The COVID-19 nephrology compendium: AKI, CKD, ESKD and transplantation

The pandemic of coronavirus disease 2019 (CoVID-19) has been an unprecedented period. The disease afflicts multiple organ systems, with acute kidney injury (AKI) a major complication in seriously ill patients. The incidence of AKI in patients with CoVID-19 is variable across numerous international studies, but the high incidence of AKI and its associated worse outcomes in the critical care setting are a consistent finding. A multitude of patterns and mechanisms of AKI have been elucidated, and novel strategies to address shortage of renal replacement therapy equipment have been implemented. The disease also has had consequences on longitudinal management of patients with chronic kidney disease and end stage kidney disease. Kidney transplant recipients may be especially susceptible to CoVID-19 as a result of immunosuppression, with preliminary studies demonstrating high mortality rates. Increased surveillance of disease with low threshold for testing and adjustment of immunosuppression regimen during acute periods of illness have been recommended.


Background
The coronavirus disease 2019 (CoVID-19) pandemic has strained medical systems globally. The disease results from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and it results in multiorgan injury including the kidneys. The disease has unique implications for patients developing acute kidney injury (AKI), as well as patients with chronic kidney disease (CKD) or end stage kidney disease (ESKD) and kidney transplant recipients (KTR). In this review, we provide a comprehensive overview of the effect of CoVID-19 on these aspects of kidney disease.
We elucidate the epidemiology and associated clinical characteristics of AKI by analyzing various studies that have reported outcomes related to AKI and renal replacement therapy (RRT). We also discuss the mechanisms and patterns of AKI. In the CKD and ESKD sections we discuss the controversy of renin angiotensin system blockade, along with recommendations for managing patients on chronic dialysis in the era of CoVID-19. Kidney transplantation requires particular emphasis during the pandemic due to concern for increased susceptibility to infection. The segment on kidney transplantation incorporates current outcomes of kidney transplant patients with CoVID-19 and recommendations for management of immunosuppression. Finally, we highlight a need for consideration of how the CoVID-19 pandemic is impacting socially disadvantaged populations known to experience worse outcomes in kidney disease.

United Kingdom and France
Hospital groups from the UK and France have largely focused on patients in the critical care setting. In the study from the UK (n = 6143), 24% required renal replacement therapy, and of these, 95.3% required advanced respiratory support (invasive ventilation, extracorporeal respiratory support) and 71% died [6]. A smaller study from Bordeaux (n = 71) demonstrated higher mortality in patients with AKI, and 64% of surviving patients recovered kidney function by day 21 of follow up [24]. Similar to data from China, less than 6% of patients in both studies had CKD. A larger dataset from the UK (n = 20,133), however, found that 16.2% of patients with COVID-19 had CKD [26]. A prospective cohort study from Spain (n = 1603) demonstrated that an increased serum creatinine on arrival was a risk factor for poor outcome, whether it is present acutely or as a consequence of CKD [25].

United States
New York City and New Orleans, Louisiana, were 2 of the more intensely affected regions of the United States. In New York, 2 large cohorts revealed AKI rates in excess of 20%, with higher proportion of CKD patients affected (10-28%) in comparison to data from China and Europe. The New Orleans (n = 575), Mount Sinai (n = 3235), Montefiore (n = 3345), and Northwell (n = 5449) hospital groups have specifically assessed AKI and associated outcomes over 5-7 weeks, with the following findings:  [7]. AKI in hospitalized patients is associated with significant risk for inhospital death (incidence rate of in-hospital death: 37.5/1000 patient-days in those with AKI vs 10.8/ 1000 patient-days in those without) [33]. 9. 43% (211/486) of patients with AKI had evidence of persistent abnormal kidney function at discharge [7].

