Saudi Journal of Kidney Diseases and Transplantation

REVIEW ARTICLE
Year
: 2021  |  Volume : 32  |  Issue : 5  |  Page : 1220--1234

Coronavirus Disease 2019 and the Kidney


Ajay Jaryal1, Sanjay Vikrant2,  
1 Department of Medicine, All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India
2 Department of Nephrology, All India Institute of Medical Sciences, Bilaspur, Himachal Pradesh, India

Correspondence Address:
Sanjay Vikrant
Department of Nephrology, All India Institute of Medical Sciences, Bilaspur - 174 001, Himachal Pradesh
India

Abstract

Coronaviruses are ubiquitous pathogens and have caused epidemics in the recent past. Coupled with globalization, they have the potential to transform into the pandemic, as is the case of coronavirus disease 2019 (COVID-19). Primarily to start as a respiratory illness, they are known to cause systemic disease and affect many organ systems. Due to the lack of, universally proven, specific anti-viral therapy, the mainstay of treatment is “supportive care” and some of the patients afflicted with it, require intensive care and organ support for lungs and/or kidneys. Patients with the diseases of the kidney, particularly those on dialysis and kidney transplant recipients, are predisposed to the worst outcomes with COVID-19. It also leads to acute kidney injury, which is an important and independent determinant of prognosis in these patients. It also creates a huge demand for the delivery of renal replacement therapy. COVID-19 is an emerging and evolving disease, and so, it is important to understand the mechanism and management of kidney diseases in COVID-19.



How to cite this article:
Jaryal A, Vikrant S. Coronavirus Disease 2019 and the Kidney.Saudi J Kidney Dis Transpl 2021;32:1220-1234


How to cite this URL:
Jaryal A, Vikrant S. Coronavirus Disease 2019 and the Kidney. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jul 1 ];32:1220-1234
Available from: https://www.sjkdt.org/text.asp?2021/32/5/1220/344741


Full Text



 Introduction



Human coronaviruses (CoV) are zoonotic pathogens. They are usually known to cause respiratory infections in humans and intestinal infections in animals. Before the epidemic of severe acute respiratory syndrome (SARS), they were known to cause mild infections in immuno-competent people, but this perception changed with the discovery of the first epidemic of SARS in 2002.[1],[2] Subsequently the Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in the Kingdom of Saudi Arabia in September 2012 and is still continuing.[3] Some authorities rightly consider SARS, to be the first emerging disease of the age of globalization, which was readily transmissible and where a contagion from one part of the world traveled to another part rapidly (with jet travel).[4] The current SARS CoV disease which started in China in December 2019, has already reached pandemic proportion and is still ensuing. It has been named as coronavirus disease 2019, (COVID-19) or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[5] Involvement of the kidney, with CoV, is quite common. What are CoV? And how they cause kidney injury? And how best such patients can be managed is reviewed here.

 What are Coronaviruses?



Human CoV were first characterized in the 1960s, by the efforts of many scientists, and were named so, because of their typical appearance on electron microscopy.[6] CoV belong to order Nidovirales, family Corona-viridae and subfamily Coronavirinae.[1] Based on their genomic structure and phylogenetic relationships the subfamily Coronavirinae is further divided into four genera namely–alphacoronavirus, betacoronavirus (infect only mammals), gammacoronavirus, and delta-coronavirus (usually infect birds, but some of them can also cause infection in mammals).[1],[2] Human CoV are enveloped single-stranded RNA viruses. They contain the largest known, positive-sense RNA genomes, ranging from 25.5 – nearly 32 Kb in length. The diameter of virus particles ranges from 70 to 120 nm and is surrounded by characteristic spike-shaped glycoprotein (180 kDa). The spike glycoprotein mediates the attachment and entry of the coronavirus utilizing virus and host-specific receptors.[5],[7] The receptor-binding domain (RBD) of the spike glycoprotein is poorly conserved among CoV, contributing to their broad host range and capability to breach tissue and host species barriers.[7] Bats are known to be a huge reservoir of coronavirus, and the diversity of coronavirus in bats and other species is not fully known. The origin of all the SARS CoV can be traced to bats. It is hypothesized that direct progenitors of SARS-CoV were produced by recombination in the bats or other animals (natural selection in the animal host before zoonotic transfer) which acted as intermediate hosts such as civets, Pangolins, and dromedary camel (in the case of MERS CoV), where it acquired more mutations and then spilled over to humans, or by natural selection in human-to-human transmission.[2],[7],[8]

