448	74652-74829	Sentence	denotes	Doctors, nurses and care-workers have been adequately trained on the prevention measures, on the use and disposal of medical devices and any contaminated clothing/objects [137].
T449	74830-74953	Sentence	denotes	In all the centers, a member of staff was assigned to perform the nasopharynx swabs for COVID-19 polymerase chain reaction.
T450	74954-75119	Sentence	denotes	The indicated professional figures were trained on the correct methods of performing the diagnostic test but also on the type of devices needed during the procedure.
T451	75120-75326	Sentence	denotes	Each operator, in fact, must be equipped with a protective mask (FFP2) capable of filtering 95% of particulates and aerosols in the inhaled air, glasses, mobcap, disposable surgical blouse and gloves [137].
T452	75327-75423	Sentence	denotes	Furthermore, all eligible healthcare staff were trained to perform an accurate telephone triage.
T453	75424-75619	Sentence	denotes	The early recognition of suspect patients allows them to be prepared on their arrival, so that they can direct them towards the most suitable path, avoiding interaction with other patients [136].
T454	75620-75702	Sentence	denotes	The second crucial step concerned the training of patients in the dialysis center.
T455	75703-76014	Sentence	denotes	In fact, it was important that each patient drastically reduced interpersonal interactions outside the dialysis center, limiting exits only to travel to and from dialysis facilities, using individual transport to reach the dialysis center, decreasing contact with family members, especially with children [137].
T456	76015-76148	Sentence	denotes	The pediatric population, in fact, can act as a carrier of the disease often without showing symptoms or showing mild symptoms [144].
T457	76149-76316	Sentence	denotes	All patients also received instructions relating to how and when to perform hand hygiene, the use of face masks and the disposal of these and any contaminated objects.
T458	76317-76576	Sentence	denotes	Family members living with dialysis patients were also sensitized and prompted to follow precautionary procedures, including measuring body temperature, good personal hygiene, frequent hand washing and prompt reporting of potential infected individuals [137].
T459	76577-76658	Sentence	denotes	Of course, organizational adjustments had to be made in dialysis centers as well.
T460	76659-76726	Sentence	denotes	The preventive measures, in fact, must start from the waiting room.
T461	76727-76832	Sentence	denotes	All dialysis centers have had to adapt their waiting rooms to ensure a safe first reception for patients.
T462	76833-77181	Sentence	denotes	It is in fact essential that patients come together in large rooms that can allow a distance of at least 2 m between the patients, equipped with air conditioning and ventilation systems capable of removing particles and droplets of aerosol from the air, equipped with distributors of hydroalcoholic solutions for the hygiene of the hands [137,142].
T463	77182-77295	Sentence	denotes	Additional preventive measures must be implemented in the transition from the waiting room to the treatment room.
T464	77296-77510	Sentence	denotes	All patients must be subjected to temperature measurement and must be encouraged to perform hand hygiene and hygiene of the fistula arm, as well as to practice accurate disinfection of the venipuncture areas [145].
T465	77511-77601	Sentence	denotes	At the end of these steps, the patient equipped with a mask can access the treatment room.
T466	77602-77786	Sentence	denotes	These, like the waiting rooms, must be equipped with suitable air conditioning/ventilation systems and must guarantee a distance of at least 2 m between the individual positions [137].
T467	77787-77992	Sentence	denotes	If patients with suspected symptoms for COVID-19 (fever, cough, conjunctivitis) are identified after the arrival at the Dialysis Center, these must be immediately isolated and subjected to screening tests.
T468	77993-78119	Sentence	denotes	Pending the test results, if hemodialysis treatment is not postponed, the patient should be treated as a confirmed case [145].
T469	78120-78256	Sentence	denotes	Therefore, the patient must dialyze in a default room; the room reserved for HBV positive patients could be adequate if available [142].
T470	78257-78414	Sentence	denotes	If the Center does not have a default room, the patient must wait in an isolated room and receive dialysis treatment at the end of the last shift of the day.
T471	78415-78569	Sentence	denotes	If, at the end of the treatment, the result of the swab is not present yet, it is necessary to proceed with the immediate disinfection of the rooms [137].
T472	78570-78661	Sentence	denotes	If the outcome of the swab is negative, patients can return to the dialysis facility [145].
T473	78662-78883	Sentence	denotes	The management of patients on dialysis with confirmed COVID-19 infection must be carried out according to strict protocols in order to minimize the risk for both other patients and personnel taking care of these patients.
T474	78884-79108	Sentence	denotes	Most of the guidelines suggest that dialysis patients, a cause of their management complexity, their fragility and their risk of sudden decompensating, whenever possible, should be hospitalized until complete recovery [145].
T475	79109-79340	Sentence	denotes	The hemodialysis sessions, in this case, can be regularly performed in rooms in isolation or, alternatively, at the patient’s bed with machines usually used for patients with acute renal failure or home hemodialysis machines [136].
T476	79341-79564	Sentence	denotes	In the case of an infected patient with mild symptoms and not hospitalized, the hemodialysis sessions must be performed as his therapeutic scheme, in an isolated environment with appropriately organized medical staff [146].
T477	79565-79870	Sentence	denotes	All personnel involved in the direct care of COVID-19 patients must undertake full protection, including hair caps, gloves, long-sleeved waterproof isolation clothing, goggles and medical masks (FFP2 or FFP3 mask, if available) filtering 95–99% of particulate matter and aerosols in inhaled air [137,147].
T478	79871-80024	Sentence	denotes	It is important not only to avoid contact of these patients with healthy patients, but also to prevent the mixing of suspected and confirmed cases [137].
T479	80025-80258	Sentence	denotes	If there are more infected, asymptomatic or paucisymptomatic patients in the same Center, without the need for hospitalization, they can be dialyzed together in a specific section of the unit, preferably as the last shift of the day.
T480	80259-80379	Sentence	denotes	A select group of healthcare professionals must be assigned to these patients and must apply all precautionary measures.
T481	80380-80548	Sentence	denotes	The hemodialysis room must be properly sanitized at the end of the session and medical waste must be considered highly infectious and disposed of accordingly [137,142].
T482	80549-80841	Sentence	denotes	In case of peripheral centers without the possibility of creating conditions for isolation, and where an infectious disease unit and intensive care unit are both not available, patients with suspected or confirmed COVID-19 disease should be moved into hospitals having these facilities [145].
T483	80842-80943	Sentence	denotes	Management of the peritoneal dialysis patient was less complex than that of the hemodialysis patient.
T484	80944-81083	Sentence	denotes	In fact, they usually carry out purification treatment at their home and go to the nephrological center only for scheduled periodic checks.
T485	81084-81205	Sentence	denotes	The pandemic from COVID-19 has made the expansion of a telemedicine network necessary to manage patients from home [124].
T486	81206-81294	Sentence	denotes	Telematic support was also indispensable for the management of the transplanted patient.
T487	81295-81528	Sentence	denotes	Kidney transplant patients need to perform periodic checks at the post-transplant surgery of the nephrological structure of territorial jurisdiction and at the post-transplant surgery of the Center where the transplant was performed.
T488	81529-81639	Sentence	denotes	Telemedicine techniques have made it possible to monitor patients remotely and reduce outpatient visits [136].
T489	81640-81785	Sentence	denotes	Finally, in many hospitals the ordinary nephrological hospitalization wards have been closed due to the need to make space for the “COVID areas”.
T490	81786-81994	Sentence	denotes	The setting up of a single room for patients awaiting the result of the screening buffer for COVID-19, was fundamental for the restart of admissions for nephrology patients requiring hospital treatment [136].
T491	81995-82223	Sentence	denotes	It is important to emphasize that current guidelines and recommendations relating to the management of renal patients must be considered “provisional” and must undergo continuous reviews and updates in light of new developments.
T492	82225-82244	Sentence	denotes	Overview of Therapy
T493	82245-82357	Sentence	denotes	COVID-19 treatment is essentially supportive and, in fact, specific vaccines or therapies are not yet available.
T494	82358-82434	Sentence	denotes	The COVID-19 vaccine is considered to be an effective prophylactic strategy.
T495	82435-82535	Sentence	denotes	About 90 institutions around the world are working on identifying a specific and safe vaccine [148].
T496	82536-82660	Sentence	denotes	As of 8 April 2020, the global research and development landscape for COVID-19 vaccines has included 115 vaccine candidates.
T497	82661-82958	Sentence	denotes	Most of these are currently in the preclinical phase and only some of these (mRNA-1273 from Moderna, Ad5-nCoV from CanSino Biologicals, INO-4800 from Inovio and LV-SMENP-DC and pathogen-specific aAPC from Shenzhen Geno-Immune Medical Institute) have recently moved into clinical development [149].
T498	82959-83125	Sentence	denotes	The therapeutic protocols used for the general population have also been adopted in patients with chronic renal failure, regardless of the stage of the disease [150].
T499	83126-83440	Sentence	denotes	Antiviral drugs (Lopinavir/ritonavir (200/50 mg 2 cp × 2/day), Darunavir (800 mg/day), Ritonavir (100 mg/day), Darunavir/cobicistat (800/150 mg/day)) have been effective for the management of SARS-CoV-2 infection, in asymptomatic/paucisymptomatic patients and in patients with more severe manifestations [150,151].
T500	83441-83670	Sentence	denotes	Hydroxychloroquine (known as an antimalarial drug) was successfully used in the early stages of the pandemic until May 26th, 2020, when AIFA suspended authorization for its use for the treatment of SARS-CoV-2 infection [152,153].

T1

0-24

Sentence

denotes

COVID-19 and the Kidney:

T2

25-63

Sentence

denotes

From Epidemiology to Clinical Practice

T3

65-73

Sentence

denotes

Abstract

T4

74-397

Sentence

denotes

The new respiratory infectious disease coronavirus disease 2019 (COVID-19) that originated in Wuhan, China, in December 2019 and caused by a new strain of zoonotic coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), to date has killed over 630,000 people and infected over 15,000,000 worldwide.

T5

398-502

Sentence

denotes

Most of the deceased patients had pre-existing comorbidities; over 20% had chronic kidney disease (CKD).

T6

503-698

Sentence

denotes

Furthermore, although SARS-CoV-2 infection is characterized mainly by diffuse alveolar damage and acute respiratory failure, acute kidney injury (AKI) has developed in a high percentage of cases.

T7

699-838

Sentence

denotes

As AKI has been shown to be associated with worse prognosis, we believe that the impact of SARS-CoV-2 on the kidney should be investigated.

T8

839-997

Sentence

denotes

This review sets out to describe the main renal aspects of SARS-CoV-2 infection and the role of the virus in the development and progression of kidney damage.

T9

998-1282

Sentence

denotes

In this article, attention is focused on the epidemiology, etiology and pathophysiological mechanisms of kidney damage, histopathology, clinical features in nephropathic patients (CKD, hemodialysis, peritoneal dialysis, AKI, transplantation) and prevention and containment strategies.

T10

1283-1473

Sentence

denotes

Although there remains much more to be learned with regards to this disease, nonetheless it is our hope that this review will aid in the understanding and management of SARS-CoV-2 infection.

T11

1475-1477

Sentence

denotes

1.

T12

1478-1490

Sentence

denotes

Introduction

T13

1491-1618

Sentence

denotes

By December 2019, unusual cases of pneumonia had been reported in the city of Wuhan, located in central China’s Hubei province.

T14

1619-1967

Sentence

denotes

On January 12th 2020, the World Health Organization (WHO) stated that the disease was caused by a novel coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), belonging to the β-coronavirus cluster, which also includes the severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) viruses [1,2].

T15

1968-2236

Sentence

denotes

The resulting SARS-CoV-2 related disease was defined as the novel coronavirus disease 2019, or COVID-19, that rapidly spread throughout China, followed by an increasing number of cases in all continents with the exception of Antarctica, resulting in a global pandemic.

T16

2237-2294

Sentence

denotes

The data of the global burden of COVID-19 are impressive.

T17

2295-2505

Sentence

denotes

Indeed, currently (available data up to 23 July 2020) the coronavirus is affecting 212 countries and territories around the world, with over 15 million cases and over 630,000 confirmed deaths (global mortality:

T18

2506-2518

Sentence

denotes

5.4%) [3,4].

T19

2519-2589

Sentence

denotes

The Americas and Europe are the most affected continents in the world.

T20

2590-2691

Sentence

denotes

In the United States of America (U.S.A.), 4,103,674 cases and over 146,000 deaths have been reported.

T21

2692-2820

Sentence

denotes

In Europe, many outbreaks are steadily rising in Russia, Spain, UK and Italy, with over 200,000 overall deaths in the continent.

T22

2821-2919

Sentence

denotes

However, in China the rate of new cases has progressively decreased substantially since March [3].

T23

2920-2971

Sentence

denotes

The pandemic has also had a severe economic impact.

T24

2972-3236

Sentence

denotes

In fact, to help improve the clinical management of patients infected with the virus, Europe has mobilized more than 10 million euros from research funding and the United Kingdom has also invested £20,000,000 to allow for the development of a COVID-19 vaccine [5].

T25

3237-3850

Sentence

denotes

It has also been estimated that in the U.S.A., the health care costs for a single infected patient is over $3000, resulting in an overall predicted expenditure of $654.0 billion over the entire period of the pandemic [6,7].A flu-like syndrome of mild severity has been observed in most cases (80%) of COVID-19 [8,9], but in 20% of cases there have been other complications such as interstitial pneumonia with a variable degree of respiratory failure [10] as well as thromboembolic complications, including venous thromboembolism (VTE), ischemic stroke and acute coronary syndrome (ACS)/myocardial infarction [11].