Summary of outcomes
There is evidence of disparate incidence and outcomes of AKI across the 3 continents, with AKI reported in 0.5-46%. Reports from Europe and the United States describe a greater burden of co-morbid disease in association with the higher rates of AKI. Additionally, the prevalence of CKD, which is a risk factor for AKI, has Legend: G-general ward, I-intensive care unit, NR-not reported, CKD-chronic kidney disease, CVD-cardiovascular and cerebrovascular disease, HTN-hypertension, WBC-white blood cell, BUN-blood urea nitrogen, ESKD-end stage kidney disease, RRT-renal replacement therapy, CHF-congestive heart failure, DM-diabetes mellitus, BP-blood pressure, SOFA-sequential organ failure assessment a -utilized KDIGO guidelines. b -Data from the same hospital system not been reported in most studies from China, with a low proportion of disease (~2%) reported in recent studies. This could be explained by absence of baseline creatinine values and/or utilization of differing criteria for diagnosis. AKI often develops early during hospitalization, with 37-57% of patients developing AKI within 0-4 days of admission [9,10]. Severity of pneumonia was commonly associated with lower chance of renal recovery and lower remission of proteinuria or hematuria [22]. The highest incidence of AKI (19-90%) occurs in the critical care setting, with the majority of patients requiring RRT also supported with mechanical ventilation [10].
AKI is associated with increased length of stay and mortality [7,13,16,22], and this is supported by 2 meta-analyses demonstrating AKI to be an unfavorable clinical predictor associated with high mortality [34,35]. Development of AKI appears to be a consequence of severity of illness, and its occurrence portends a worse prognosis. Current studies demonstrate up to half of patients with AKI did not recover to baseline creatinine levels and may have persistent CKD [7,22]. Given the lack of long-term follow-up of hospitalized patients to date, the AKI recovery rate remains unknown.

Mechanisms and patterns of injury
AKI in patients with CoVID-19 is postulated to occur via multiple, often co-existing mechanisms ( Table 2).
Acute tubular injury is the most common etiology of AKI based on autopsy and biopsy reports [18,22,23,40,51,52,59], and lymphocytic infiltration is commonly present. Proximal tubular dysfunction has been demonstrated in a subset of patients with COVID-19, with resultant hypouricemia and inappropriate uricosuria correlating with disease severity and respiratory decompensation [60]. Microangiopathic injury has been infrequently observed in autopsy and biopsy series to date [52]. Hypercoagulability is a well-recognized feature of CoVID-19, although most attention has been focused on pulmonary microangiopathy, venous thromboembolism, and stroke. Terminal complement activation (C5b-9) has been demonstrated in kidney, lung, and skin, although the mechanisms underlying complement activation remain to be clarified. It has been suggested complement and neutrophil extracellular traps generate a coagulopathic milieu leading to formation of microthrombi, thereby leading to severe manifestations of COVID-19 such as lung and cardiac injury [61]. It is intriguing that despite the susceptibility of the kidney to thrombotic microangiopathy in general, most of the microangiopathic injury in CoVID-19 has been documented in extra-renal organs [18,62,63].
Hematuria (27-53%) and proteinuria (36-66%) are common, with higher rates reported in patients with AKI [13,20,22,64]. Proteinuria is often transient, similar to Middle East Respiratory Syndrome (MERS)-CoV, although the mechanism is not known with certainty. It may be a consequence of fever, systemic inflammation, or possibly direct viral infection of renal epithelium [3,22]. Nevertheless, the severity of proteinuria and hematuria is associated with an increased risk of mortality in patients with CoVID-19 [13]. Hematuria is often multifactorial in origin, and detailed studies on the mechanism of hematuria are lacking.
Lastly, collapsing glomerulopathy has been reported in the context of COVID-19 infection [9,[51][52][53][54]. Not surprisingly, this lesion has developed in patients homozygous for APOL1 G1 risk alleles. This pattern of injury is most strongly associated with viral infection, particularly HIV and parvovirus. This finding suggests the presence Table 2 Patterns and associated mechanisms of acute kidney injury in patients with COVID-19

Pattern
Mechanisms of Injury Viral cytopathic effect Proteins critical for mediating cellular SARS-CoV-2 infection-ACE2, TMPRSS2, and CTSL-are highly expressed in kidney [18,[36][37][38][39]. Expression is mainly localized to the apical brush border of proximal tubular cells and podocytes [36]. Viral protein and RNA have been demonstrated at the cellular level in kidney tissue, supporting a potential role for direct viral infection in the pathogenesis of AKI [18,[38][39][40][41]. Studies have demonstrated presence of mRNA in post mortem kidney tissues and its presence may correlate with clinical outcomes [42]. However, the specificity of these reports have been questioned, and the actual presence of replicating virus in renal epithelium remains controversial [43][44][45], as nucleic acid tests and immunohistochemistry failed to detect the virus in kidney tissues [23].
Hemodynamic compromise AKI is more common in patients requiring mechanical ventilation and vasopressor support [7,10]. Inadequate volume resuscitation and tissue hypoperfusion may lead to AKI. Hemodynamic compromise from pulmonary embolism, right ventricular dysfunction, and myocardial injury may contribute [46,47].
of a high risk APOL1 genotype and may increase the risk for interferon mediated podocyte injury due to CoVID-19. Homozygosity for high-risk APOL1 alleles is present in 14% of African Americans, who collectively represent 12.9% of the US population but have suffered an estimated 25.1% of U.S. COVID-19 deaths [53,54]. It remains to be determined if infection will lead to increased rates of CKD/ESKD in this population as compared to other groups.