 Pathogenesis of Coronavirus Diseases 2019



The transmission, replication, and pathogenesis of coronavirus are determined by the viral genome and host receptors. Corona virion completes its life cycle in the host cells in the following steps, i.e., entry by utilizing viral and host receptors, expression of replicase, replication, and transcription of genome and release of progeny. It contains a few essential structural glycoproteins like–spike (S), membrane (M), envelope (E), and nucleocapsid (N), and many non-structural proteins like proteases, primase, RNA helicase and RNA dependent RNA polymerase (RdRp).[9] S protein is required for the initial attachment of the virus to the host cell and gives a characteristic appearance to the virus and hence the name “corona.” M protein maintains the structure of the virus and E protein is required for viral assembly and release. Many CoV bind to host cells through their S protein and host peptidases receptors. SARS-CoV2 shares 79% similarity with SARS-CoV, and 50% homology with MERS, however, it is more closely related to a few of the bat CoV.[5] SARS-CoV and SARS-CoV2 use angiotensin-converting enzyme type 2 (ACE2) and MERS-CoV uses Dipeptidyl peptidase (DPP4) as a receptor to bind to the host cell membrane. The fusion of the virus with the host membrane after attachment to ACE 2 receptors is mediated by proteases like transmembrane protein serine protease 2 (TMPRSS2) and furin.[9],[10],[11] Virus-infected cells release interferons (IFN), which are primary cytokines of defense against the virus. IFN is one of the constituents of the innate immune system. IFN I molecule binds to cell surface receptors and triggers Jak-Stat (Janus kinase/signal transducer and activator of transcription) signaling pathway which switches on many antiviral genes, which further are translated into various proteins, which inhibit viral replication. Cells of adaptive immunity like T-cells, memory B-cells and antibodies are also produced which have a protective role against infection, and reinfection. The kinetics of these cells of adaptive immunity in COVID-19 is variable, with the level of IgG to spike protein was found to be stable over six months, level of spike specific memory B-cells was more abundant at month 6 than on month 1, and level of SARS-CoV 2 specific CD4+ T cells and CD 8+ T cells declined with a half-life of 3–5 months after the onset of symptoms.[12] In patients who recovered from SARS-CoV infection, memory CD4 and CD8 T-cells have been found to last up to 11 years.[13]

 Angiotensin-converting Enzyme Type 2: A Central Molecule in the Coronavirus Disease Pathogenesis



The renin-angiotensin system (RAS) is a complex system of various bioactive components and has not been fully elucidated yet. ACE and its homolog ACE2 play an important role in the renin-angiotensin-aldosterone axis, which regulates vascular tone, fluid and electrolyte hemostasis, cell growth, and inflammation. ACE and ACE2 usually have an opposite action to each other. ACE converts angiotensin 1 (AG I) to angiotensin II (AG II), which increases blood pressure. AG1 and AGII are also acted upon by ACE 2 and hydrolyzed to form angiotensin 1-7, which has vasodilator properties and lowers blood pressure.[14] Drugs that inhibit ACE (ACEI), upregulate ACE2 [Figure 1]. Hence, the people on ACEI would have increased expression of ACE 2, and ACE2 also acts as a cellular receptor for SARS CoV 2. Hence, it is hypothesized that people on ACEI might have increased susceptibility to infection with SARS-CoV 2 and may have even severe infection, however, ACE2 is also known to have anti-inflammatory effects.[15] A meta-analysis previously has shown that people on ACEI have significantly less risk of pneumonia and may even have less mortality.[16] It may be related to upregulation of ACE2 level which has vasodilatory effects and protect pneumocytes from injury by improving pulmonary blood flow and surfactant properties.[17] Similarly in the case of COVID-19 also studies did not find any association with the use of ACEI/angiotensin receptor blocker (ARB) and COVID-19 positivity and even found lower all-cause mortality in the patients who were hospitalized with COVID-19 and using ACEI/ARB versus nonusers.[18],[19] A large prospective cohort study also found a decreased risk of COVID-19, and no increased or decreased need of intensive care unit (ICU) care in patients on ACEI/ARB, although it may not hold true across all the ethnicities.[20] ACE2 is more avidly expressed in type II alveolar epithelial cells than epithelial cells of the upper respiratory tract and that may be a plausible cause of predominant lower respiratory tract symptoms. It is also extensively expressed in kidneys especially apical cells of proximal convoluted tubules (PCT), myocardial cells, enterocytes, urothelial cells, and in many other organs, and viral sequences have been isolated from urine and feces.[21] Infection of cells with SARS-CoV2 leads to downregulation of ACE2 and alters AG II/AG 1-7 and ACE/ACE2 balance in favor of increased vascular permeability, inflammation, coagulation, and microcirculatory disturbance.[21]{Figure 1}