T26

3851-4099

Sentence

denotes

Although the principal features associated with COVID-19 are diffuse alveolar damage and acute respiratory failure, kidney impairment has also often developed, with the frequent onset of acute kidney injury (AKI) in patients infected by SARS-CoV-2.

T27

4100-4199

Sentence

denotes

In addition, more than 20% of deceased patients were affected by chronic kidney disease (CKD) [11].

T28

4200-4276

Sentence

denotes

For this reason, the kidney’s role in COVID-19 needs to be investigated [8].

T29

4277-4523

Sentence

denotes

The aim of this review is to describe the main aspects of COVID-19 infection, namely the epidemiology and pathophysiology, together with prevention strategies and the contribution of kidney diseases to the prognosis of COVID-19 affected patients.

T30

4525-4527

Sentence

denotes

2.

T31

4528-4540

Sentence

denotes

Epidemiology

T32

4541-4641

Sentence

denotes

Globally, over 15 million confirmed cases of COVID-19 have been reported to date (23 July 2020) [4].

T33

4642-4745

Sentence

denotes

Such a large number of affected patients have been caused by the way in which the virus is transmitted.

T34

4746-4904

Sentence

denotes

COVID-19 is more contagious when compared to MERS and SARS since the virus spreads by human-to-human transmission via direct or fecal contact or droplets [7].

T35

4905-5105

Sentence

denotes

Furthermore, the possibility that the virus may be transmitted by asymptomatic individuals or by individuals within the incubation period, may also explain the high contagiousness of the disease [12].

T36

5106-5271

Sentence

denotes

COVID-19 infection is thought to have an incubation period up to 14 days following exposure, with most symptoms showing around four to five days after exposure [13].

T37

5272-5370

Sentence

denotes

However, case reports with longer incubation periods (up to 27 days) have also been reported [11].

T38

5371-5474

Sentence

denotes

An updated publication confirmed these findings, with the incubation lasting as long as 24 days (range:

T39

5475-5493

Sentence

denotes

0–24 days; median:

T40

5494-5508

Sentence

denotes

3.0 days) [7].

T41

5509-5673

Sentence

denotes

Nonetheless, the onset of symptoms is variable amongst infected patients, and the interval during which an individual with COVID-19 is contagious remains uncertain.

T42

5674-5799

Sentence

denotes

It appears that SARS-CoV-2 can be transmitted prior to the development of symptoms and throughout the course of illness [14].

T43

5800-6037

Sentence

denotes

The infection can involve all age groups, including children, and, moreover, males suffer a disproportionately higher number of deaths than females according to data from cohorts of patients in China, Italy and the United States [15,16].

T44

6038-6455

Sentence

denotes

Patients admitted at the Tongji Hospital, the major endemic area, and positive for COVID-19, showed a median age of over 60-years and a large part (up to 42%) were affected by 1 or more comorbidities, including diabetes mellitus, cardiovascular disease, hypertension, chronic lung disease, cancer, chronic kidney disease, immunocompromising conditions, severe obesity (body mass index ≥ 40) and liver disease [17,18].

T45

6456-6613

Sentence

denotes

Similar evidence was derived from a cohort of 5700 hospitalized patients on the other side of the world, namely in the New York city area in the U.S.A. [15].

T46

6614-6714

Sentence

denotes

Moreover, the data of 333 children with confirmed SARS-CoV-2 from 11 case series were analyzed [19].

T47

6715-6918

Sentence

denotes

Intriguingly, despite the recent evidence that children have the same risk for infection than adults, few cases have been admitted to intensive care units (3%) and only a few deaths have been registered.

T48

6919-7145

Sentence

denotes

The less-severe infection has been principally related to the fact that children have a stronger innate immune response and a minor prevalence of comorbidities (arterial hypertension, cardiovascular diseases) than adults [20].

T49

7146-7310

Sentence

denotes

Most patients also showed an inflammatory status and coagulopathies with elevated levels of high-sensitivity C-reactive protein and serum lactose dehydrogenase [8].

T50

7311-7554

Sentence

denotes

Interestingly, up to 15% of the hospitalized COVID-19 patients had at least one kidney abnormality represented by increased blood urea nitrogen or reduced estimated glomerular filtration rate (eGFR) which is the best marker of kidney function.

T51

7555-7821

Sentence

denotes

Moreover, findings from different cohorts of hospitalized patients showed that 26–63% of patients presented proteinuria at admission or developed proteinuria during their stay in hospital, proteinuria being considered the most recognized sign of kidney damage [7,8].

T52

7822-8060

Sentence

denotes

An individual risk profile also found that COVID-19 patients with kidney abnormalities, compared with those with normal renal function at admission, were more likely to be males, with advanced age and with a worse coagulation profile [8].

T53

8061-8176

Sentence

denotes

In addition, a meta-analysis [21] has confirmed that CKD is associated with an enhanced risk of COVID-19 infection.

T54

8177-8371

Sentence

denotes

As previously mentioned, an urgent epidemiological effort has been undertaken to understand what risk factors are responsible for the principal outcome associated with COVID-19, i.e., mortality.

T55

8372-8742

Sentence

denotes

From Chinese studies, mortality rates were increasing along age categories (mortality rate of 1.3% in the 50–59 range, 3.6% in the 60–69 range, 8% in the 70–79 range and 14.8% in the ≥range 80 years), the presence of cardiovascular diseases (10.5%), diabetes (7.3%), chronic respiratory diseases (6.3%), arterial hypertension (6%) and neoplasms (mortality 5.6%) [22,23].

T56

8743-8974

Sentence

denotes

In Italy, data from ISS—i.e., the Italian Health Institute—indicates that 1% of the patients who died did not suffer from any other diseases, 26% had only one disease, 26% had 2 diseases and 47% had 3 or more pathologic conditions.

T57

8975-9354

Sentence

denotes

The most common chronic preexisting diseases in deceased patients were: arterial hypertension (70%), followed by diabetes mellitus (31.7%), chronic kidney disease CKD (23.1%), atrial fibrillation (22.5%), chronic obstructive pulmonary disease (COPD) (18.1%), the presence of an active cancer within the previous 5 years (16.8%), ischemic heart disease (16%) and obesity 10% [20].

T58

9355-9571

Sentence

denotes

It is very remarkable that CKD was present in more than 20% of the deceased patients due to COVID-19, also surpassing, in prevalence, those affected by COPD and/or those with an active cancer within the last 5 years.

T59

9572-9818

Sentence

denotes

In addition to the presence of CKD, it also has been demonstrated that COVID-19 patients are at increased risk of developing acute kidney injury (AKI), a clinical condition that is associated with unfavorable outcomes, including mortality [8,24].

T60

9819-9903

Sentence

denotes

The incidence of AKI in COVID-19 patients is similar to that found in SARS patients.

T61

9904-10158

Sentence

denotes

This sudden loss of kidney function is strongly associated with increased mortality and morbidity and is a complication that can occur during the progression of COVID-19 in patients suffering from kidney disease as well as in those who are not [8,23,25].

T62

10159-10325

Sentence

denotes

From the analysis of several studies, this incidence varies from 0.5% to 23%, with an interval from baseline visit to the onset of AKI of 7–15 days in median [25,26].

T63

10326-10545

Sentence

denotes

Patients who developed AKI had a more critical prognosis, in terms of mortality rate compared with those who only had chronic illness as comorbidity (AKI increased the risk of death by 5.3 times in these patients) [27].

T64

10546-10768

Sentence

denotes

All these observations suggest that AKI could be one of the risk factors for mortality in COVID-19 patients, and a recent meta-analysis of 26 studies suggested that mortality from AKI may, in fact, be 13 times higher [28].

T65

10769-10964

Sentence

denotes

Overall, either the presence of CKD at hospital admission or the development of AKI during the COVID-19 infection have been both recognized as two independent risk factors of mortality [8,29,30].

T66

10965-11039

Sentence

denotes

COVID-19 has also affected patients on renal replacement treatments (RRT).

T67

11040-11300

Sentence

denotes

The Italian Society of Nephrology (S.I.N.) report found 521 patients (2.8%) positive for SARS-CoV-2 in a population of 17,848 patients undergoing hemodialysis, 18 patients (0.65%) were positive in a population of 2252 patients treated with peritoneal dialysis.

T68

11301-11480

Sentence

denotes

In positive RRT patients, 54% were dialyzed at their own dialysis center, 18% required hospitalization in sub-intensive care unit and 4.7% were dialyzed in an intensive care unit.

T69

11481-11546

Sentence

denotes

Death occurred in a non-trivial proportion of cases (25.8%) [31].

T70

11547-11856

Sentence

denotes

Indeed, data from the Dialysis Units of Piedmont and Aosta Valley (two Italian Northern West regions) found that absolute mortality risk was higher in males than in females (31.1% vs. 4%, respectively) and in presence of cardiovascular disease (29.9% vs. 10.7%) whereas it was not related to dialysis vintage.

T71

11857-11927

Sentence

denotes

Diabetes was a risk factor in transplanted patients (66.7% vs. 13.6%).

T72

11928-12024

Sentence

denotes

A history of neoplasia was also associated with an increase in risk of death (40% vs. 19%) [32].

T73

12025-12125

Sentence

denotes

These data demonstrate how hemodialysis patients are particularly susceptible to COVID-19 infection.

T74

12127-12129

Sentence

denotes

3.

T75

12130-12138

Sentence

denotes

Etiology

T76

12139-12272

Sentence

denotes

Coronaviruses are a group of single-stranded RNA viruses (ssRNAs) with positive polarity, belonging to the Coronaviridae family [33].

T77

12273-12355

Sentence

denotes

Until 2019, six coronavirus strains, which were able to infect humans, were known.

T78

12356-12452

Sentence

denotes

Four strains usually circulate in the human population causing mild respiratory infections [34].

T79

12453-12581

Sentence

denotes

In 2003 and 2012, the first two zoonotic strains of coronaviruses capable of infecting humans through an animal were identified.

T80

12582-12674

Sentence

denotes

These have caused severe lung syndromes in recent times: SARS in 2003 and MERS in 2012 [34].

T81

12675-12901

Sentence

denotes

Studies carried out on these strains showed that zoonotic coronaviruses use the bat as the primary host and are transmitted to humans through an intermediate host, represented by the civet for SARS and the camel for MERS [35].

T82

12902-13047

Sentence

denotes

However, some bat coronaviruses have been recently identified as being able to infect human cells without the need for an intermediate host [35].

T83

13048-13371

Sentence

denotes

The new respiratory infection originating from Wuhan (Hubei Province) in China that spread rapidly to the rest of the country, was initially traced back to Huanan Seafood Wholesale Market [13]; but only in January 2020 was a strain of coronavirus, which was unknown, identified as the responsible pathogen of the infection.

T84

13372-13480

Sentence

denotes

It was named as SARS-CoV-2 and belongs to the β-coronavirus cluster that includes SARS-CoV and MERS-CoV [2].

T85

13481-13558

Sentence

denotes

SARS-CoV-2 is the third strain of zoonotic coronaviruses currently known [1].

T86

13559-13730

Sentence

denotes

Subsequently, it was documented that SARS-CoV-2 is a chimaeric virus resulting from pre-existing viruses: a bat coronavirus and another coronavirus of unknown origin [36].

T87

13731-14038

Sentence

denotes

Its genomic sequence corresponds to the bat coronavirus with an 88% identity [37] and the pangolin coronavirus with a 99% identity [38], although the genetic analysis performed on the pangolin coronavirus did not involve the whole viral genome, but a specific site known as the receptor binding domain [37].

T88

14039-14159

Sentence

denotes

However, it emerged that SARS-CoV-2 and the pangolin coronavirus did not share the same structural characteristics [39].

T89

14160-14324

Sentence

denotes

Therefore, pangolin was identified as the intermediate species of transition from bat to humans rather than directly responsible for the SARS-CoV-2 pandemic [3,11].

T90

14326-14328

Sentence

denotes

4.

T91

14329-14344

Sentence

denotes

Pathophysiology

T92

14345-14503

Sentence

denotes

To understand the pathophysiological mechanism of SARS-CoV-2, its genomic sequence was compared to the other two similar coronaviruses, SARS-CoV and MERS-CoV.

T93

14504-14615

Sentence

denotes

In fact, it emerged that SARS-CoV-2 has a sequence identity of 79% with SARS-CoV and 50% with MERS-CoV [37,40].

T94

14616-14864

Sentence

denotes

Upon analysis of certain proteins, such as the coronavirus main proteinase (3CLpro), papain-like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), it was observed that the sequence identity value between SARS-CoV and SARS-CoV-2 is 96% [41].

T95

14865-14983

Sentence

denotes

Therefore, an analogy between the physiopathological mechanisms of SARS-CoV and SARS-CoV-2 has been hypothesized [42].

T96

14984-15116

Sentence

denotes

Many studies reported that SARS-CoV-2, like SARS-CoV, uses Angiotensin converting enzyme 2 (ACE-2) to enter target cells [43,44,45].

T97

15117-15424

Sentence

denotes

ACE-2 is a carboxypeptidase expressed on the cell surface which cleaves Angiotensin I (Ang I) into Angiotensin 1–9 and Angiotensin II (Ang II) into Angiotensin 1–7, counteracting the vasoconstrictor, proliferative and fibrotic effects of Angiotensin II generated by Angiotensin converting enzyme (ACE) [46].

T98

15425-15590

Sentence

denotes

Single-cell RNA sequencing analysis demonstrated a wide distribution of ACE-2 in different tissues [12,47] and histochemical staining then confirmed these data [48].

T99

15591-15856

Sentence

denotes

However, since low levels of ACE-2 expression were found on several cells types [47], it was supposed that cellular interaction and internalization by SARS-CoV-2did not depend only on ACE-2, but depended also on other auxiliary cell membrane receptors and proteins.