Renal replacement therapy
Reported rates of RRT also vary widely, with overall rates of 2-73% in the critical care setting [6,7,14,64]. The rapid surge of patients requiring RRT has led to shortages of staffing, dialysis machines, and dialysis fluid, particularly for continuous renal replacement therapy (CRRT). At the time of writing, several states in the US are expected to experience CRRT equipment shortages during the pandemic based on mathematical models [65]. This has accelerated interest in hybrid therapies such as prolonged intermittent RRT (PIRRT) with careful titration of therapy fluid rates to minimize waste [63,66,67]. Protocols for on-site preparation of CRRT therapy fluid have been described by multiple groups including Vanderbilt University Medical Center, Cleveland Clinic, and Johns Hopkins Hospital [68][69][70]. The pandemic has helped rejuvenate the utilization of acute peritoneal dialysis (PD), and data suggest the increased peritoneal pressure in setting of ARDS does not worsen hypoxemia or respiratory mechanics [71][72][73]. Acute PD, however, may not be suitable for prone patients. Nevertheless, even vascular access is challenging in prone patients, although skilled operators can often still insert internal jugular catheters and novel access sites such as the popliteal vein have been reported [74]. Low copies of viral RNA are present in the effluent of both PD and hemodialysis (HD) [75,76], but there has not been isolation of infectious virus from these fluids. Current guidelines do not recommend special decontamination of effluent, and effluent should be discarded in accordance with standard practice.

