COVID-19: A nephrologists' perspectiveTE Jamale, SB Thakare
Department of Nephrology, Seth GSMC and KEMH, Mumbai, Maharashtra, India
After its identification in late 2019 in Wuhan, China as the cause of severe pneumonia, SARS-CoV-2 (COVID-19) pandemic spread to most parts of the world. SARS-CoV-2 virus primarily affects the respiratory system, with manifestations ranging from mild upper respiratory tract infection to severe acute respiratory distress syndrome, multiorgan dysfunction, and death. COVID-19 disproportionately affects patients with pre-existing comorbid conditions like diabetes, hypertension, and those with various types of kidney diseases. Severe COVID-19 is associated with a high risk of acute kidney injury (AKI). Patients with pre-existing kidney diseases, chronic kidney disease (CKD), end-stage renal disease (ESRD), and renal allograft recipients are amongst the most vulnerable subsets of patients. They have a high risk of getting infected, are more likely to develop severe disease, and also experience high mortality.
Although reported incidence of AKI in COVID-19 varies widely depending upon the population characteristics under study, it is consistently reported to be much higher (30%-50%) than adults hospitalized for reasons not related to COVID-19. AKI developing in these patients portends a poor prognosis, with reported mortality rates as high as 60%. The excess risk of AKI is only partially explained by the traditional risk factors like advanced age, hypertension, diabetes, and baseline CKD.
AKI in COVID-19 is multifactorial. Apart from traditional risk factors like hypovolemia, hemodynamic instability, exposure to nephrotoxic drugs (like nonsteroidal anti-inflammatory agents, antibiotics), and superimposed sepsis contributing to the development of AKI, other factors specific to the pathophysiology of COVID-19 like inflammation, immune activation, tissue hypoxia, increased intrarenal pressure, microthrombosis, and direct viral cytopathic effects also play a role. COVID-19 is characterized by severe systemic inflammation and a procoagulant state, both of which may induce AKI by tubular injury and renal microthrombi, leading to further ischemic tubular damage. Immunological injury, to the glomerulus and tubulointerstitial compartment, is also hypothesized to be a contributor to the damage. Angiotensin-converting enzyme 2 (ACE2) receptors are richly expressed in the kidney parenchyma, which may explain the susceptibility to kidney injury in COVID-19. Several initial reports demonstrated presence of virus in the tubular epithelial cells, however, these have not been substantiated by others. The role of direct viral cytopathic effect remains uncertain. This is especially because endosomal subcellular structures like clathrin-coated vesicles and multivesicular bodies can mimic viral particles on ultrastructural examination. While all of the aforesaid factors are proposed as mechanisms of AKI, the exact role and relative contribution of each of them is debated, and a unifying mechanism of AKI in COVID-19 remains to be defined. Rather than being mutually exclusive, different factors may play a dominant role in different patients and also the predominant factor may vary in an individual patient at different points of time during the course of the disease [Figure 1].
Most patients with AKI present with asymptomatic rise in the blood urea nitrogen and creatinine, and close monitoring for the development of complications of AKI is needed. Of note, proteinuria and hematuria are observed in about 80% of the cases, unlike other settings of AKI where it would raise the suspicion of acute nephritis. Some experts have suggested the use of early renal support with continuous renal replacement therapy (CRRT). However, there are no data supporting preferential use of CRRT. Cytokine levels in COVID-19 are reported to be much lower than sepsis, a condition where strategies of early and aggressive renal support with the hope of cytokine removal were not found to be useful. Instead, close monitoring of the patient's volume status, acid base and electrolyte homeostasis, and initiation of renal support whenever indicated seems to be a prudent approach. Intermittent hemodialysis (IHD), sustained low efficiency dialysis (SLED), peritoneal dialysis (PD), and CRRT are all valid modalities of renal support in these patients based upon the available evidence in critically ill patients with AKI. IHD and SLED can be easily set up at bed side and are particularly suited, given the logistic challenge of dialyzing large number of patients during a pandemic. PD is another modality that facilitates dialysis at home for mild cases, reduces exposure to healthcare, and is efficacious. PD effluent has not been found to contain significant viral load and thus PD is not considered to involve a significant risk for the spread of infection.