T100

15857-15939

Sentence

denotes

In fact, it is recognized that ssRNA viruses tend to have multiple receptors [49].

T101

15940-16117

Sentence

denotes

Qi et al. analyzed the expression of ACE-2 on 119 cell types from 13 human tissues and the coexpression characteristics of the ssRNA human viral receptors and membrane proteins.

T102

16118-16244

Sentence

denotes

Pearson correlation analysis of gene expression matrices showed 94 genes were found to be significantly correlated with ACE-2.

T103

16245-16437

Sentence

denotes

Among these, the coding genes of the peptidases alanylaminopeptidase (ANPEP), glutamyl aminopeptidase (ENPEP) and dipeptidyl peptidase 4 (DPP 4) showed the highest correlation with ACE-2 [12].

T104

16438-16731

Sentence

denotes

While both ANPEP and DPP4 are already known as a target receptors for other coronaviruses (human coronavirus 229E, swine epidemic diarrhea virus, canine coronavirus, feline coronavirus, for ANPEP and MERS-CoV for DPP4), the relationship between ENPEP and viral infection is not yet known [12].

T105

16732-16862

Sentence

denotes

ENPEP is a member of the M1 family of endopeptidases which are mammalian type II integral membrane zinc-containing endopeptidases.

T106

16863-17093

Sentence

denotes

It is mainly expressed in the terminal ileum and in the renal cortex and plays a role in the catabolic pathway of the Renin-Angiotensin system (RAAS), in the regulation of blood pressure and in the formation of blood vessels [50].

T107

17094-17228

Sentence

denotes

While the observations of Qi et al. suggest ENPEP may be a coronavirus receptor, further investigation is needed to confirm this [12].

T108

17229-17341

Sentence

denotes

However, the low expression of ACE-2 on the cell surface could also be interpreted as a viral defense mechanism.

T109

17342-17514

Sentence

denotes

In the past, the down regulation of ACE-2 had been correlated with faster cell-cell spread of human coronaviruses [51] and with more severe clinical manifestations [52,53].

T110

17515-17704

Sentence

denotes

Guzzi et al., in a recent study, hypothesized that even for COVID-19 the down regulation of ACE-2 could be a mechanism induced by SARS-CoV-2 to obtain a faster intercellular diffusion [54].

T111

17705-17938

Sentence

denotes

Studies carried out to understand the effect of angiotensin receptor blocker (ARB) drugs in patients with COVID-19, have suggested mechanisms through which the upregulation of ACE-2 may be protective during SARS-CoV-2 infection [55].

T112

17939-18009

Sentence

denotes

ARBs, in fact, greatly increase the cellular expression of ACE-2 [56].

T113

18010-18348

Sentence

denotes

However, since SARS-CoV-2-ACE-2 interaction represents the first step of a chain of events, if the upregulation of ACE-2 is not followed by the increase of certain cell proteases essential for internalization and viral activation, it would only result in the sequestration of SARS-CoV-2 on the cell membrane limiting viral infection [35].

T114

18349-18480

Sentence

denotes

Furthermore, the metalloproteinase ADAM17 can act upon the membrane-bound ACE-2, leading to the release of a soluble form of ACE-2.

T115

18481-18661

Sentence

denotes

If the increased expression of ACE-2 correlates with an increase in soluble ACE-2, this might act as a decoy receptor for SARS-CoV-2 by limiting viral entry into target cells [35].

T116

18662-18859

Sentence

denotes

Upon analysis of the SARS-CoV-2-ACE-2 interaction, there was confirmation that this occurs through the spike glycoprotein expressed on the viral envelope, being the same for all coronaviruses [35].

T117

18860-19113

Sentence

denotes

The coronavirus spike protein is composed of an intracellular segment, a transmembrane segment and a large ectodomain formed by an S1 subunit for interaction with the target receptor and an S2 subunit for fusion between the viral and cell membrane [57].

T118

19114-19230

Sentence

denotes

Subunit S1 consists of four domains, one N terminal domain (NTD) and three C-terminal domains (CTD1, CTD2 and CTD3).

T119

19231-19375

Sentence

denotes

The cell receptor and the viral protein bind through the receptor-binding domain (RBD), located in the CTD1 domain in the case of SARS-CoV [58].

T120

19376-19590

Sentence

denotes

Experiments undertaken to investigate virus-receptor interaction with resolution at the atomic level showed that SARS-CoV and SARS-CoV-2 had a high sequence similarity (89.2%) and sequence identity (73.7%) [14,22].

T121

19591-19758

Sentence

denotes

However, a more targeted evaluation of SARS-CoV-2 RBD revealed peculiar characteristics that are probably responsible for the greater diffusion compared with SARS-CoV.

T122

19759-19873

Sentence

denotes

Wan et al. found that the SARS-CoV-2 RBD has a single mutation that improves its binding affinity with ACE-2 [59].

T123

19874-20088

Sentence

denotes

Heet al. have shown that the characteristics of SARS-CoV-2 RBD make the virus more soluble, therefore capable of binding ACE-2 more easily, but also more stable, therefore able to survive at high temperatures [42].

T124

20089-20206

Sentence

denotes

At the same time, the SARS-CoV-2 RBD has greater flexibility than the SARS-CoV RBD, especially near the binding site.

T125

20207-20401

Sentence

denotes

For this reason, SARS-CoV-2 is much more sensitive to temperature than SARS-CoV in terms of the RBD-ACE-2 bond and this would cause the decrease in infectivity with increasing temperatures [42].

T126

20402-20552

Sentence

denotes

The SARS-CoV RBD-ACE-2 binding induces conformational changes in the S2 subunit, such as to induce the fusion between the viral membrane and the cell.

T127

20553-20671

Sentence

denotes

A low pH and pH-dependent endosomal cysteine proteases called cathepsins facilitate endosomal cell entry of the virus.

T128

20672-20884

Sentence

denotes

Furthermore, the S protein is cleaved into the S1 and S2 subunits by the host transmembrane cell proteases [60], which are necessary for the entry of the virus through the cell surface non-endosomal pathway [61].

T129

20885-21044

Sentence

denotes

Hoffmann et al. have shown that in particular SARS-CoV-2 S protein depends on the cellular protease Transmembrane Serine Protease 2 (TMPRSS2) for priming [62].

T130

21045-21171

Sentence

denotes

Therefore, the coexpression of ACE-2 and TMPRSS2 is a determining factor for the entry of SARS-CoV-2 into the host cells [63].

T131

21172-21317

Sentence

denotes

After entering the cell and becoming activated, SARS-CoV-2 uses the endogenous transcription mechanism of the cells to replicate and spread [60].

T132

21318-21445

Sentence

denotes

Cells infected by SARS-CoV-2 can recruit and modulate immune cells through the secretion of chemokines or other cytokines [12].

T133

21446-21492

Sentence

denotes

The role of macrophages remains to be defined.

T134

21493-21658

Sentence

denotes

In fact, the interaction between macrophages and cells expressing ACE-2 is known, suggesting a primary role of macrophages as a sentinel during viral infection [12].

T135

21659-21768

Sentence

denotes

A recent study, however, has shown a down regulation of mitochondrial proteins that interact with SARS-CoV-2.

T136

21769-21890

Sentence

denotes

This mechanism could be interpreted as a process through which the virus prevents apoptosis induced by mitochondria [54].

T137

21892-21894

Sentence

denotes

5.

T138

21895-21949

Sentence

denotes

Pathophysiology of Kidney Damage Induced by SARS-CoV-2

T139

21950-22082

Sentence

denotes

The expression of ACE-2 has been shown not only in the lung but also in the liver, stomach, ileum, colon, esophagus and kidney [47].

T140

22083-22352

Sentence

denotes

These data associated with the evidence that AKI (7%), myocardial dysfunction with acute cardiovascular events (12%) and gastrointestinal disorders are among the most frequent clinical manifestations of COVID-19 [23], suggesting that SARS-CoV-2 can infect these organs.

T141

22353-22512

Sentence

denotes

However, whether SARS-CoV-2 replication occurs in these organs causing functional damage and contributing to the systemic spread of the virus is not yet clear.

T142

22513-22693

Sentence

denotes

Zou et al. [47], stratifying the human organs in high and low risk according to the level of ACE-2 expression, have shown that the kidney is very vulnerable to SARS-CoV-2infection.

T143

22694-23042

Sentence

denotes

Qi et al. [12], through single cell RNA sequencing studies, have shown that ACE-2 in the kidney is expressed primarily by renal proximal tubular cells (~82%) and also to a lesser extent by cells of the intercalated duct, main cells of the collecting duct, renal distal tubular cells, glomerular parietal epithelium cells and immune cells (8%) [12].

T144

23043-23203

Sentence

denotes

Pan et al. [63], using single cell transcriptome analysis, confirmed the cellular co-expression of ACE-2and TMPRRS genes in proximal tubule cells and podocytes.

T145

23204-23379

Sentence

denotes

Batlle et al. have also suggested whether the expression of other cellular TMPRSSs other than TMPRSS2 (such as TMPRSS 4, 5 or 9) may also play a role in the priming step [64].

T146

23380-23644

Sentence

denotes

Studies showed that the co-expression of the ACE-2 receptor and TMPRSS genes in kidney epithelial cells was as significant as in the lung, esophagus, small intestine and colon, suggesting that the kidney might also be an important target organ for SARS-CoV-2 [63].

T147

23645-23774

Sentence

denotes

In particular, a high co-expression of ACE-2 and TMPRSS genes was found in podocytes and proximal rectangular tubular cells [63].

T148

23775-24005

Sentence

denotes

Other noteworthy observations include the presence ofSARS-CoV-2 nucleocapsid protein in renal tubular structures and virus-like particles in podocytes and renal tubular epithelial cells, as observed by electron microscopy [65,66].

T149

24006-24117

Sentence

denotes

Together these observations suggest the virus may cause AKI through a direct cytopathic effect on kidney cells.

T150

24118-24336

Sentence

denotes

In particular, it is conceivable that the virus may enter the kidney by invading the podocytes first, thereby gaining access to the tubular fluid and thence to the proximal tubule cells where it may bind to ACE-2 [64].

T151

24337-24499

Sentence

denotes

The viral replication in podocytes and the resulting damage could explain the proteinuria and hematuria reported in a high percentage of COVID-19 patients [8,27].

T152

24500-24686

Sentence

denotes

However, if the renal dysfunction is caused only by direct damage of SARS-CoV-2 or is secondary also to other systemic processes triggered by the virus, it has not been well defined yet.

T153

24687-24938

Sentence

denotes

Diao et al. [65] observed that kidney damage associated with COVID-19 is an acute tubular necrosis induced directly by SARS-CoV-2 during infection and replication, but also indirectly through the complex immune mechanisms triggered by cellular damage.

T154

24939-25315

Sentence

denotes

In fact, the histopathological examination performed on kidney specimens, obtained from autopsy of COVID-19 patients with renal function impairment, showed viral antigens in the cytoplasm of the tubular cells, but also a strong presence of CD68+ macrophages in the tubulo-interstitium and strong C5b-9 depositions on the apical brush border of tubular epithelial cells (TECs).

T155

25316-25538

Sentence

denotes

This suggested that proinflammatory cytokines derived from macrophages in the tubulo-interstitium and complement-mediated mechanisms resulting from cell damage participate in the pathogenesis of tubulo-interstitial damage.

T156

25539-25787

Sentence

denotes

In fact, despite the infiltration of infected tissue by host immune cells in order to contain viral replication, the hyperactivation of these immune cells may lead to fibrosis, epithelial cell apoptosis and cause microvasculature damage [67,68,69].

T157

25788-25999

Sentence

denotes

Studies performed on SARS-CoV suggested that AKI in SARS patients was the result of specific pathogenic conditions, such as the cytokine release syndrome [70], rather than active viral replication in the kidney.

T158

26000-26200

Sentence

denotes

In consideration of the analogy between SARS-CoV and SARS-CoV-2, flow cytometry was used to study the immune phenotype and the function of peripheral blood mononuclear cells in COVID-19 patients [71].

T159

26201-26466

Sentence

denotes

Studies showed that patients infected by SARS-CoV-2 showed lymphopenia, mainly related to the significant reduction in absolute T cell counts, particularly cytotoxic T lymphocytes (CD8+), increased neutrophil counts and elevated levels of proinflammatory cytokines.

T160

26467-26566

Sentence

denotes

In particular, high levels of interleukin (IL)-2, IL-6, IL-10 and interferon (IFN)-γ were observed.

T161

26567-26702

Sentence

denotes

Therefore, it has been speculated that a loss of T cells during the viral infection may result in enhanced inflammatory responses [72].

T162

26703-26828

Sentence

denotes

In fact, it is known that T cells are important for dampening overactive innate immune responses during viral infection [73].

T163

26829-27035

Sentence

denotes

In accordance with this hypothesis, it has been observed that when the T cell count drops the serum levels of IL-2, IL-4, IL-10, tumour necrosis factor (TNF)-α and interferon (IFN)-γ reach their peaks [72].

T164

27036-27202

Sentence

denotes

Another important finding is that COVID-19 patients with more severe clinical manifestations have higher serum concentrations of IL-6 and lower IFN-γ than mild forms.

T165

27203-27276

Sentence

denotes

This is mainly due to the decrease in CD4+, CD8+ and NK lymphocytes [74].

T166

27277-27406

Sentence

denotes

Interferons (IFN) are a family of cytokines that play a central role in innate immunity to viruses and other microbial pathogens.

T167

27407-27579

Sentence

denotes

The IFN-receptor binding induces a cascade of signals with activation of genes coding for proteins with antiviral, antiproliferative or immunomodulatory properties [70,75].