 Cytokine Release Syndrome



The outcome of coronavirus infection depends on the interplay of viral and host factors including age, sex, and comorbidities. Beside it, the other important determinant is a balance between protective host immune response and devastating effects of immune dysregulation. Hyper-immune response, characterized by markedly elevated cytokines and systemic upset, can be given an umbrella term as “cytokine release syndrome or cytokine storm (CRS)”, and is known to occur after various therapies, cancers, pathogens, and autoimmune disorders. There is no uniformly accepted definition for CRS and its distinction from the normal immune response is also blurry, however, it is uniformly characterized by markedly elevated cytokines, systemic inflammation, constitutional symptoms, and multiorgan dysfunction.[22] In some severe cases of CRS, a combination of renal dysfunction, endothelial cell dysfunction, and acute hypoalbuminemia can occur leading to capillary leak syndrome and anasarca. Laboratory investigations are nonspecific and are influenced by the underlying cause. However, the level of CRP (almost uniformly elevated and correlate with disease severity),[23] erythrocyte sedimentation rate, triglyceride, ferritin, lactate dehydrogenase, interleukin (IL)-6, IL-10, tumor necrosis factor-alpha, IFN gamma, and D-dimer are usually elevated. Hemogram may show leukocytosis, lymphopenia, leukopenia, pancytopenia, anemia, and thrombocytopenia. Some people with dysregulated IFN response to COVID-19 may have severe disease. CRS has been implicated in the pathogenesis and is a determinant of disease outcome in SARS, MERS, and SARS-CoV 2.[24] It is important to differentiate CRS from normal immune response, as the institution of immunosuppressive therapy may prove to be counterproductive in the later situation.

 Kidney Pathology in Coronavirus Disease 2019



Autopsy studies in patients with SARS and SARS-CoV 2 have shown diffuse alveolar damage in the lungs, with hyaline membrane formation.[25],[26] Viral particles have been demonstrated in the pneumocytes. Lungs in a patient infected with COVID-19 also showed microthrombi in pulmonary microcirculation, deep vein thrombosis, and pulmonary embolism.[26] Although the major brunt of the disease pathology is borne by the lungs, kidneys showed focal necrosis, monocytic infiltration, and vasculitis of small veins in the renal interstitium and acute tubular necrosis (ATN). Viral particles have been demonstrated in renal tubular epithelial cells in SARS-CoV.[25] In patients with COVID-19 autopsy studies showed changes in kidneys varying from acute tubular injury, congestion of peritubular capillaries, and hemosiderin deposits in the tubular lumen and viral particles have been also demonstrated in the kidney tissue.[26],[27] COVID-19 affects all the compartments of the kidney, i.e., glomerulus, tubulointerstitial and vascular. In a multi-centric study analyzing, 17 kidney biopsies in COVID-19 patients (14 native and 3 transplant) found that only three had severe COVID-19 disease at presentation. Indications for performing kidney biopsies were acute kidney injury (AKI) (n = 15) and proteinuria (n = 11), developing concurrently or within one week of COVID-19 symptoms in all the patients. The most common findings were acute tubular injury (n = 14), collapsing glomerulopathy (n = 7), and endothelial injury/thrombotic microangiopathy (n = 6). Two of the three transplant recipients developed active antibody-mediated rejection weeks after COVID-19. Eight patients required dialysis, and it highlights that many patients may present with exclusive renal dysfunction.[28] COVID-19 associated viral microangiopathy may be an important mechanism for COVID-19 associated renal involvement.[29] Proximal tubule dysfunctions, with transmission electron microscopy showing viral particles, has also been shown with COVID-19.[30] In one study collapsing glomerulopathy was the commonest biopsy findings, however evidence of SARS-CoV 2 in kidney tissue was not demonstrated.[31] In another kidney biopsy study of 10 patients, ATN was the commonest finding, with no evidence of SARS-CoV 2 in biopsied kidney tissue.[32] So kidney involvement in SARS-CoV 2 occurs by direct viral cytopathic effects and is also mediated by systemic effects of COVID-19 infection.