Chronic kidney disease
While there has been extensive early reporting on the impact of CoVID-19 on the kidneys in the acute setting, and the association of worse short-term outcomes including in-hospital mortality in patients with any kidney involvement, much less has been published on the impact of CoVID-19 in patients with underlying CKD. However, prior research has demonstrated that patients with CKD, and particularly those with ESKD, have been found to have immune dysregulation and increased susceptibility for infections [77]. In addition, large national organizations such as the National Kidney Foundation have published general guidelines for the care of patients with CKD in the setting of CoVID-19 [78]. Patients with any degree of CKD, for instance, have been recommended to adhere strictly to guidelines on the importance of self-isolation, and when it becomes necessary, to use face masks in public and avoid or limit exposure to large gatherings of people. For many patients with CKD, renin-angiotensinaldosterone system (RAAS) blockade is a mainstay of therapy. However, there has been some controversy regarding the use of RAAS blockade in the setting of COVID-19. SARS-CoV-2, similar to the SARS-CoV-1 virus that originated in 2003, uses the angiotensinconverting enzyme 2 (ACE2) receptor for viral entry [79]. ACE2 is widely expressed in a number of tissues, including the type 2 alveolar cells of lung epithelium and renal tubular epithelial cells [79]. While the more commonly recognized ACE converts angiotensin I to angiotensin II, ACE2 converts angiotensin II to angiotensin- [1][2][3][4][5][6][7], which acts on the Mas receptor present in many tissues throughout the body. This pathway ultimately leads to vasodilation and the systemic reduction in inflammation, as a counter-regulatory system to the vasoconstriction induced by angiotensin-II binding to angiotensin 1 receptor (AT1R).
The use of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), therefore, has come under more intense scrutiny in the face of this current pandemic [80]. Controversy surrounds the potential detrimental effect of ongoing ACEIs or ARBs use, with potential up regulation of the ACE2 receptor which could then increase the ability of the virus to enter cells. It is also possible that ACEIs help by blocking the ACE2 receptor and blocking viral entry. Over the past several months, a number of large studies have explored the potential association between ACEIs or ARBs use with adverse outcomes, including COVID-19 positivity and mortality, in detail [81,82]. Mancia and colleagues performed a population-based case-control study in Italy and demonstrated that while ACEI and ARB use was more common among patients with COVID-19, they did not find any significant association between ACEI or ARB use with risk of COVID-19 [81]. Reynolds and colleagues conducted a retrospective review of all patients admitted to the New York University Langone Health system tested for COVID-19 from March 1 to April 15, 2020, and demonstrated no substantial increase in the likelihood of COVID-19 test positivity, or severe COVID-19, based on ACEI or ARB use [82].
Various professional societies and councils have also contributed to the debate, with the American Heart Association, American College of Cardiology, and Council on Hypertension of the European Society of Cardiology, all recommending the continued use of ACEIs and ARBs. Within the field of nephrology, investigators across several institutions jointly published a perspective emphasizing the lack of clear evidence for either benefit or risk with ACEIs/ARBs use and COVID-19 [80,83]. Without additional and high-quality clinical trial data, clinical equipoise dictates the continued use of RAAS blockade in patients who are already on these medications for other indications.
End stage kidney disease Among Medicare beneficiaries, patients with ESKD have the highest hospitalization rate for CoVID-19 at 1341 cases per 100,000 [84]. Patients with ESKD who are on home dialysis therapy, either PD or home HD have been able to continue dialysis while safely self-isolating. However, there are a number of unique challenges that patients undergoing in-center HD may face. While the U.S. Centers for Disease Control and Prevention (CDC) has published recommendations to reduce the spread of this highly contagious respiratory pathogen, patients undergoing in-center HD necessarily remain in dialysis units for 3 h or longer, 3 times per week, sometimes surrounded by 20 to 30 other patients, along with dialysis staff including nurses, technicians, and nephrologists. In addition to potential lack of appropriate spacing, patients with ESKD on in-center HD sometimes present to their dialysis units with symptoms of cough and shortness of breath. Such patients may then be denied entry to the HD center and require transfer to a dedicated dialysis unit and shift specific for patients under investigation (PUIs) or those with confirmed CoVID-19.
Additionally, since the start of the pandemic, the use of telemedicine has become increasingly common for the care of patients with ESKD on home therapies [85,86]. Indeed, the International Society of Peritoneal Dialysis has provided recommendations on management of patients receiving PD in the setting of COVID-19 [87]. Overall, the use of telemedicine has allowed for continued follow-up of patients on a monthly basis with specific outlines for how to manage suspected or confirmed COVID-19, in order to minimize exposure risk.
Current recommendations for patients receiving incenter HD include screening upon entry to their dialysis unit to evaluate symptoms (e.g., shortness of breath, cough) and objective measures such as temperature checks [88]. For patients who are cleared, they should be kept at a safe distance from one another for the duration of their HD treatment. While the use of gowns, gloves, and masks have been routinely used by HD center staff at the start and end of each HD treatment, even greater emphasis should be placed on the use of personal protective equipment and hand hygiene, including masking all patients and staff during treatment. Additionally, patients with confirmed CoVID-19 or under investigation for CoVID-19 have been isolated at the level of the HD center. Among HD centers designated to take care of such patients, PUIs and patients with confirmed cases have been dialyzed on separate shifts (typically the last shift of the day), possibly on separate days depending on patient volume at the dialysis center. Another major consideration for these patients is transportation. Public transportation and dedicated mobility transportation, upon which many patients rely to and from HD centers, may not be available to those with confirmed or suspected CoVID-19 infection.

Kidney transplantation
CoVID-19 has posed challenges to the practice of organ transplantation. Kidney transplant recipients (KTRs) are at high risk for illness, due to chronic immunosuppression and co-morbidities [89,90]. A significant temporal association has been observed between increase in CoVID-19 infections and reduction in overall solid organ transplantation procedures [91]. This reduction in transplantation rates has been mostly seen in kidney transplantation, even in regions where CoVID-19 cases are low.

Current experience
At the time of writing this review, there are currently five case series along with cohort studies from US and Europe, that have reported clinical course of KTRs with COVID-19 infection (n = 10-1216) [85,89,[92][93][94][95][96][97][98]. Fever and cough remain the most common symptoms of presentation, although atypical initial presentation with gastrointestinal symptoms has also been reported [99]. These series show a preponderance of male recipients, with median age 51-62 years (Table 3). Duration elapsed since transplantation to presentation with viral disease is highly variable with a range of 2-13 years. Of note, in two of the series, 2 patients had evidence of COVID-19 within 3 months of transplantation [92,94]. Most of the KTRs on presentation were on maintenance immunosuppression comprising of tacrolimus (FK), mycophenolate mofetil (MMF) and prednisone. A high proportion of patients experienced AKI (30-57%) with variable rates of RRT (5-43%). Even accounting for a sizeable number of KTRs still being inpatient at the time of publication of these case series, mortality is as high as 32% [95].