T168

27580-27866

Sentence

denotes

Normally the interaction between the IFN-γ and IL-6/sIL-6R signals contributes to the recruitment and subsequent clearance of neutrophils, thereby controlling infection and resolution of acute inflammation as well as influencing the transition between innate and adaptive immunity [76].

T169

27867-27979

Sentence

denotes

In patients infected by SARS-CoV-2, a higher IL-6/IFN-γ ratio may be related to an enhanced cytokine storm [74].

T170

27980-28133

Sentence

denotes

These observations suggest that in both SARS patients, and in patients with COVID-19, AKI may have an inflammatory etiology mediated by a cytokine storm.

T171

28134-28269

Sentence

denotes

The cytokine storm is associated with an inflammatory process that originates in a local site and spreads via the systemic circulation.

T172

28270-28451

Sentence

denotes

The inflammatory process can cause dysfunction in organs, particularly when tissue edema causes an increase in extravascular pressures and a consequent decrease in tissue perfusion.

T173

28452-28611

Sentence

denotes

Compensatory repair processes arise soon after the beginning of inflammation, and in a lot of cases they can completely re-establish tissue and organ function.

T174

28612-28770

Sentence

denotes

However, when a severe inflammation condition injures local tissue structures, healing occurs with fibrosis, which can cause permanent organ dysfunction [70].

T175

28771-28933

Sentence

denotes

In fact, when a cytokine storm occurs, the immune system may not be able to kill SARS-CoV-2, but it can kill large numbers of normal cells and damage organs [63].

T176

28934-29156

Sentence

denotes

In support of the hypothesis that AKI in COVID-19 patients may be the consequence of inflammatory damage, a cohort study found that the CT scan of kidneys showed a reduced density, indicative of inflammation and edema [8].

T177

29157-29292

Sentence

denotes

In addition to being frequently associated with the cytokine storm, severe lung infections often require prolonged ventilatory support.

T178

29293-29428

Sentence

denotes

This predisposes to the development of sepsis, classically defined by marked hypotension which requires treatment with inotropic drugs.

T179

29429-29698

Sentence

denotes

Therefore, in patients with COVID-19 or acute respiratory distress syndrome (ARDS), it is plausible that persistent hypotension and vasoconstriction induced by inotropics can participate in the fall of the glomerular filtrate and consequent acute tubular necrosis [77].

T180

29699-29812

Sentence

denotes

In the most recent studies, the hypothesis of a multifactorial etiology of renal damage in COVID-19 is confirmed.

T181

29813-29983

Sentence

denotes

Su et al. [66] in a study performed by analyzing autopsy kidney samples showed pigmented casts with high levels of creatine phosphokinase, attributable to rhabdomyolysis.

T182

29984-30085

Sentence

denotes

In rhabdomyolysis the massive release of myoglobin due to muscle damage can cause kidney dysfunction.

T183

30086-30348

Sentence

denotes

Myoglobin, in fact, shows its renal toxicity through various mechanisms: renal vasoconstriction related to the hyperactivation of RASS by hypoperfusion and the reduction of nitric oxide levels; intratubular cast formation; direct toxicity on renal tubular cells.

T184

30349-30403

Sentence

denotes

These processes result in acute tubular necrosis [78].

T185

30404-30473

Sentence

denotes

Rhabdomyolysis in COVID-19 patients is hypothetically multifactorial.

T186

30474-30636

Sentence

denotes

In fact, it may be secondary to a direct cytotoxic effect of SARS-CoV-2 on the muscle, tissue hypoxia due to hyperventilation or also to drug-induced damage [66].

T187

30637-30744

Sentence

denotes

Presumably, in COVID-19 patients who develop rhabdomyolysis, it may participate in the pathogenesis of AKI.

T188

30745-30948

Sentence

denotes

Su et al. [66] demonstrated the presence of erythrocyte aggregates, without platelets or fibrinoid fragments, which obstructs the lumen of the peritubular and glomerular capillaries in COVID-19 patients.

T189

30949-31193

Sentence

denotes

Erythrocyte aggregation, presumably induced by inflammation (reflected by a high rate of erythrocyte sedimentation) and hypotension, can potentiate oxidative stress, inflammation and complement activation, aggravating microvascular damage [64].

T190

31194-31320

Sentence

denotes

Furthermore, occlusion of microvascular lumens by erythrocytes has been associated with a variety of endothelial lesions [66].

T191

31321-31419

Sentence

denotes

Normally, in endothelial cells of the kidney, only ACE is expressed without detectable ACE-2 [79].

T192

31420-31495

Sentence

denotes

Therefore, the renal endothelium cannot be infected directly by SARS-CoV-2.

T193

31496-31614

Sentence

denotes

However, this cannot be totally excluded, since ACE-2expressioncan be changed in pathological states or by drugs [66].

T194

31615-31810

Sentence

denotes

Varga et al. recently concluded that SARS-CoV-2 infection induces endothelitis in various organs, directly and indirectly, and that could explain the systemic impairment of microcirculation [80].

T195

31811-31903

Sentence

denotes

Further studies are necessary to better understand the genesis of renal endothelial lesions.

T196

31904-32151

Sentence

denotes

Of note, a recent study has proposed a new route for SARS-CoV-2 invasion of host cells via an alternative cell receptor known as CD147 (and also called basigin), which is a transmembrane glycoprotein and is expressed on all endothelial cells [81].

T197

32152-32304

Sentence

denotes

Recently, the high incidence of thromboembolic events in COVID-19 patients suggests that SARS-CoV-2 may play an important role in inducing coagulopathy.

T198

32305-32401

Sentence

denotes

Analyzing the hematological profile of COVID-19 patients, a state of hypercoagulability emerged.

T199

32402-32558

Sentence

denotes

In fact, high plasma levels of reactive protein C, fibrinogen, D-dimer and ferritin, associated with thrombocytopenia, were found in these patients [71,82].

T200

32559-32771

Sentence

denotes

Recently, clinical and autopsy reports from China and the U.S. confirm the development of disseminated intravascular coagulation following SARS-CoV-2 infection, with evidence of microangiopathy in several organs.

T201

32772-33030

Sentence

denotes

In fact, the activation of macrophages associated with COVID-19, the storm of cytokines and the molecular proteins associated with the damage can cause both tissue factors’ release and the activation of coagulation factors predisposing to hypercoagulability.

T202

33031-33215

Sentence

denotes

In some cases, this state of hypercoagulability could favor the evolution of acute tubular necrosis into cortical necrosis and, therefore, the development of irreversible renal damage.

T203

33216-33372

Sentence

denotes

These observations suggest that low back pain and microhematuria observed in some positive COVID-19 patients may be manifestations of renal infarction [64].

T204

33373-33505

Sentence

denotes

The SARS-CoV-2 contribution to the development of CKD could involve pathways similar to those described for the acute kidney injury.

T205

33506-33641

Sentence

denotes

Indeed, it has been observed that a non-trivial portion of patients develop signs of tubular or glomerular damage during the infection.

T206

33642-33820

Sentence

denotes

The direct tubule-glomerular cellular injury, due to the virus, often manifests with proteinuria and hematuria that, in turn, could start a chronic, non-reversible, process [83].

T207

33821-33954

Sentence

denotes

It has been shown that proteinuria exerts a direct toxic effect on renal tubular cells and promotes renal fibrosis over time [84,85].

T208

33955-34166

Sentence

denotes

In conclusion, the renal damage observed in COVID-19 patients is the result of complex mechanisms induced directly and indirectly by SARS-CoV-2 that predispose to the development of renal dysfunction (Figure 1).

T209

34167-34399

Sentence

denotes

Further studies are needed to better understand the pathophysiological mechanisms of kidney injury, to develop new therapeutic strategies able to limit and/or prevent kidney damage, and to improve the prognosis of COVID-19 patients.

T210

34401-34403

Sentence

denotes

6.

T211

34404-34418

Sentence

denotes

Histopathology

T212

34419-34684

Sentence

denotes

As mentioned before, the virus gains access to the kidney via the ACE-2receptor for which it uses to enter entrance to target cells [62,86,87] and it has been shown that the ACE-2 receptor of SARS-CoV-2 is highly expressed in renal proximal tubule cells [63,88,89].

T213

34685-34789

Sentence

denotes

Possible mechanisms for kidney injury in COVID-19 include direct infection of the renal parenchyma [47].

T214

34790-35007

Sentence

denotes

Diao et al. [65] retrospectively analyzed the clinical data on renal function from 85 cases of COVID-19; a similar analysis on kidney abnormalities in 26 autopsies of COVID-19 patients was conducted by Su et al. [66].

T215

35008-35148

Sentence

denotes

Using light microscopy, ultrastructural observation and immunostaining have been very informative to understand the extent of kidney injury.

T216

35149-35384

Sentence

denotes

Light microscopy examination using Hematoxylin and Eosin staining may show the extent of tubular atrophy and interstitial disease, these are strong histological markers of renal damage and may also predict progression of renal failure.

T217

35385-35692

Sentence

denotes

Using light microscopy, proximal tubule injurywas observed with the loss of brush border and vacuolar degeneration with necrosis and detachment of the epithelium observed in the lumen of the tubules; dilatation of the tubular lumen was also noted together with cellular debris resulting from necrosed cells.

T218

35693-36023

Sentence

denotes

Erythrocyte aggregates were also observed, causing obstruction of peritubular and glomerular capillary loops, with no obvious erythrocyte or platelet fragmentation or any fibrin thrombi, and less erythrocyte aggregation was observed in peritubular capillaries in those cases with predominantly glomerular loop obstruction [65,66].

T219

36024-36264

Sentence

denotes

Hemosiderin granules were identified in the renal tubular epithelium of a few patients, while pigmented casts were found in a small number of patients who had high levels of creatine phosphokinase, indicating the presence of rhabdomyolysis.

T220

36265-36452

Sentence

denotes

Su et al. noted some cellular swelling of the renal distal tubules and collecting ducts, with some edematous expansion of the interstitial space, but without any significant inflammation.

T221

36453-36558

Sentence

denotes

They also noted infiltration of lymphocytesin areas of nonspecific fibrosis, including subcapsular areas.

T222

36559-37049

Sentence

denotes

Glomeruli were intact, with various degrees of morphologic changes: nodular mesangial expansion and arteriolar hyalinosis; endothelial cell swelling and degeneration was observed in a small number of COVID-19 patients but these were older individuals with a history of diabetes and hypertension; in other cases podocyte vacuolation and detachment from the glomerular basement membrane was seen; in 2 patients with proteinuria and diabetes, focal segmental glomerulosclerosis was also noted.

T223

37050-37360

Sentence

denotes

Immunohis to chemical studies utilizing an anti-SARS-CoV nucleoprotein antibody against the viral nucleocapsid protein (NP) and indirect fluorescence microscopy, showed the NP antigen was present in the renal tubular cells of the infected tissues, suggesting that SARS-CoV-2 can directly infect kidney tubules.

T224

37361-37653

Sentence

denotes

Moreover, Diao et al. observed that the presence ofSARS-CoV-2 virus resulted in the infiltration of high levels of CD68+ macrophages into the tubulo-interstitium, and it is feasible that these macrophages could release proinflammatory cytokines which in turn would cause renal tubular damage.

T225

37654-37817

Sentence

denotes

In contrast, CD8+ T cells were observed only in moderate numbers in the examined tissues, while CD4+ T cells and CD56+ natural killer (NK) cells were seldom found.

T226

37818-38065

Sentence

denotes

Diao et al. also observed the deposition of the C5b-9 complement complex (also known as the membrane attack complex pathway) on the apical brush border of renal tubular epithelial cells, whereas C5b-9 expression was absent in normal kidney tissue.

T227

38066-38215

Sentence

denotes

The complex may cause cell death and therefore renal injury and may be an important factor in the pathogenesis of tubulo-interstitial damage [90,91].

T228

38216-38377

Sentence

denotes

All these findings suggest that SARS-CoV-2 infection causes acute tubular necrosis not only through direct cytotoxicity, but also via immune mediated mechanisms.

T229

38378-38679

Sentence

denotes

Observations using transmission electron microscopy (EM) of kidney tissue from autopsies of COVID-19 cases has shown the presence of coronavirus-like particles in the cytoplasm of proximal and distal tubular cells; as well as in podocytes, podocyte foot processes and the glomerular basement membrane.

T230

38680-38921

Sentence

denotes

In two autopsy specimens observed by Diao et al., it was noted that the cells in infected kidney tissue were swollen, with enlargement of mitochondria and lysosomes, and viral particles were observed in the broken lysosomes in the cytoplasm.

T231

38922-39069

Sentence

denotes

These findings demonstrate SARS-CoV-2 can directly infect kidneys and why patients with COVID-19 often present with proteinuria, hematuria and AKI.

T232

39070-39243

Sentence

denotes

As has already been mentioned with the light microscopy observations, EM also showed erythrocytic obstruction of peritubular capillary lumens with injury of the endothelium.

T233

39244-39363

Sentence

denotes

Aggregation of erythrocytes in segmental glomerular capillary loops was frequent, but without inflammation or necrosis.

T234

39364-39684

Sentence

denotes

Intriguingly, according to a recent study [14] about endothelial cell infection and endothelitis in COVID-19, endothelial dysfunction is probably one of the main causes of microvascular dysfunction by causing vasoconstriction leading to organ ischemia, inflammation with associated tissue edema and a procoagulant state.

T235

39685-39777

Sentence

denotes

The principal findings of light microscopy, immunofluorescence and EM are shown in Figure 2.

T236

39779-39781

Sentence

denotes

7.

T237

39782-39799

Sentence

denotes

Clinical Features

T238

39800-39901

Sentence

denotes

Most COVID-19 infections are not severe, with the spectrum of symptoms ranging from mild to critical.