 Epidemiology of Kidney Disease in Coronavirus Disease 2019



Kidneys are affected in systemic viral infections by various mechanisms namely: direct viral effects on glomeruli, vasculature and renal tubular cells, immune-mediated effects on glomeruli and tubulointerstitial, toxic effects of drugs and endogenous toxins like myoglobin and hemoglobin, generalized endothelial dysfunction, renal hypoperfusion, hypoxia, and cytokine release [Figure 2]. Kidneys play an important role in maintaining blood pressure, fluid, electrolyte, and acid-base hemostasis. RAS axis is also orchestrated in the kidneys and besides this, there is abundant expression of ACE 2 in kidney tissue.[33] AKI is also recognized to be the most common complication in a patient with acute respiratory distress syndrome (ARDS), occurring in almost 50% of the patients and is also an independent determinant of mortality in ARDS.[34] ARDS per se is a leading cause of death in a patient with COVID-19. All these factors predispose kidneys to be affected with COVID-19 leading to either AKI or acute on chronic kidney disease (CKD).{Figure 3}

 Acute Kidney Injury in Coronavirus Disease 2019



The incidence of AKI was around 9.6% in patients with SARS with mortality around 98.9%, and the incidence of AKI was 42% in patient with MERS with 100% mortality. CKD, end-stage renal disease (ESRD), and the need for urgent renal replacement therapy (RRT) are also associated with increased mortality in SARS, MERS, and SARS-CoV 2.[35] The incidence of AKI in COVID-19 varies from (5.1% to 56.9%). An early study in the pandemic emanating from patients admitted to a teaching hospital with COVID-19 showed that 43.9% of patients had proteinuria, and 26.7% had hematuria at the time of admission in hospital with COVID-19. AKI developed in 5.1% of the patients during the hospital stay. Elevated baseline creatinine, blood urea nitrogen, proteinuria, hematuria, and AKI were independent risk factors for in-hospital death.[36] A retrospective study found a higher incidence of AKI in patient admitted with COVID vs non-COVID (56.9% vs. 25.1%). Patients with COVID-19 were more likely to need RRT (less likely to recover renal function), ICU support, mechanical ventilation and also had more in-hospital death.[37] One study showed an incidence of AKI to be 36.6% in patients infected with COVID 19. The risk factors for AKI in this study were old age, diabetes mellitus, cardiovascular disease, blacks, hypertension, need for ventilatory support, and need of vasopressors drugs. 35% of the patients with AKI died. Authors found AKI to occur early and in temporal relation with respiratory failure and a marker of poor prognosis.[38] In another multicenter cohort of study of 3099 critically ill adults with COVID-19, it was found that a total of 637 of 3099 patients (20.6%) developed RRT requiring AKI (AKI-RRT) within 14 days of ICU admission, and 350 of whom (54.9%) died within 28 days of ICU admission. At the end of a median follow-up of 17 days (range, 1–123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. It implies poor immediate and long-term outcomes for the patients who develop AKI-RRT with COVID-19.[39] Hence, all these diverse studies inform us that, there is a high incidence of AKI in COVID-19, and it is associated with the increased need for ICU care, RRT, and mortality, and is in itself an independent determinant of outcomes.

 Coronavirus Disease 2019 in Dialysis and Kidney Transplant Recipients



Uremia leads to immune dysfunction in the form of immunodepression and inflammation, and so the patients of ESRD on hemodialysis (HD) or peritoneal dialysis (PD) are predisposed to infections.[40] The incidence of COVID-19 is around 8% in patients on maintenance HD (MHD) which is the same as in the general population but mortality is around 25.7%, which is almost the same as SARS but lower than MERS.[35] Patient on home-based PD may have the theoretical advantage of getting less infected with COVID-19 over in-center HD if proper infection control measures are used. In a study of 818 patients on PD, eight patients were diagnosed with COVID-19 during the studied period (January 1, 2020, to April 12, 2020), two of whom died and six survived. In this study incidence of symptomatic COVID-19 in patients on PD was close to that of the general population of the same city.[41] In another study of 11 patients on chronic PD with COVID-19, three patients required mechanical ventilation, two of whom died and nine of the 11 patients (82%) were discharged alive.[42] Kidney transplant recipients (KTRs) are predisposed to various viral infections due to the use of immunosuppressant medications, and hence there is worry about them getting infected with COVID-19. In an observational cohort study, high mortality of 26.7% in the dialysis patients and 29.2% in the transplant patients were found.[43] In another study of 20 KTRs, six patients developed AKI, with one requiring HD, and five KTRs died after a median period of 15 days, from symptom onset.[44] So, patients of ESRD on MHD and PD, and KTR have uniformly adverse outcomes once they contract COVID-19.

