7. Clinical Features
Most COVID-19 infections are not severe, with the spectrum of symptoms ranging from mild to critical.
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: 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]. 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]. COVID-19 infection is frequently severe among patients of advanced age and other medical comorbidities. 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].
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. Other reported symptoms can include the following: headache, sore throat, rhinorrhea and conjunctivitis [93]. 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]. However, common symptoms in patients infected by COVID-19 are smell and taste disorders (e.g., anosmia and dysgeusia) [93]. Gastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain and diarrhea) have also been described [94]. There have been rare dermatological reports of erythematous rash, widespread urticaria and chickenpox-like vesicles and transient livedo reticularis [11]. 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.
As mentioned previously, epidemiological data from many countries report that children make up a small minority of those who test positive. 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]. 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]. The emergence of a severe Kawasaki-like disease in children related to COVID-19 has now shifted focus on the vulnerability of children [99]. It is a rare acute pediatric vasculitis, with the development of coronary artery aneurysms as its main complication. Diagnosis of this disease is based on the presence of persistent fever, lymphadenopathy, conjunctival injection exanthema and changes to the mucosae and extremities. 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. 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].
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. Other reported complications are acute cardiac injury, arrhythmias, AKI and shock [25]. Thromboembolic complications, including pulmonary embolism and acute stroke, have also been reported [101].

7.1. Clinical Features in Patients with Chronic Kidney Disease (CKD)
Chronic kidney disease (CKD) seems to be associated with enhanced risk of severe COVID-19 infection and mortality. Cheng et al. evaluated the association between markers of renal impairment and death in a cohort of 701 COVID-19 patients. 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. Estimated glomerular filtration rate < 60 mL/min per 1.73 m2was found in 13.1% of patients [8]. 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. These hazard ratios (HR)were higher than risk factors such as advanced age (HR: 2.43), severe disease (HR: 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].
This significant association of CKD with severe COVID-19 infection was observed also in the meta-analysis by Lippi [21]. This can be explained by the pro-inflammatory state and by the alterations of the innate and adaptive immune response associated with CKD. This immune profile increases susceptibility to all infections [104]. 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. 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]. Among these comorbidities, the presence of chronic kidney disease is an independent risk factor of poor prognosis. 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]. 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]. 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]. 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). 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. 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. 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. 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.

7.2. Clinical Features in Patients with Acute Kidney Injury (AKI)
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]. AKI represents a life-threatening complication, often leading to increased risk of death. 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. 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. 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. Patients with increased baseline serum creatinine levels were more likely to develop AKI (11.9%) than patients with normal baseline values (4.0%). 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. 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]. In ARDS, patients age, severity of illness and the presence of diabetes are all risk factors for acute kidney injury. Furthermore, the patient’s BMI value and any previous history of heart failure may also be associated with the severity of AKI. All these risk factors may count for the higher incidence of AKI in the elderly. 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. They found that among those with AKI, 694 died (35%), 519 (26%) were discharged and 780 (39%) were still hospitalized. 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. 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. 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. 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].
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]. 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. Males and those with pre-existing hypertension and/or diabetes were highly prevalent among 5700 case series with a median age of 63 years. In this study, AKI was observed among 8.4% discharged live patients and among 63% dead patients. On hospital admission, a significant percentage of patients had renal impairment, presenting proteinuria and hematuria. AKI incidence in the overall cohort was in the range of 4.7–7.5%. A higher incidence of proteinuria and hematuria was reported in patients with severe or critically ill COVID-19 pneumonia. 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. Almost 50% of the critically ill cases developed AKI during hospitalization, especially those who were in the intensive care unit (ICU). 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. Urine dipstick testing in most of the patients with proteinuria and hematuria were reported as negative after follow-up. The mean time for AKI recovery was seen to be 6 days. The percentage of patients who developed AKI was increased in patients with diabetes. 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. However, adverse short-term outcomes of patients with kidney impairment are also associated with high rate of mortality in COVID-19 infected patients [15].
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. 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. In addition, both blood urea and serum creatinine levels progressively increased along the course of COVID-19 infection. 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. 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. The abdomen CT showed kidneys with reduced density, suggestive of inflammation and edema of the renal parenchyma. 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). 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. As already mentioned, COVID-19 patients with AKI have a higher mortality risk than those without AKI [27,28]. 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. Furthermore, one study reported a 100% mortality rate for patients with stage 3 AKI [113]. Therefore, the presence of a renal impairment in COVID-19 patients is an important negative prognostic factor for their survival. 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]. If conservative treatments fail, RRT should be considered in patients with volume overload, especially those with refractory hypoxemia. 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]. 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. 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]. 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].