T239

39902-40050

Sentence

denotes

Based on all confirmed, suspected and asymptomatic cases of COVID-19 in the world on 23 July, the ISS—i.e., Italian Health Institute, reported that:

T240

40051-40482

Sentence

denotes

80% of infections are mild(asymptomatic 29% or with flu-like symptoms paucisymptomatic 12%, mild 35%), and those with these symptoms being able to recover at home; 10% are severe, developing severe diseases including pneumonia and dispnea; and 2% are critical and include: respiratory failure, septic shock and multi-organ failure requiring intensive care assistance; in about 2% of overall reported cases, the virus is fatal [92].

T241

40483-40794

Sentence

denotes

Comorbidities which have been associated with illness severity and mortality include the following ones: diabetes mellitus, cardiovascular disease, hypertension, chronic lung disease, cancer, chronic kidney disease, immunocompromising conditions, severe obesity (body mass index ≥ 40) and liver disease [90,91].

T242

40795-40898

Sentence

denotes

COVID-19 infection is frequently severe among patients of advanced age and other medical comorbidities.

T243

40899-41070

Sentence

denotes

Males, compared with females, suffer a disproportionately higher number of deaths according to data from cohorts of patients in China, Italy and the United States [15,92].

T244

41071-41355

Sentence

denotes

The most frequent serious clinical manifestation of infection appears to be pneumonia, which is primarily characterized by fever (which can even be absent), dry cough, fatigue, anorexia, myalgias, dyspnea, sputum production, and the presence of bilateral infiltrates on chest imaging.

T245

41356-41465

Sentence

denotes

Other reported symptoms can include the following: headache, sore throat, rhinorrhea and conjunctivitis [93].

T246

41466-41704

Sentence

denotes

However, no specific clinical features that can reliably distinguish COVID-19 from other viral respiratory infections have been reported, although development of dyspnea several days after the onset of initial symptoms is suggestive [25].

T247

41705-41828

Sentence

denotes

However, common symptoms in patients infected by COVID-19 are smell and taste disorders (e.g., anosmia and dysgeusia) [93].

T248

41829-41939

Sentence

denotes

Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain and diarrhea) have also been described [94].

T249

41940-42094

Sentence

denotes

There have been rare dermatological reports of erythematous rash, widespread urticaria and chickenpox-like vesicles and transient livedo reticularis [11].

T250

42095-42284

Sentence

denotes

Reddish-purple nodules on the distal digits similar in appearance to pernio (chilblains) have also been anecdotally described in children and young adults with suspected COVID-19 infection.

T251

42285-42424

Sentence

denotes

As mentioned previously, epidemiological data from many countries report that children make up a small minority of those who test positive.

T252

42425-42610

Sentence

denotes

Children account for 1–5% of patients and are less likely to become severely ill compared with adults, though preschool children and infants might have severe clinical features [95,96].

T253

42611-42927

Sentence

denotes

The small rate of COVID-19 infection for children has also been confirmed by another study which showed that children younger than 18 years made up less than 2% of national cases in different countries [97], so that, also in this case, that proportion reflects lower susceptibility among children versus adults [98].

T254

42928-43068

Sentence

denotes

The emergence of a severe Kawasaki-like disease in children related to COVID-19 has now shifted focus on the vulnerability of children [99].

T255

43069-43185

Sentence

denotes

It is a rare acute pediatric vasculitis, with the development of coronary artery aneurysms as its main complication.

T256

43186-43351

Sentence

denotes

Diagnosis of this disease is based on the presence of persistent fever, lymphadenopathy, conjunctival injection exanthema and changes to the mucosae and extremities.

T257

43352-43602

Sentence

denotes

Pediatricians in the United Kingdom identified a small group of children presenting with shock and a multisystem inflammation, some of whom had coronary artery aneurysms, and a further group of less severely ill children with a Kawasaki-like disease.

T258

43603-43915

Sentence

denotes

Based on the review of clinical and laboratory features, a case definition of the syndrome named “pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS)” was formulated by experts in the United Kingdom and published by the Royal College of Paediatrics and Child Health [100].

T259

43916-44159

Sentence

denotes

Some COVID-19 patients who at first do not show anysevere symptoms may nonetheless do so over the course of a week, with acute respiratory distress syndrome (ARDS) manifesting shortly after the onset of dyspnea in patients with severe disease.

T260

44160-44247

Sentence

denotes

Other reported complications are acute cardiac injury, arrhythmias, AKI and shock [25].

T261

44248-44355

Sentence

denotes

Thromboembolic complications, including pulmonary embolism and acute stroke, have also been reported [101].

T262

44357-44361

Sentence

denotes

7.1.

T263

44362-44425

Sentence

denotes

Clinical Features in Patients with Chronic Kidney Disease (CKD)

T264

44426-44540

Sentence

denotes

Chronic kidney disease (CKD) seems to be associated with enhanced risk of severe COVID-19 infection and mortality.

T265

44541-44663

Sentence

denotes

Cheng et al. evaluated the association between markers of renal impairment and death in a cohort of 701 COVID-19 patients.

T266

44664-44862

Sentence

denotes

They found that 43.9% of patients admitted had proteinuria and 26.7% had hematuria, serum creatinine and blood urea nitrogen (BUN) levels were increased in 14.4% and 13.1% of patients, respectively.

T267

44863-44958

Sentence

denotes

Estimated glomerular filtration rate < 60 mL/min per 1.73 m2was found in 13.1% of patients [8].

T268

44959-45241

Sentence

denotes

In particular, the authors have shown that, at univariate analysis the presence of proteinuria was associated with a 4 up to 11-fold increased risk of in-hospital death compared with COVID-19 patients without kidney damage, whereas hematuria increased the risk of death by 12 times.

T269

45242-45321

Sentence

denotes

These hazard ratios (HR)were higher than risk factors such as advanced age (HR:

T270

45322-45348

Sentence

denotes

2.43), severe disease (HR:

T271

45349-45665

Sentence

denotes

6.10) and remained significantly associated with mortality even after adjustment (therefore to multivariate analysis) by age, gender, disease severity, lymphocyte count, comorbidity, thus demonstrating that measures of kidney damage play a very important role in assessing prognosis of COVID-19 patients [8,102,103].

T272

45666-45786

Sentence

denotes

This significant association of CKD with severe COVID-19 infection was observed also in the meta-analysis by Lippi [21].

T273

45787-45925

Sentence

denotes

This can be explained by the pro-inflammatory state and by the alterations of the innate and adaptive immune response associated with CKD.

T274

45926-45995

Sentence

denotes

This immune profile increases susceptibility to all infections [104].

T275

45996-46287

Sentence

denotes

These findings suggest that COVID-19 patients with high baseline serum levels of creatinine are more likely to be led to intensive care unit treatment and to undergo mechanical ventilation, because the presence of a renal disease on admission constitutes a higher risk of negative prognosis.

T276

46288-46450

Sentence

denotes

It has been recently shown that a large part of COVID-19 patients suffer from other comorbidities and most of these patients are also elderly and males [102,103].

T277

46451-46565

Sentence

denotes

Among these comorbidities, the presence of chronic kidney disease is an independent risk factor of poor prognosis.

T278

46566-46842

Sentence

denotes

It is also true, on the contrary, that nephropathic patients are mainly affected by hypertension and cardiovascular disease per se and this can lead to a higher risk of COVID-19 infection when compared with the general population or with patients without kidney disease [105].

T279

46843-47023

Sentence

denotes

Nephropathic patients are also patients with cardiovascular disease which is currently considered a biomarker of increased risk for COVID 19 infection and for poor prognosis [105].

T280

47024-47239

Sentence

denotes

However, an increased risk of death, about 3–8 times, was found in patients infected with other viruses such as H1N1 flu virus and who developed kidney injury during infection as compared to those who had not [106].

T281

47240-47488

Sentence

denotes

Moreover, patients who enter the hospital with elevated serum creatinine levels were predominantly male and older (median age was 73 years) and were more severely ill compared with patients who had normal serum creatinine (median age was 61 years).

T282

47489-47700

Sentence

denotes

In addition, patients with increased baseline serum creatinine levels show an alteration of leukocyte count with an increase in the absolute number of leukocytes and a decrease in lymphocyte and platelet counts.

T283

47701-47899

Sentence

denotes

Coagulation pathway abnormalities, which include prolonged activated partial thromboplastin time and higher D-dimer, are more frequent in patients with increased baseline serum levels of creatinine.

T284

47900-48095

Sentence

denotes

The rate of patients with increased procalcitonin, and the plasma levels of aspartate aminotransferase and LDH are also higher in patients with CKD compared with those with normal renal function.

T285

48096-48260

Sentence

denotes

The incidence of in-hospital death in patients with CKD was found to be significantly higher than in those patients with normal baseline serum levels of creatinine.

T286

48262-48266

Sentence

denotes

7.2.

T287

48267-48327

Sentence

denotes

Clinical Features in Patients with Acute Kidney Injury (AKI)

T288

48328-48521

Sentence

denotes

It is not the first time that a virus mainly involving the respiratory tract can also involve the kidney, as it has been already reported during the course of the SARS epidemic in 2003 [8,107].

T289

48522-48611

Sentence

denotes

AKI represents a life-threatening complication, often leading to increased risk of death.

T290

48612-48780

Sentence

denotes

One possible explanation of the high prevalence of kidney involvement at hospital admission is that some of the COVID-19 patients may already have had a history of CKD.

T291

48781-48963

Sentence

denotes

Such patients tend to have a pro-inflammatory state with functional defects in their immune system [108] and are at a higher risk for upper respiratory tract infection and pneumonia.

T292

48964-49111

Sentence

denotes

Cheng et al. [8], as mentioned before, in their study of a cohort of 701 patients found that 5.1% of patients developed AKI during hospitalization.

T293

49112-49258

Sentence

denotes

Patients with increased baseline serum creatinine levels were more likely to develop AKI (11.9%) than patients with normal baseline values (4.0%).

T294

49259-49539

Sentence

denotes

This means that, while renal complications are more likely in patients with pre-existing chronic impairment of kidney function, moderate-to-severe AKI can also be found in patients with normal serum creatinine levels these may represent a higher-risk subset of patients with ARDS.

T295

49540-49769

Sentence

denotes

Wilson et al. [109] noted that similar observations have been reported for COVID-19-associated ARDS, which could develop into AKI on average 9 days after admission together with secondary infections and acute cardiac damage [26].

T296

49770-49887

Sentence

denotes

In ARDS, patients age, severity of illness and the presence of diabetes are all risk factors for acute kidney injury.

T297

49888-50015

Sentence

denotes

Furthermore, the patient’s BMI value and any previous history of heart failure may also be associated with the severity of AKI.

T298

50016-50096

Sentence

denotes

All these risk factors may count for the higher incidence of AKI in the elderly.

T299

50097-50381

Sentence

denotes

Hirsch et al. recently analyzed risk factors, clinical presentation and outcomes of AKI among hospitalized COVID-19 patients in the metropolitan New York area, encompassing twenty three hospitals within urban and suburban areas and including academic tertiary and community hospitals.

T300

50382-50500

Sentence

denotes

They found that among those with AKI, 694 died (35%), 519 (26%) were discharged and 780 (39%) were still hospitalized.

T301

50501-50730

Sentence

denotes

In addition to the known risk factors for AKI mentioned before, namely older age, cardiovascular disease, hypertension, diabetes mellitus and need for ventilation and of vasopressor drugs, black race was also included among them.

T302

50731-50920

Sentence

denotes

Indeed, individuals from minority communities, in particular African Americans and Hispanics have been disproportionately affected by and have had worse outcomes after SARS-CoV-2 infection.

T303

50921-51097

Sentence

denotes

Finally, they did not find that use of blockers of the Renin-Angiotensin and aldosterone system at hospital admission for COVID-19 disease was associated with greater AKI risk.

T304

51098-51334

Sentence

denotes

As expected, in their study involving different ethnicities in U.S.A., they confirmed that early AKI occurs frequently among COVID-19 patients and in temporal association with respiratory failure, with a consequent poor prognosis [110].

T305

51335-51502

Sentence

denotes

The standard assessment of AKI is still based on serum creatinine levels and daily urine output, but these represent only indicators of established renal damage [111].

T306

51503-51673

Sentence

denotes

Recently, Richardson et al. enrolled in the New York City Area (U.S.A.), the largest number of cases of sequentially hospitalized patients with confirmed COVID-19 in USA.

T307

51674-51812

Sentence

denotes

Males and those with pre-existing hypertension and/or diabetes were highly prevalent among 5700 case series with a median age of 63 years.

T308

51813-51909

Sentence

denotes

In this study, AKI was observed among 8.4% discharged live patients and among 63% dead patients.

T309

51910-52029

Sentence

denotes

On hospital admission, a significant percentage of patients had renal impairment, presenting proteinuria and hematuria.

T310

52030-52095

Sentence

denotes

AKI incidence in the overall cohort was in the range of 4.7–7.5%.

T311

52096-52218

Sentence

denotes

A higher incidence of proteinuria and hematuria was reported in patients with severe or critically ill COVID-19 pneumonia.

T312

52219-52372

Sentence

denotes

Among all patients with renal impairment, the patients with AKI had a higher incidence rate of proteinuria and hematuria compared with the non-AKI group.

T313

52373-52509

Sentence

denotes

Almost 50% of the critically ill cases developed AKI during hospitalization, especially those who were in the intensive care unit (ICU).

T314

52510-52652

Sentence

denotes

Patients were followed up for a median duration of 12 days, during which time most of the COVID-19 patients showed remission of the pneumonia.

T315

52653-52773

Sentence

denotes

Urine dipstick testing in most of the patients with proteinuria and hematuria were reported as negative after follow-up.