One of the important characteristics of COVID-19 AKI is its dismal prognosis which is far worse both in terms of patient and renal survival. Our patient cohort had high rates of dialysis requiring AKI (2.73%), high mortality (43.9%), and an alarmingly high rate (67.7%) of dialysis dependency at discharge. High mortality rates are consistently reported, although these might be decreasing, a significant number of AKI survivors remains dialysis dependent, thus further contribute to the excess burden of CKD and ESRD in population.
CKD not only increases the susceptibility to develop infection but also increases the risk of developing severe disease, superimposed AKI, and further on, the risk of permanent loss of kidney function., Prevalence of CKD was significantly higher in patients with severe COVID-19 in a meta-analysis of 4 studies involving 1,389 patients. Our patient cohort had a high prevalence of hypertension (77.3%) and CKD (77.6%) at baseline.
Use of ACE inhibitors increases the level of ACE2 and it was initially speculated that this increases the risk of severe disease. However, a randomized controlled trial and several observational studies failed to show any such association., Withholding these drugs may lead to exacerbation of hypertension and heart failure, which may in turn lead to increased mortality and hence is not recommended. However, in patients with COVID-19, absolute or relative hypotension is common and antihypertensive medications may be required to be withheld or decreased. This practice is supported by a large randomized controlled trial which observed the reduced risk of AKI with a higher mean arterial pressure target in patients with baseline hypertension.
Patients on dialysis for ESRD are particularly susceptible to infection with COVID-19 due to multiple factors. In addition to highly prevalent comorbidities like diabetes, hypertension, and cardiovascular disease increasing susceptibility, increased exposure during travel to the dialysis centre 3 times per week, and during the dialysis procedure, may be significant factors. Supporting this hypothesis, a study reported significantly lower incidence of COVID-19 in patients on home-based dialysis (PD or HD) than those on in-centre dialysis. ESRD patients also develop severe disease and experience one of the highest reported mortality rates due to COVID-19. A report from India highlighted the significantly higher mortality (32.7%) in the second wave of the pandemic as compared to the first wave and pre-COVID-19 mortality rates. Patients with fever and upper respiratory tract symptoms should be dialyzed preferably in a 'suspect area' and if not possible, then in the last shift, and at the end of the row with adequate distancing and barrier precautions. Distancing and other respiratory precautions should be observed in the waiting area as well.
Management of hospitalized patients with COVID-19 and ESRD is particularly challenging not only due to illness severity but also due to multiple comorbidities and need of interdisciplinary care. Renal replacement therapy needs to be continued during hospital stay with a modality that suits the hemodynamic needs of a given patient. Many symptoms overlap between severe COVID-19 and ESRD (dyspnea, fatigue, and chest X-ray findings of fluid overload) and this can delay the recognition of severe disease. Initial high mortality may be due to absence of early warning signs or quick deterioration in the later course of the disease, highlighting need for careful triage at initial evaluation. Non-COVID-19 factors like dialysis access dysfunction or failure, access-related sepsis, missed dialysis sessions, inadequate dialysis, inadequate supply of dialysis consumables due to lockdown also played a crucial role in the reported high mortality in the first two waves. Thus, the susceptibility to COVID-19 and poor outcomes in ESRD is a composite effect of multiple factors, [Figure 2] and multifaceted interventions are hence needed to manage these patients. We and others have reported successful use of citywide dashboard for timely allocation of the dialysis slots and hospital beds. Quick expansion of the facilities to cater to the increasing number of admitted ESRD patients, colocalizing infected dialysis patients to a single ward or floor, bedside dialysis facility, and dedicated COVID-19 dialysis staff is needed to optimally care for these patients as discussed later in our experience of High Dependency Renal Unit (HDRU).
Most dialysis patients are on erythropoiesis stimulating agents, and due to the risk of thrombosis with these, some experts have suggested lowering the target hemoglobin level. However, in our opinion, this decision should be individualized based on the severity of COVID-19, symptoms of anemia, and candidacy for kidney transplant after duly considering the risk of HLA (Human Leukocyte Antigen) sensitization after blood transfusion.