Management of immunosuppression
In-vitro studies have demonstrated that calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus strongly inhibit the growth of coronavirus via inhibition of cyclophilin and immunophilin pathways [100,101]. It is not known whether this effect of CNIs translates into clinical efficacy against the virus, but the current recommendation is to continue the CNI in KTRs since  Withdrawal of an antimetabolite in 24/28 patients (86%). FK was also withheld in 6/28 severely ill patients (21%  Factors that were independently associated with COVID-19 in-cluded non-White race and comorbidities, including obesity, di-abetes, and asthma and chronic pulmonary disease.
Legend: IS-immunosuppression, AKI-acute kidney injury, RRT-renal replacement therapy, BMI-body mass index, FK-Tacrolimus, CNI-calcineurin inhibitors, M-mycophenolate mofetil/mycophenolic acid, S-steroid, AZA-azathioprine, B-belatacept, mTORi-mammalian target of rapamycin inhibitor, HCQ-hydroxychloroquine, AZT-azithromycin, KTR-kidney transplant recipient, ATG-anti-thymocyte globulin, LDH-lactate dehydrogenase, IL-6-interleukin 6 cessation may lead to increased risk of rejection and greater use of corticosteroids [102][103][104]. Lymphopenia is a common sign of viral infections including coronavirus, suggesting that anti-metabolites such as MMF and azathioprine be decreased or discontinued. A systematic review from 2011 showed that, in general, there is weak evidence that reduction or cessation of MMF may increase rejection rate and graft loss [103]. As such, the risk of rejection with discontinuing the anti-metabolite may be outweighed by the potential benefit in countering infection.
Based on experience from (SARS)-CoV and MERS-CoV, steroid use has been associated with delayed clearance from blood and respiratory tract [105,106]. If steroids are a part of maintenance immunosuppression, cessation would not be recommended, although increment in dose would not be deemed beneficial unless compelling indication exists.

Future directions
It is difficult to ascertain the incidence and impact of COVID-19 in KTRs based on the aforementioned data. Initial reports from our center have shown an incidence of rate of 0.67% (n = 20), in a cohort of about 3000 patients followed with a low threshold for viral disease testing. This probably reflects that the incidence rates might be similar to normal population, but still warrants analysis of larger cohorts. It is also encouraging to note that many outpatient KTRs with known or suspected COVID-19 infection had symptomatic resolution without requiring hospitalization [107]. There is a need, however, for development of anti-viral therapy since it appears that a subset of KTRs may especially be susceptible to the disease. While hydroxychloroquine, azithromycin and tocilizumab were employed as therapy in studies discussed, it cannot be deduced that these agents are beneficial in KTRs and trials are ongoing to ascertain efficacy. Delay in transplantation is ultimately deleterious to patients in the long term, and a concerted effort on part of transplant societies and government agencies is currently paramount in overcoming this crisis.

Socially disadvantaged populations
It is important to note that in many settings throughout the world, rates of kidney disease and the provision of its care are defined by socioeconomic, cultural, and political factors, leading to profound disparities in kidney disease burden across social strata [108]. Similarly, CoVID-19 is disproportionately impacting socially disadvantaged individuals. Such persons are often overrepresented in low-wage, public-service professions that raise risk of exposure to CoVID-19. Moreover, they may dwell in crowded, poor-quality housing that limits ability to physically distance from others to reduce infection risk [109]. In many communities, socially disadvantaged persons may also face barriers to CoVID-19 testing, fragmented access to health care, and disruptions in social services as well as greater risk of the economic consequences of CoVID-19. We will likely find that these challenges lead to delayed presentation to nephrology care (e.g. presenting with more advanced disease) and worsening of disparities in CKD and ESKD [110].

Conclusion
CoVID-19 has been a unique challenge to the field of nephrology. Not only has it shown to be associated with high rates and vast array of presentations of AKI, it has also overwhelmed capabilities of medical systems to provide acute and chronic renal replacement therapies. Mortality in CoVID-19 patients afflicted with AKI and those with kidney transplants is high, with a high requirement for mechanical ventilation. Importantly, the disease has also further exposed glaring disparities in care of the socially disadvantaged. As our understanding of CoVID-19 will continue to evolve, there is an impetus for innovation to overcome these obstacles and develop therapeutics to support this vulnerable population.