T316

52774-52827

Sentence

denotes

The mean time for AKI recovery was seen to be 6 days.

T317

52828-52913

Sentence

denotes

The percentage of patients who developed AKI was increased in patients with diabetes.

T318

52914-53118

Sentence

denotes

In conclusion, despite the high morbidity of kidney impairment, the short-term renal prognosis of those patients is still good: in fact 50% achieved remission in 3 weeks after the onset of their symptoms.

T319

53119-53274

Sentence

denotes

However, adverse short-term outcomes of patients with kidney impairment are also associated with high rate of mortality in COVID-19 infected patients [15].

T320

53275-53457

Sentence

denotes

The pattern described by Richardson regarding AKI was similar to data reported from China: a study [112] of 138 patients with COVID-19 reported that ~4% of COVID-19 patients had AKI.

T321

53458-53611

Sentence

denotes

Huang et al. [23] reported that among 41 patients with COVID-19 infection, 10% had elevated serum creatinine levels on admission and 7% had suffered AKI.

T322

53612-53732

Sentence

denotes

In addition, both blood urea and serum creatinine levels progressively increased along the course of COVID-19 infection.

T323

53733-53926

Sentence

denotes

In comparison with patients with normal serum creatinine levels, those who entered the hospital with high serum creatinine levels were predominantly male and old and were more severely ill too.

T324

53927-54165

Sentence

denotes

Another study [27] involving 193 patients with COVID-19 infection has reported that, at hospital admission, 59% of the patients had proteinuria, 44% hematuria, 14% increase in BUN plasma levels and 10% increase in serum creatinine values.

T325

54166-54279

Sentence

denotes

The abdomen CT showed kidneys with reduced density, suggestive of inflammation and edema of the renal parenchyma.

T326

54280-54414

Sentence

denotes

Li et al. also observed that as many as 28% of COVID-19 patients developed AKI (9% of non-severe patients and 66% of severe patients).

T327

54415-54629

Sentence

denotes

During hospitalization with a median of 2 days, there was an increase in BUN plasma levels in 30% of patients and, with a median of about 5 days, there was an increase in serum creatinine levels in 22% of patients.

T328

54630-54739

Sentence

denotes

As already mentioned, COVID-19 patients with AKI have a higher mortality risk than those without AKI [27,28].

T329

54740-55043

Sentence

denotes

In contrast, patients with chronic illnesses (cardiovascular and cerebrovascular diseases, nervous system diseases, respiratory system diseases, digestive system diseases, urinary system diseases, reproductive system diseases and endocrine system diseases) had only on average ~1.5 times mortality risk.

T330

55044-55134

Sentence

denotes

Furthermore, one study reported a 100% mortality rate for patients with stage 3 AKI [113].

T331

55135-55264

Sentence

denotes

Therefore, the presence of a renal impairment in COVID-19 patients is an important negative prognostic factor for their survival.

T332

55265-55650

Sentence

denotes

However, dissimilar conclusions have been reported by Pei et al. who in a retrospective study, finding renal abnormalities in most of the patients with COVID-19 pneumonia, showed that renal complications in COVID-19 patients were associated with higher mortality, although proteinuria, hematuria and AKI often resolved in such patients within 3 weeks after the onset of symptoms [114].

T333

55651-55786

Sentence

denotes

If conservative treatments fail, RRT should be considered in patients with volume overload, especially those with refractory hypoxemia.

T334

55787-56002

Sentence

denotes

In patients with COVID-19 and AKI, early initiation of RRT and sequential extracorporeal organ support (ECOS) seem to provide adequate organ support and seem to prevent the worsening of the disease’s severity [115].

T335

56003-56432

Sentence

denotes

A high degree of AKI has been reported to require extracorporeal therapies, such as (RRT) in critically ill patients, preferentially utilizing CRRT (continuous renal replacement therapies) for patients in the ICU [115]; recently Nalesso et al. have reported to have designed a continuous veno-venous hemodialysis (CVVHD) with a high cut-off membrane (HCO) in regional citrate anticoagulation (RCA) named by them as RCA-HCO-CVVHD.

T336

56433-56827

Sentence

denotes

This treatment gives several advantages, when comparing it with an equivalent dose in continuous veno-venous hemofiltration, which include a lower effluent volume, fewer bag interventions (hence reducing nurses’ time for this), lower filtration fractions with a higher filter and circuit lifespan and fewer complications with blood flow as a result of central venous catheter malfunction [116].

T337

56828-57078

Sentence

denotes

Grasselli et al., in a study conducted in Italy and involving 1591 ICU patients with COVID-19, have reported that 27% of them required prone ventilation and that Extra Corporeal Membrane Oxygenation (ECMO) was performed in 1% of these patients [117].

T338

57080-57084

Sentence

denotes

7.3.

T339

57085-57135

Sentence

denotes

Clinical Features in Patients in Hemodialysis (HD)

T340

57136-57480

Sentence

denotes

The ERA-EDTA has created a European database that collects individual data of dialysis patients with COVID-19; in the last update dating back to 23rd July, 5596 cases of COVID-19 and 1331 deaths were reported among hemodialysis patients [118].Patients undergoing dialysis have impaired immune systems and have a high risk of infectious disease.

T341

57481-57756

Sentence

denotes

Kwan et al. [119] reported that dialysis patients had a higher rate of contracting SARS compared with an individual from the general population, but both the degree of disease severity and the mortality rate of the dialysis group were similar to the one of the control group.

T342

57757-57922

Sentence

denotes

Based on SARS-CoV-2′s sequence similarity with SARS, it is possible that COVID-19 could follow the same trend as the one of SARS in patients undergoing hemodialysis.

T343

57923-58136

Sentence

denotes

To understand the clinical features of COVID-19 infection, it is of interest to consider the first multicenter study focused on 7154 patients undergoing long term hemodialysis in 65 centers in Wuhan (China) [120].

T344

58137-58323

Sentence

denotes

Among all patients in HD, 154 had laboratory-confirmed COVID-19 tests with an incidence of COVID-19 infection in 2% of patients, which is much higher than that of the general population.

T345

58324-58587

Sentence

denotes

This may be explained with the advanced age of the dialysis population, to the altered immune systems because of their uremic condition and the significant comorbidities that accompany this group, like cardiovascular disease, diabetes and cerebrovascular disease.

T346

58588-58696

Sentence

denotes

Among 154 patients with COVID-19, 77% were mild/moderate patients, whilst 23% were severe/critical patients.

T347

58697-58841

Sentence

denotes

The primary causes of end stage kidney disease (ESKD) in patients with severe/critical disease were similar to those with mild/moderate disease.

T348

58842-59007

Sentence

denotes

The presence of cardiovascular disease was more likely to be present in patients with severe/critical infectious disease than among those with mild/moderate disease.

T349

59008-59238

Sentence

denotes

Moreover, there were no significant differences between severe/critical and mild/moderate COVID- 19 infection regarding age, gender, smoking status and complications like diabetes, chronic obstructive pulmonary disease and cancer.

T350

59239-59358

Sentence

denotes

The dialysis model, access, frequency of dialysis had no significant effect on the degree of COVID-19 disease severity.

T351

59359-59525

Sentence

denotes

The most common symptoms, especially in the severe/critical group, were: fever, cough, fatigue, sputum production, dyspnea, nausea/vomiting, diarrhea and sore throat.

T352

59526-59892

Sentence

denotes

An interesting case report of one of the first patients with COVID-19 in ESKD suffering from gastrointestinal (GI) problems highlights the importance of considering other clinical presentations of COVID-19 infection and not just focusing on the typical respiratory symptoms, in order to prevent exposure of potentially affected individuals to the general population.

T353

59893-60001

Sentence

denotes

GI symptoms are somewhat unusual and seem to be a delayed clinical presentation of COVID-19 infection [121].

T354

60002-60087

Sentence

denotes

However, some of those symptoms may be difficult to distinguish from uremic symptoms.

T355

60088-60148

Sentence

denotes

Diabetic patients showed more likely symptoms when infected.

T356

60149-60361

Sentence

denotes

The disease symptoms of hemodialysis patients were similar to those of the general population, but only 50% of them had fever and nearly 25% were asymptomatic over the whole clinical course of COVID-19 infection.

T357

60362-60488

Sentence

denotes

Since hemodialysis patients have disorders of B- and T-cell function [122], patients may show atypical clinical presentations.

T358

60489-60577

Sentence

denotes

The most common finding on chest computed tomography was ground-grass or patchy opacity.

T359

60578-60680

Sentence

denotes

These lesions often involved both the lungs; on the other hand, consolidation in lungs was not common.

T360

60681-60883

Sentence

denotes

These radiological findings were similar to those shown in the general population, but sometimes it was difficult to distinguish them from lung changes due to their uremia status or inadequate dialysis.

T361

60884-61151

Sentence

denotes

Data from laboratory tests showed that lymphocytopenia was common in patients described in other reports [26,120], and there was a trend for the decline of lymphocytesin the severe/critical group, which is consistent with the results of other recent clinical reports.

T362

61152-61327

Sentence

denotes

The uremic state of these patients is associated with a wide range of impairments in lymphocyte and granulocyte functions; lymphocytopenia is also common in dialysis patients.

T363

61328-61491

Sentence

denotes

Considering low lymphocyte counts in chronic hemodialysis patients [108], lymphopenia is unlikely to be helpful for identifying individuals infected by SARS-CoV-2.

T364

61492-61654

Sentence

denotes

Procalcitonin levels have similar limitations: in fact, its levels are chronically elevated in hemodialysis patients, even in the absence of severe acute illness.

T365

61655-61734

Sentence

denotes

In addition, the majority of patientshad normal white cell and platelet counts.

T366

61735-61819

Sentence

denotes

Serum albumin levels were also within the normal range for most of the patients too.

T367

61820-62058

Sentence

denotes

Conversely, considering these limitations and the high prevalence of comorbid conditions, COVID-19 pneumonia diagnosis in hemodialysis patients is based on clinical epidemiology, radiographic findings and viral nucleic acid testing [123].

T368

62059-62244

Sentence

denotes

Interestingly, diabetes, as a primary cause of ESKD or a coexisting disorder, was much more common in symptomatic patients affected by COVID-19 and lymphocytopenia was also more severe.

T369

62245-62391

Sentence

denotes

In total, about 40% of patients had at least one compromised organ, including cardiac injury, liver dysfunction, ARDS and a cerebrovascular event.

T370

62392-62589

Sentence

denotes

Most patients undergoing hemodialysis (HD), who were regularly monitored, showed stable clinical conditions in the course of treatment of COVID-19 and pulmonary inflammation was gradually absorbed.

T371

62591-62595

Sentence

denotes

7.4.

T372

62596-62650

Sentence

denotes

Clinical Features in Peritoneal Dialysis Patients (PD)

T373

62651-62864

Sentence

denotes

The Italian report created by SIN has collected individual data of peritoneal dialysis (PD) patients with COVID-19; in the last update dating back to May, 57 cases of COVID-19 and 28 deaths were reported in total.

T374

62865-62957

Sentence

denotes

This report shows a higher rate of mortality, almost 49%, than the general population [124].

T375

62958-63105

Sentence

denotes

Notably, SARS-CoV-2 positivity corresponded with peritoneal dialysis failure, suggesting a possible effect of the virus on the peritoneal membrane.

T376

63106-63275

Sentence

denotes

The first case in the literature which demonstrated SARS-CoV-2 in the peritoneal fluid, was described during an emergency surgical laparotomy in a COVID-19 sick patient.

T377

63276-63497

Sentence

denotes

During the procedure laparotomy, two swabs were obtained from peritoneal fluid and then sent for SARS-CoV-2 detection by specific real-time reverse transcriptase–polymerase chain reaction targeting three SARS-CoV-2 genes.

T378

63498-63605

Sentence

denotes

It was then detected in the peritoneal fluid at a higher concentration than in the respiratory tract [125].

T379

63606-63773

Sentence

denotes

Recently, an Italian study described for the first time the detection of SARS-CoV-2 in the peritoneal waste of a patient with COVID-19 and ESKD on peritoneal dialysis.

T380

63774-63894

Sentence

denotes

The patient showed the following common COVID-19 infection symptoms: fever, cough, myalgia, headache and mild hypoxemia.

T381

63895-64066

Sentence

denotes

Chest computed tomography reported bilateral multiple ground-glass opacities and laboratory tests showed mild lymphopenia, increased C-reactive protein and D-dimer levels.

T382

64067-64193

Sentence

denotes

The patient’s peritoneal dialysate was tested for SARS-CoV-2 by polymerase chain reaction, and was found to be positive [126].

T383

64194-64405

Sentence

denotes

According to the International Society Peritoneal Dialysis (ISPD) strategies regarding COVID-19 in peritoneal dialysis patients, the management of infection is the same for PD patients as for all other patients.

T384

64406-64545

Sentence

denotes

Mild or moderate patients on PD can continue PD treatment as usual, with prescription adjustment according to the usual general evaluation.

T385

64546-64785

Sentence

denotes

Those cases that aresevere or critically severe and requiring life support due to multiple organ dysfunction syndrome, can be temporarily transferred to automated peritoneal dialysis or bedside continuous kidney replacement therapy (CKRT).

T386

64786-64949

Sentence

denotes

As for patients on hemodialysis, it is advisable to keep patients in a ‘dry’ status, so that an increased ultrafiltration may be required if remaining on PD [127].

T387

64951-64955

Sentence

denotes

7.5.

T388

64956-65003

Sentence

denotes

Clinical Features in Kidney Transplant Patients

T389

65004-65242

Sentence

denotes

The European database created by ERA-EDTA [118] (collects individual data of dialysis patients and transplant patients with COVID-19; in the last update dating back to 23 July, 1403 cases of COVID-19 and 276 deaths were reported in total.