It is reasonable to defer elective live donor kidney transplant surgeries during the peak of a pandemic wave; however, life-saving deceased donor transplant offers need not be refused. Donor and recipient both should be tested by Nucleic Acid Amplification Test (NAAT) within 48-72 hours of the surgery. There have been reports of successful use of nonrespiratory organs from donors dying from COVID-19. Frequency and magnitude of viremia is low and blood-borne spread is not considered important.
Clinical features of COVID-19 in kidney transplant recipients may be atypical; patients can present with diarrhea, respiratory distress without preceding upper respiratory tract symptoms, and even without fever. We reported a high incidence of diarrhea (52%) and anemia (82%) as a presenting feature. In our cohort, kidney transplant recipients with a low baseline cardiovascular risk were also observed to develop myocardial injury and arrhythmias, solely because of severe COVID-19 disease. Our treatment strategies included antimetabolite withdrawal (85%), calcineurin inhibitor (CNI) decrease or withdrawal (64%), increased steroids (53%), hydroxychloroquine (21%), remdesivir (28.3%), and tocilizumab (3.3%). Persistent swab positivity at discharge was also observed in our patients. Initial reports showed high mortality in transplant recipients,, while a subsequent large multicenter study done later showed a much lower risk of death. Significant interaction of the baseline comorbidities like diabetes and hypertension make it difficult to assess the impact of kidney transplant on risk of infection, illness severity, and death.
In hospitalized patients with moderate or severe disease, it is suggested to reduce or stop the antimetabolite (azathioprine or mycophenolate). In those with progressive disease, further reduction in immunosuppression may be needed and this decision should be individualized based on the risk and history of rejection vis-a-vis the risk of severe disease. CNIs (tacrolimus and cyclosporine) inhibit IL6 and IL1 pathways which are important in pathogenesis of severe COVID-19 and therefore may the be continued as far as possible.
In our experience, risk of AKI in kidney transplant recipients was much higher than the reported literature and may be related to multiple factors. Late presentation with severe disease, relative hypotension, and a lack of autoregulation in the kidney allograft increase risk of AKI. Moreover, tacrolimus toxicity contributing to AKI was noted in a large number of kidney allograft recipients hospitalized for COVID-19. Tacrolimus level may be increased due to diarrhea (a common presenting feature), which is known to increase tacrolimus exposure. Whether COVID-19 alters P450 expression leading to higher tacrolimus levels remains to be seen. In one of the few studies of long duration follow-up after COVID-19, AKI in a cohort of veterans was observed to be protracted, with a large number of patients having residual renal damage at 12 months after COVID-19. This has major implications for those with kidney transplant, given the fact that chronic allograft injury is cited as the most common cause of graft loss in long term.
The city of Mumbai saw its first case of COVID-19 on March 11, 2020. Institutional dialysis services all over the country faced challenges like outbreaks among patients and staff, frequent closures, lack of guiding policies, and expensive and often unavailable infection control measures. In addition, disruption of hospital services, transport barriers, shortage of drugs, and consumables directly impacted morbidity index, rates of hospitalization, and death. Existing public sector infrastructure for dialysis was put to immense strain. An urgent need to create more facilities to accommodate this large number of patients with ESRD and COVID-19 emerged. India has an estimated 1,75,000 patients of ESRD on chronic dialysis across the country. The city of Mumbai alone has 174 dialysis centers with 10,000 dialysis patients on regular dialysis within the city. Dedicated COVID-19 hospitals were specially created by the Brihanmumbai Municipal Corporation during the pandemic. Few such designated units were also capable of providing bedside dialysis and managing critically ill patients with severe COVID-19 and ESRD. Another novel initiative which addressed this crisis in Mumbai was the multicenter 'Project Victory', where a citywide dashboard was created to facilitate timely allocation of dialysis slots to patients on maintenance dialysis as soon as they were detected COVID-19 positive. More than 1,000 patients could be allocated a slot at a COVID-19 dialysis facility within 48 hours through this portal. This served the purpose of optimum utilization of existing dialysis resources.