7.3. Clinical Features in Patients in Hemodialysis (HD)
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. 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. 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. 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]. 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. 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. Among 154 patients with COVID-19, 77% were mild/moderate patients, whilst 23% were severe/critical patients. The primary causes of end stage kidney disease (ESKD) in patients with severe/critical disease were similar to those with mild/moderate disease. 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. 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. The dialysis model, access, frequency of dialysis had no significant effect on the degree of COVID-19 disease severity. The most common symptoms, especially in the severe/critical group, were: fever, cough, fatigue, sputum production, dyspnea, nausea/vomiting, diarrhea and sore throat. 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. GI symptoms are somewhat unusual and seem to be a delayed clinical presentation of COVID-19 infection [121]. However, some of those symptoms may be difficult to distinguish from uremic symptoms. Diabetic patients showed more likely symptoms when infected. 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. Since hemodialysis patients have disorders of B- and T-cell function [122], patients may show atypical clinical presentations. The most common finding on chest computed tomography was ground-grass or patchy opacity. These lesions often involved both the lungs; on the other hand, consolidation in lungs was not common. 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.
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. 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. Considering low lymphocyte counts in chronic hemodialysis patients [108], lymphopenia is unlikely to be helpful for identifying individuals infected by SARS-CoV-2. Procalcitonin levels have similar limitations: in fact, its levels are chronically elevated in hemodialysis patients, even in the absence of severe acute illness. In addition, the majority of patientshad normal white cell and platelet counts. Serum albumin levels were also within the normal range for most of the patients too. 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]. 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. In total, about 40% of patients had at least one compromised organ, including cardiac injury, liver dysfunction, ARDS and a cerebrovascular event. 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.

7.4. Clinical Features in Peritoneal Dialysis Patients (PD)
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. This report shows a higher rate of mortality, almost 49%, than the general population [124]. Notably, SARS-CoV-2 positivity corresponded with peritoneal dialysis failure, suggesting a possible effect of the virus on the peritoneal membrane. 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. 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. It was then detected in the peritoneal fluid at a higher concentration than in the respiratory tract [125]. 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. The patient showed the following common COVID-19 infection symptoms: fever, cough, myalgia, headache and mild hypoxemia. Chest computed tomography reported bilateral multiple ground-glass opacities and laboratory tests showed mild lymphopenia, increased C-reactive protein and D-dimer levels. The patient’s peritoneal dialysate was tested for SARS-CoV-2 by polymerase chain reaction, and was found to be positive [126]. 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. Mild or moderate patients on PD can continue PD treatment as usual, with prescription adjustment according to the usual general evaluation. 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). 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].

7.5. Clinical Features in Kidney Transplant Patients
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. Similarly, the last Italian report of SIN observed 218 kidney transplant patients affected by COVID-19, of whom 54 died [124]. Both reports show a higher rate of mortality (ERA-EDTA 19% and SIN 25%) than the general population. 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]. 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. 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.
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]. 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]. Both reports described management, clinical course and outcomes of those patients living with a kidney transplant affected by COVID-19. Patients were predominantly men, and the median age was 55 years. The most common comorbidities were the following: hypertension, diabetes mellitus, history of smoking and heart disease. Almost all patients were receiving tacrolimus, prednisone and mycophenolate mofetil or mycophenolic acid. The patients reported symptom onset ranging from 1 day to nearly 3 weeks before admission. The most common initial symptom was fever, but also cough, dyspnea, malaise, diarrhea and myalgias. Over 50% of the patients had bilateral/multifocal opacities noted on initial chest x-ray radiographic. Laboratory findings were lymphopenia, thrombocytopenia, low CD3, CD4 and CD8 cell counts. As inflammatory markers, ferritin levels, C- reactive protein, procalcitonin and D-dimer were high. Patients who were in a stable condition without major respiratory symptoms were monitored at home. 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. These patients therefore required close clinical monitoring to prevent their organ deterioration until symptoms’ resolution [133]. 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. 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]. Among the patients who developed AKI, only 20% of patients required RRT. At a median follow-up of 21 days, the mortality rate was about 28% of the kidney-transplant recipients [131,132]. Patients were managed with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin.
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]. Regarding treatment of transplant recipients, one challenge was adjusting immunosuppressive agents and at the same time protecting graft function. 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]. 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].
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. 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. 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. Of note, 25% of the patients died despite an aggressive approach to immunosuppression withdrawal and early administration of antiviral therapy [130].