T390

65243-65369

Sentence

denotes

Similarly, the last Italian report of SIN observed 218 kidney transplant patients affected by COVID-19, of whom 54 died [124].

T391

65370-65470

Sentence

denotes

Both reports show a higher rate of mortality (ERA-EDTA 19% and SIN 25%) than the general population.

T392

65471-65689

Sentence

denotes

Moreover, as a population living with immunosuppression, the clinical manifestations, treatment and prognosis of COVID-19 pneumonia for renal transplant recipients may differ from those of the general population [128].

T393

65690-65874

Sentence

denotes

The immune response of renal transplant recipients, particularly the T-cell immune response, is significantly suppressed because of the long-term assumption of immunosuppressive drugs.

T394

65875-66146

Sentence

denotes

In the first reported renal transplant recipient with COVID-19 pneumonia described in Wuhan (China) [129], the clinical characteristics were similar to those of other non-transplanted adult patients with COVID-19 pneumonia; at the end, the patient successfully recovered.

T395

66147-66334

Sentence

denotes

However, kidney-transplant recipients appear to be at particularly high risk for critical COVID-19 illness because of both their chronic immunosuppression and coexisting conditions [130].

T396

66335-66642

Sentence

denotes

Recently, at Montefiore Medical Center, NY, 36 consecutive adult kidney-transplant recipients who were positive for COVID-19 were identified [131], and Columbia University Kidney transplant program enrolled 15 kidney transplant recipients who required hospitalization for confirmed COVID-19 infection [132].

T397

66643-66778

Sentence

denotes

Both reports described management, clinical course and outcomes of those patients living with a kidney transplant affected by COVID-19.

T398

66779-66844

Sentence

denotes

Patients were predominantly men, and the median age was 55 years.

T399

66845-66965

Sentence

denotes

The most common comorbidities were the following: hypertension, diabetes mellitus, history of smoking and heart disease.

T400

66966-67071

Sentence

denotes

Almost all patients were receiving tacrolimus, prednisone and mycophenolate mofetil or mycophenolic acid.

T401

67072-67162

Sentence

denotes

The patients reported symptom onset ranging from 1 day to nearly 3 weeks before admission.

T402

67163-67262

Sentence

denotes

The most common initial symptom was fever, but also cough, dyspnea, malaise, diarrhea and myalgias.

T403

67263-67365

Sentence

denotes

Over 50% of the patients had bilateral/multifocal opacities noted on initial chest x-ray radiographic.

T404

67366-67455

Sentence

denotes

Laboratory findings were lymphopenia, thrombocytopenia, low CD3, CD4 and CD8 cell counts.

T405

67456-67555

Sentence

denotes

As inflammatory markers, ferritin levels, C- reactive protein, procalcitonin and D-dimer were high.

T406

67556-67654

Sentence

denotes

Patients who were in a stable condition without major respiratory symptoms were monitored at home.

T407

67655-67966

Sentence

denotes

In another report, among 41 outpatient kidney transplant recipients with suspected or known COVID-19 infection, about one third required hospitalization by the end of their follow-up; there were no differences in demographics or medical comorbidities between those who were or were not admitted to the hospital.

T408

67967-68097

Sentence

denotes

These patients therefore required close clinical monitoring to prevent their organ deterioration until symptoms’ resolution [133].

T409

68098-68357

Sentence

denotes

As reported by Montefiore Medical Center and Columbia University, almost half of the patients had AKI, although none had a kidney biopsy performed to determine the cause, and required intubation and mechanical ventilation between 0 and 9 days after admission.

T410

68358-68526

Sentence

denotes

In particular, Columbia University’s report observed that 27% of their cases required intubation, a proportion that is similar for cases in New York City overall [132].

T411

68527-68599

Sentence

denotes

Among the patients who developed AKI, only 20% of patients required RRT.

T412

68600-68713

Sentence

denotes

At a median follow-up of 21 days, the mortality rate was about 28% of the kidney-transplant recipients [131,132].

T413

68714-68825

Sentence

denotes

Patients were managed with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin.

T414

68826-69051

Sentence

denotes

Therefore, among kidney transplant recipients, overall presentation was similar to the one reported for the general population and more than 50% of the patients were successfully discharged home by the end of follow-up [131].

T415

69052-69198

Sentence

denotes

Regarding treatment of transplant recipients, one challenge was adjusting immunosuppressive agents and at the same time protecting graft function.

T416

69199-69563

Sentence

denotes

When treating pneumonia due to opportunistic virus infections following kidney transplantation, a reduction (or even temporary) discontinuation of immunosuppressant drugs is a common therapeutic strategy, consequently allowing recipients the opportunity to reacquire anti-infection immunity within a short period, which is conducive to eliminating the virus [134].

T417

69564-69836

Sentence

denotes

The Columbia University Kidney Transplant Program’s clinical practice has suggested to delay reintroduction of these drugs for up to 2 weeks after discharge, recognizing that prolonged reduction of immunosuppression therapy increases the risk of allograft rejection [132].

T418

69837-70119

Sentence

denotes

Similarly, Alberici et al., in a single center observational study which was conducted in Italy, described a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in 20 kidney transplant recipients with SARS-CoV-2 pneumonia.

T419

70120-70304

Sentence

denotes

Thus, in this limited cohort of long-term renal transplant patients, SARS-CoV-2 induced pneumonia is characterized by a high risk of renal progression and a significant mortality rate.

T420

70305-70495

Sentence

denotes

Despite on average a relatively benign onset of the disease, a large rate of the patients showed worsening chest radiographs and consequently needed an escalation of the supplemental oxygen.

T421

70496-70645

Sentence

denotes

Of note, 25% of the patients died despite an aggressive approach to immunosuppression withdrawal and early administration of antiviral therapy [130].

T422

70647-70649

Sentence

denotes

8.

T423

70650-70688

Sentence

denotes

Management of the Nephropathic Patient

T424

70689-70864

Sentence

denotes

The patient with chronic kidney disease (CKD) is a fragile patient who in most cases suffers from several comorbidities that predispose to the development of infections [135].

T425

70865-71039

Sentence

denotes

For this reason, after the declaration of the pandemic state by the WHO, protective measures were developed for the patient with CKD without signs of ongoing acute pathology.

T426

71040-71183

Sentence

denotes

All nephrology units have been invited to establish a telemedicine system, through which the clinical progress of the patients may be followed.

T427

71184-71253

Sentence

denotes

In this way, hospital access was limited only for urgent cases [136].

T428

71254-71466

Sentence

denotes

For patients with the need to prepare arterial venous fistula for the initiation of hemodialysis treatment, the centers specializing in vascular access management organized screening of all patients for COVID-19.

T429

71467-71634

Sentence

denotes

Interventions for patients with confirmed or suspected infection needed to be carried out in designated premises with the necessary protection for medical staff [137].

T430

71635-71758

Sentence

denotes

In addition, for kidney transplants, it was necessary to develop preventive measures that could allow for their management.

T431

71759-71982

Sentence

denotes

In particular, each Transplant Center had to evaluate the possibility of performing a kidney transplant in relation to the availability of intensive care units and the risk of ICU admission for the individual patient [138].

T432

71983-72255

Sentence

denotes

In addition, during the course of the COVID-19 pandemic, organ donation and transplantation experienced significant changes: organ authorization decreased by 11%; the number of organs transplanted decreased by 18%; and organ recovery for transplantation fell by 17% [139].

T433

72256-72366

Sentence

denotes

Dialysis patients are even more prone to develop severe infectious diseases than the general population [135].

T434

72367-72535

Sentence

denotes

In fact, in previous epidemics or catastrophic situations, the case fatality rate has always been much higher in dialysis patients than in the general population [137].

T435

72536-72672

Sentence

denotes

In addition, for SARS-CoV-2 infection, patients on hemodialysis treatment have proved to be a population at risk of developing COVID-19.

T436

72673-72901

Sentence

denotes

In most cases, in fact, they are patients of advanced age and with many comorbidities (cardiovascular disease, high blood pressure, diabetes and lung disease) often associated with worse prognosis in COVID-19 patients [140,141].

T437

72902-73033

Sentence

denotes

The logistical aspects associated with dialysis treatment further increase the risk of contraction and transmission of the disease.

T438

73034-73189

Sentence

denotes

The patient on hemodialysis, in fact, must carry out the treatment generally three times a week and this implies the recurrent access to health structures.

T439

73190-73322

Sentence

denotes

Furthermore, the hemodialysis session is performed simultaneously by several patients who inevitably interact with each other [142].

T440

73323-73534

Sentence

denotes

These circumstances, associated with the possibility of non-specific clinical manifestations due to immune suppression related to uremia, cause a higher risk of diffusing the infection in the dialysis ward [83].

T441

73535-73705

Sentence

denotes

In some guidance documents, the possibility of performing home hemodialysis with telematic support of the patient and home visits when necessary was also considered [11].

T442

73706-73871

Sentence

denotes

In other papers, however, the reduction of hemodialysis sessions from 3 to 2 times a week has been indicated as an alternative in patients who tolerate this regimen.

T443

73872-74013

Sentence

denotes

This would reduce the risk of exposure to infections during transport and the probability of spreading to the dialysis unit or hospital [12].

T444

74014-74145

Sentence

denotes

Being prepared for a sudden and high amount of patients, suspected or confirmed, was crucial for the control of COVID-19 infection.

T445

74146-74348

Sentence

denotes

The Chinese Society of Nephrology [143], the Centers for Disease Control and Prevention, and also the various dialysis organizations developed guidelines for dialysis units during the COVID-19 epidemic.

T446

74349-74533

Sentence

denotes

In addition, the EUDIAL ERA-EDTA working group [137] provided recommendations for the prevention and containment of the emerging SARS-CoV-2 pandemic (COVID-19) in hemodialysis centers.

T447

74534-74651

Sentence

denotes

The first step in managing the COVID-19 pandemic in dialysis centers was to ensure training for all healthcare staff.

T448

74652-74829

Sentence

denotes

Doctors, nurses and care-workers have been adequately trained on the prevention measures, on the use and disposal of medical devices and any contaminated clothing/objects [137].

T449

74830-74953

Sentence

denotes

In all the centers, a member of staff was assigned to perform the nasopharynx swabs for COVID-19 polymerase chain reaction.

T450

74954-75119

Sentence

denotes

The indicated professional figures were trained on the correct methods of performing the diagnostic test but also on the type of devices needed during the procedure.

T451

75120-75326

Sentence

denotes

Each operator, in fact, must be equipped with a protective mask (FFP2) capable of filtering 95% of particulates and aerosols in the inhaled air, glasses, mobcap, disposable surgical blouse and gloves [137].

T452

75327-75423

Sentence

denotes

Furthermore, all eligible healthcare staff were trained to perform an accurate telephone triage.

T453

75424-75619

Sentence

denotes

The early recognition of suspect patients allows them to be prepared on their arrival, so that they can direct them towards the most suitable path, avoiding interaction with other patients [136].

T454

75620-75702

Sentence

denotes

The second crucial step concerned the training of patients in the dialysis center.

T455

75703-76014

Sentence

denotes

In fact, it was important that each patient drastically reduced interpersonal interactions outside the dialysis center, limiting exits only to travel to and from dialysis facilities, using individual transport to reach the dialysis center, decreasing contact with family members, especially with children [137].

T456

76015-76148

Sentence

denotes

The pediatric population, in fact, can act as a carrier of the disease often without showing symptoms or showing mild symptoms [144].

T457

76149-76316

Sentence

denotes

All patients also received instructions relating to how and when to perform hand hygiene, the use of face masks and the disposal of these and any contaminated objects.

T458

76317-76576

Sentence

denotes

Family members living with dialysis patients were also sensitized and prompted to follow precautionary procedures, including measuring body temperature, good personal hygiene, frequent hand washing and prompt reporting of potential infected individuals [137].

T459

76577-76658

Sentence

denotes

Of course, organizational adjustments had to be made in dialysis centers as well.

T460

76659-76726

Sentence

denotes

The preventive measures, in fact, must start from the waiting room.

T461

76727-76832

Sentence

denotes

All dialysis centers have had to adapt their waiting rooms to ensure a safe first reception for patients.

T462

76833-77181

Sentence

denotes

It is in fact essential that patients come together in large rooms that can allow a distance of at least 2 m between the patients, equipped with air conditioning and ventilation systems capable of removing particles and droplets of aerosol from the air, equipped with distributors of hydroalcoholic solutions for the hygiene of the hands [137,142].

T463

77182-77295

Sentence

denotes

Additional preventive measures must be implemented in the transition from the waiting room to the treatment room.

T464

77296-77510

Sentence

denotes

All patients must be subjected to temperature measurement and must be encouraged to perform hand hygiene and hygiene of the fistula arm, as well as to practice accurate disinfection of the venipuncture areas [145].

T465

77511-77601

Sentence

denotes

At the end of these steps, the patient equipped with a mask can access the treatment room.

T466

77602-77786

Sentence

denotes

These, like the waiting rooms, must be equipped with suitable air conditioning/ventilation systems and must guarantee a distance of at least 2 m between the individual positions [137].

T467

77787-77992

Sentence

denotes

If patients with suspected symptoms for COVID-19 (fever, cough, conjunctivitis) are identified after the arrival at the Dialysis Center, these must be immediately isolated and subjected to screening tests.

T468

77993-78119

Sentence

denotes

Pending the test results, if hemodialysis treatment is not postponed, the patient should be treated as a confirmed case [145].

T469

78120-78256

Sentence

denotes

Therefore, the patient must dialyze in a default room; the room reserved for HBV positive patients could be adequate if available [142].