High mortality continued to be a cause of concern for patients with renal failure and COVID-19, with almost one-third of the patients on dialysis experiencing mortality. At our centre, we audited the outcomes of hospitalized patients with COVID-19 who also had severe renal failure needing dialysis. Several gaps and logistic challenges in the process of the care were identified and to address them a high dependency renal unit (HDRU) was commissioned [Figure 3]. Concept of HDRU was based upon the unique medical needs of these patients: regular and adequate dialysis, quick identification and addressal of dialysis access dysfunction, prompt management of blood stream infections, triage of the patients for close monitoring and intensive care unit transfers, and interdisciplinary care involving intensivists, cardiologists, pulmonologists, and endocrinologists. HDRU was managed by nephrologists acting as primary care physicians. Key components of HDRU included checklist-based close clinical monitoring, care bundle approach focusing on key clinical issues, integration of multispecialty care by the primary care physician-nephrologists, and training of personnel with respect to management of COVID-19 and kidney specific issues.
Of 4,254 COVID-19 positive patients admitted to our hospital from March 28, 2020 to September 30, 2020, 238 (5.59%) patients had severe renal impairment (AKI requiring dialysis: 116, ESRD: 122). From May 29 to August 31, 160 of these patients received treatment in HDRU. A significant decline in the mortality of patients was observed after implementation of HDRU as a quality improvement initiative. Seventy six (31.9%) of 238 patients died [AKI-D: 51 (43.9%), ESRD: 25 (21.2%)]. Nineteen (36.5%) and 35 (21.9%) patients died in the pre-HDRU and post-HDRU groups. 41 kidney transplant recipients were also treated in the HDRU and this cohort reported one of the lowest mortality rates of COVID-19 in solid organ transplant recipients. Although limited by an observational design, our results suggest that HDRU is a feasible and potentially effective approach in management of COVID-19 in patients with severe renal function impairment.
The term renalism is used to describe therapeutic nihilism for renal patients leading to the inappropriately low rates of diagnostic and therapeutic interventions in patients with kidney disease. This is largely due to the lack of inclusion of patients with decreased kidney function in pivotal drug trials and concern of nephrotoxicity leading to weak recommendations or none at all for the use of therapeutic drugs in these patients.
Contrast enhanced computed tomography (CT) scan or CT pulmonary imaging which is crucial in the diagnosis, risk assessment, and therapy is often deferred in such patients due to the concerns of contrast induced AKI; however, the risk of this complication is significantly lower than believed, and if indicated, these imaging modalities should not be withheld for decreased kidney function.
Due to immunosuppression and decreased kidney function, many of these patients qualify for antibody cocktails and antivirals (e.g., nirmatrelvir-ritonavir) to prevent severe disease. However, the later should be used with extreme caution and close monitoring, due to a major interaction of this antiviral with CNIs- tacrolimus and cyclosporine. Careful consideration of risk benefit is necessary before starting this therapy and therapeutic drug monitoring with dose reduction is needed to avoid acute CNI toxicity.
Remdesivir and dexamethasone can be safely used whenever indicated with monitoring for severe disease. Remdesivir was approved by the United States Food and Drug Administration in October 2020, based on the results of RECOVERY trial, showing decreased time to recovery in the treated patients; however, drug was largely avoided in patients with kidney diseases for the lack of data and theoretical risk of nephrotoxicity due to its vehicle cyclodextrin. We first reported the use of remdesivir in 46 patients with a wide range of renal function abnormalities including AKI, CKD, ESRD, and kidney transplant recipients and found it to be largely safe with no signal of nephrotoxicity attributable to remdesivir. These findings were later substantiated by a number of reports from other countries.,
Vaccine response to mRNA vaccines is poor in organ transplant recipients. However, one published and our unpublished data from India have shown excellent seroconversion rates (>80%) even with single dose of Oxford-Astra Zeneca vaccine. This may be related to the younger age, lower comorbidity burden, and possibly high rates of symptomatic and subclinical infection. Vaccination effectively prevents severe disease and death even after one dose of the vaccine, thus wider vaccine coverage in patients with kidney disease is needed.
COVID-19 is thus a cause of significant morbidity and mortality in patients with various kidney diseases. Multiple factors related and unrelated to COVID-19 contribute to adverse outcomes. Approaches to improve outcomes in this vulnerable population are urgently needed.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]