T470

78257-78414

Sentence

denotes

If the Center does not have a default room, the patient must wait in an isolated room and receive dialysis treatment at the end of the last shift of the day.

T471

78415-78569

Sentence

denotes

If, at the end of the treatment, the result of the swab is not present yet, it is necessary to proceed with the immediate disinfection of the rooms [137].

T472

78570-78661

Sentence

denotes

If the outcome of the swab is negative, patients can return to the dialysis facility [145].

T473

78662-78883

Sentence

denotes

The management of patients on dialysis with confirmed COVID-19 infection must be carried out according to strict protocols in order to minimize the risk for both other patients and personnel taking care of these patients.

T474

78884-79108

Sentence

denotes

Most of the guidelines suggest that dialysis patients, a cause of their management complexity, their fragility and their risk of sudden decompensating, whenever possible, should be hospitalized until complete recovery [145].

T475

79109-79340

Sentence

denotes

The hemodialysis sessions, in this case, can be regularly performed in rooms in isolation or, alternatively, at the patient’s bed with machines usually used for patients with acute renal failure or home hemodialysis machines [136].

T476

79341-79564

Sentence

denotes

In the case of an infected patient with mild symptoms and not hospitalized, the hemodialysis sessions must be performed as his therapeutic scheme, in an isolated environment with appropriately organized medical staff [146].

T477

79565-79870

Sentence

denotes

All personnel involved in the direct care of COVID-19 patients must undertake full protection, including hair caps, gloves, long-sleeved waterproof isolation clothing, goggles and medical masks (FFP2 or FFP3 mask, if available) filtering 95–99% of particulate matter and aerosols in inhaled air [137,147].

T478

79871-80024

Sentence

denotes

It is important not only to avoid contact of these patients with healthy patients, but also to prevent the mixing of suspected and confirmed cases [137].

T479

80025-80258

Sentence

denotes

If there are more infected, asymptomatic or paucisymptomatic patients in the same Center, without the need for hospitalization, they can be dialyzed together in a specific section of the unit, preferably as the last shift of the day.

T480

80259-80379

Sentence

denotes

A select group of healthcare professionals must be assigned to these patients and must apply all precautionary measures.

T481

80380-80548

Sentence

denotes

The hemodialysis room must be properly sanitized at the end of the session and medical waste must be considered highly infectious and disposed of accordingly [137,142].

T482

80549-80841

Sentence

denotes

In case of peripheral centers without the possibility of creating conditions for isolation, and where an infectious disease unit and intensive care unit are both not available, patients with suspected or confirmed COVID-19 disease should be moved into hospitals having these facilities [145].

T483

80842-80943

Sentence

denotes

Management of the peritoneal dialysis patient was less complex than that of the hemodialysis patient.

T484

80944-81083

Sentence

denotes

In fact, they usually carry out purification treatment at their home and go to the nephrological center only for scheduled periodic checks.

T485

81084-81205

Sentence

denotes

The pandemic from COVID-19 has made the expansion of a telemedicine network necessary to manage patients from home [124].

T486

81206-81294

Sentence

denotes

Telematic support was also indispensable for the management of the transplanted patient.

T487

81295-81528

Sentence

denotes

Kidney transplant patients need to perform periodic checks at the post-transplant surgery of the nephrological structure of territorial jurisdiction and at the post-transplant surgery of the Center where the transplant was performed.

T488

81529-81639

Sentence

denotes

Telemedicine techniques have made it possible to monitor patients remotely and reduce outpatient visits [136].

T489

81640-81785

Sentence

denotes

Finally, in many hospitals the ordinary nephrological hospitalization wards have been closed due to the need to make space for the “COVID areas”.

T490

81786-81994

Sentence

denotes

The setting up of a single room for patients awaiting the result of the screening buffer for COVID-19, was fundamental for the restart of admissions for nephrology patients requiring hospital treatment [136].

T491

81995-82223

Sentence

denotes

It is important to emphasize that current guidelines and recommendations relating to the management of renal patients must be considered “provisional” and must undergo continuous reviews and updates in light of new developments.

T492

82225-82244

Sentence

denotes

Overview of Therapy

T493

82245-82357

Sentence

denotes

COVID-19 treatment is essentially supportive and, in fact, specific vaccines or therapies are not yet available.

T494

82358-82434

Sentence

denotes

The COVID-19 vaccine is considered to be an effective prophylactic strategy.

T495

82435-82535

Sentence

denotes

About 90 institutions around the world are working on identifying a specific and safe vaccine [148].

T496

82536-82660

Sentence

denotes

As of 8 April 2020, the global research and development landscape for COVID-19 vaccines has included 115 vaccine candidates.

T497

82661-82958

Sentence

denotes

Most of these are currently in the preclinical phase and only some of these (mRNA-1273 from Moderna, Ad5-nCoV from CanSino Biologicals, INO-4800 from Inovio and LV-SMENP-DC and pathogen-specific aAPC from Shenzhen Geno-Immune Medical Institute) have recently moved into clinical development [149].

T498

82959-83125

Sentence

denotes

The therapeutic protocols used for the general population have also been adopted in patients with chronic renal failure, regardless of the stage of the disease [150].

T499

83126-83440

Sentence

denotes

Antiviral drugs (Lopinavir/ritonavir (200/50 mg 2 cp × 2/day), Darunavir (800 mg/day), Ritonavir (100 mg/day), Darunavir/cobicistat (800/150 mg/day)) have been effective for the management of SARS-CoV-2 infection, in asymptomatic/paucisymptomatic patients and in patients with more severe manifestations [150,151].

T500

83441-83670

Sentence

denotes

Hydroxychloroquine (known as an antimalarial drug) was successfully used in the early stages of the pandemic until May 26th, 2020, when AIFA suspended authorization for its use for the treatment of SARS-CoV-2 infection [152,153].

T501

83671-83903

Sentence

denotes

Tocilizumab (anti-IL-6 monoclonal antibody) has been used in association with steroids and/or antiviral drugs, for the treatment of more severe clinical cases and patients with rapidly and significantly increasing levels of D-dimer.

T502

83904-84026

Sentence

denotes

The dosage is 8 mg/kg body weight with a maximum infusion dose of 800 mg for a maximum of three administrations [154,155].

T503

84027-84184

Sentence

denotes

Unlike hydroxychloroquine, both antiviral drugs and tocilizumab do not require dosage adjustments in relation to the values of the glomerular filtrate [150].

T504

84185-84394

Sentence

denotes

Given the state of hypercoagulability and the high incidence of thromboembolic complications in COVID-19 patients, high doses of low molecular weight heparin have been added to the therapeutic protocols [156].

T505

84395-84605

Sentence

denotes

For kidney transplant patients, immunosuppressive therapy must be reshaped, in particular, mycophenolate, azathioprine and calcineurin inhibitors must be suspended during the active phases of the disease [150].

T506

84606-84713

Sentence

denotes

Tocilizumab, on the other hand, may be effective in these patients, but randomized trials are needed [157].

T507

84714-85240

Sentence

denotes

For COVID-19 patients undergoing intermittent dialysis, the methods that obtain the greatest clearance of the pro-inflammatory molecules are preferred; in patients with AKI, hemodynamically unstable and requiring dialysis, continuous dialysis treatments are preferred (CVVH with pre and post-dilution at a dose > 25 mL/Kg/h), using citrate as the first choice anticoagulant (after serial assessments of serum calcium and lactic acid) and, alternatively, unfractionated heparin (constantly monitoring the patient’s APPT) [150].

T508

85241-85475

Sentence

denotes

Interferons have also been proposed as a possible therapy, although the timing of their use is critical since their benefit is realized if given before or early on in infection and may actually be harmful if given in the later stages.

T509

85476-85535

Sentence

denotes

Clinical studies are underway to test their efficacy [158].

T510

85536-85742

Sentence

denotes

A recent phosphoproteomics analysis of SARS-CoV-2 infected Vero E6 cells (a cell line derived from monkey kidney epithelial cells) showed dramatic changes in phosphorylation of both host and viral proteins.

T511

85743-85876

Sentence

denotes

Furthermore, viral infection induced the formation of casein kinase II (CK2)-containing filopodia containing budding viral particles.

T512

85877-86061

Sentence

denotes

The authors have stated that pharmacologic inhibition of several kinases including CK2 and p38 MAP (mitogen-activated protein) kinases may be potential future COVID-19 therapies [159].

T513

86062-86130

Sentence

denotes

A summary of the main contents of this paper is depicted in Table 1.

T514

86132-86152

Sentence

denotes

Author Contributions

T515

86153-86436

Sentence

denotes

Conceptualization, M.A., I.G. and G.P.; investigation, I.G., G.P., M.P. and M.A.; visualization, I.G., G.P., M.P. and M.A.; writing—original draft preparation, I.G., G.P., A.M., R.S., M.P. and M.A.; writing—review and editing, I.G., G.P., A.M., R.S., M.P. and M.A.; supervision, M.A.

T516

86437-86513

Sentence

denotes

All authors have read and agreed to the published version of the manuscript.

T517

86515-86522

Sentence

denotes

Funding

T518

86523-86566

Sentence

denotes

This research received no external funding.

T519

86568-86589

Sentence

denotes

Conflicts of Interest

T520

86590-86635

Sentence

denotes

The authors declare no conflicts of interest.

T521

86637-86746

Sentence

denotes

Figure 1 Pathophysiological mechanisms of kidney damage associated with coronavirus disease 2019 (COVID-19).

T522

86747-86812

Sentence

denotes

Figure 2 Histological features of kidney from COVID-19 patients.

T523

86813-86876

Sentence

denotes

Table 1 Summary of the main evidence emerging from the review.

T524

86877-86892

Sentence

denotes

- Key-Messages

T525

86893-87169

Sentence

denotes

Epidemiology The most common chronic preexisting diseases in deceased COVID-19 patients were diabetes mellitus, COPD, arterial hypertension, atrial fibrillation, chronic kidney disease (CKD), active cancer within the previous 5 years, ischemic heart disease and obesity [19].

T526

87170-87249

Sentence

denotes

CKD was present in more than 20% of the deceased patients due to COVID-19 [20].

T527

87250-87460

Sentence

denotes

Pathophysiology SARS-CoV-2 invades the target cells through a multi-step process that involves cell internalization through interaction with the ACE-2 receptor and priming by the cell protease TMPRSS2 [35,62].

T528

87461-87622

Sentence

denotes

The spike glycoprotein receptor binding domain (RBD) has biomolecular characteristics that are probably responsible for the greater diffusion of SARS-CoV-2 [42].

T529

87623-87757

Sentence

denotes

The renal damage observed in COVID-19 patients is the result of complex mechanisms induced directly and indirectly by SARS-CoV-2 [35].

T530

87758-87923

Sentence

denotes

The two main pathophysiological mechanisms of kidney damage are direct cytopathic effect of SARS-CoV-2 on renal epithelial cells and cytokine storm syndrome [64,71].

T531

87924-88131

Sentence

denotes

Hypoxia, persistent hypotension, rhabdomyolysis, over activation of the coagulation cascade and impairment of microcirculation play a role in the predisposition to the development of acute renal damage [64].

T532

88132-88266

Sentence

denotes

Histopathology SARS-CoV-2 infection induces acute tubular necrosis through direct cytotoxicity and in immune mediated damage [62,63].

T533

88267-88320

Sentence

denotes

Light microscopy: acute renal proximal tubule injury.

T534

88321-88423

Sentence

denotes

Immunohistochemistry: viral nucleocapsid protein into the renal tubular cells of the infected tissues.

T535

88424-88579

Sentence

denotes

Transmission electron microscopy: viral inclusion bodies in a peritubular space and viral particles in endothelial cells of the glomerular capillary loops.

T536

88580-88759

Sentence

denotes

Clinical Features COVID-19 patients with elevated baseline serum creatinine are more likely to be admitted to the intensive care unit and to undergo mechanical ventilation [106].

T537

88760-88833

Sentence

denotes

Kidney disease on admission is a higher risk of negative prognosis [106].

T538

88834-88926

Sentence

denotes

COVID-19 patients with AKI had ~5.3 times mortality risk higher than those without AKI [25].

T539

88927-89004

Sentence

denotes

The incidence of AKI in the overall cohort was in a range of 4.7–7.5% [8,15].

T540

89005-89241

Sentence

denotes

Dialysis patients have a higher rate of contracting SARS compared with the one of the general population, but both the degree of disease severity and the mortality rate of the dialysis group were similar to the general population [113].

T541

89242-89379

Sentence

denotes

SARS-CoV-2 was detected in peritoneal fluid; peritoneal dialysis patients have a higher mortality rate than the general population [119].

T542

89380-89623

Sentence

denotes

Kidney transplant patients have a higher mortality rate than the general population; the clinical manifestations were similar to those reported for the general population, more than half of the patients were successfully discharged home [119].

T543

89624-89959

Sentence

denotes

Management The diffusion of hygienic-behavioral rules among nephropathic patients and the preventive measures implemented in the various nephrological centers have proven effective in containing the diffusion of COVID-19 among patients with chronic kidney disease (on dialysis and non-dialysis) and transplanted kidney patients [137].

T544

89960-90014

Sentence

denotes

There is no vaccine and therapy specific for COVID-19.

T545

90015-90083

Sentence

denotes

Most of vaccine candidates are still in the preclinical phase [149].

T546

90084-90307

Sentence

denotes

Chronic renal failure patients receive the same therapeutic protocols as the general population; these include antiviral drugs, tocilizumab, low molecular weight heparin, hydroxychloroquine (recently stopped by AIFA) [150].

T547

90308-90372

Sentence

denotes

Interferons have also been proposed as a possible therapy [158].

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