 Management of Coronavirus Disease 2019 patients with Kidney Involvement



General principles

It is well-known that patients with COVID-19 can develop various types of kidney injury, and patients with underlying kidney diseases such as CKD, MHD, and KTR have adverse outcomes, which are more than the general population, once they contract COVID-19. The kidney is precariously predisposed to adverse effects of systemic inflammation, hypoxia, and hypotension, and it is also a seat of excretion and handling of many drugs. Important aspects of handling COVID-19 disease with kidney disease are:

  1. Prevention of COVID-19 in patients of CKD, MHD and KTR:


    1. Routine screening of patients on MHD (in-centre) for COVID 19 and their isolation if positive for COVID-19.
    2. Vaccination.


  2. Prevention of Kidney injury in patients with COVID-19:


    1. Periodic measurement of hemodynamic parameters, volume status, urine output, and serum creatinine.
    2. Identify patients at risk of AKI, identify new-onset AKI, establish the cause of AKI and treat the cause of AKI.
    3. Prevent further worsening of AKI:


      1. Avoiding/omitting potential nephrotoxic drugs.
      2. Dosage modification of drugs in patients with reduced GFR.
      3. Prevention of hypotension, hypoxia, dehydration, fluid overload, and systemic inflammation.


    4. Nutritional support, control of blood pressure, and glycemic control.


  3. Institution of specific drugs:


    1. Anti-viral-Likely to be effective in the initial stages of viral infection.
    2. Immunomodulators-Appropriate use during the phase of the abnormal hyperimmune response.
    3. Optimal supportive care.


  4. Institution of RRT as per expertise and clinical context of the patient:


    1. Medical measures to manage complications of AKI:


      1. Fluid overload: Fluid restriction, Diuretics if pulmonary edema.
      2. Hyperkalemia: Omit drugs likely to cause hyperkalemia like potassium-sparing diuretics, trimethoprim, ACEI/ARB, β blockers, digoxin. Medical measures to treat hyperkalemia.


    2. Appropriate and complementary use of: PD, HD, sustained low-efficiency dialysis (SLED), prolonged intermittent renal replacement therapy (PIRRT) or continuous renal replacement therapy (CRRT).


  5. Follow up:


    1. For the resolution of kidney injury.
    2. Biopsy to look for other causes, if kidney disease remains unexplained.
    3. To provide reno-protective and cardiovascular protective care to patients with AKI.


 Coronavirus Disease 2019 and Delivery of Maintenance Hemodialysis



Worldwide, around 2.5 million people are on various modes of life-sustaining RRT.[45] HD is the commonest mode of RRT and Over two million people are dependent on it,[46] and majority of them are on in-center HD. Delivery of MHD to these patients in the pandemic of COVID-19 is challenging. It not only involves adherence to infection control measures to prevent disease in the staff and patient, but also extends to ensuring logistics like travel, consultation, medication adherence, and maintenance of dialysis supplies [Figure 3]. As COVID-19 is an evolving and ongoing pandemic, it is important for renal physicians to stay abreast with the policies developed by national and international scientific bodies and local public health authorities to ensure optimal delivery of in-center MHD.{Figure 3}

 Drugs in the Management of Coronavirus Disease 2019



The diagnosis of COVID-19 is based on the nucleic acid amplification test, and this also holds true for patients with diseases of the kidney. Effective and safe drug for the treatment of any infectious agent is the cornerstone of managing any contagion, be it bacterial, fungal, or viral. This safe and effective drug is still elusive for COVID-19. Some of the drugs already in use have been repurposed for the treatment of COVID-19 like: hydroxychloroquine, azithromycin, protease inhibitors, and ivermectin. However, currently, NIH recommends against the use of chloroquine, hydroxychloroquine alone or in combination with azithromycin, or HIV protease inhibitor like lopinavir/ritonavir in the management of COVID-19, of any severity.[45] Specific antiviral drugs currently in various phases of development and approval are recombinant human monoclonal antibodies like casirivimab plus imdevimab and bamlanivimab that bind to spike protein RBD of SARS-CoV-2, and have neutralizing effect on the virus.[47]

Remdesivir

Remdesivir is one of the most widely used, specific antiviral drugs against COVID-19. It has a broad-spectrum activity against corona-viruses. It is an intravenous nucleotide prodrug that is metabolized to its active triphosphate, that binds to the viral RdRp, and inhibits viral replication through premature termination of RNA transcription. It has a short plasma half-life of 1 h but has a prolonged intra-cellular t1/2 of 40 h.[48],[49] It is rapidly metabolized by plasma hydrolases, and has less than 10% renal excretion, however, some of its metabolites may have higher renal excretion.[48],[49] In vitro studies show, that it is a weak inhibitor of cytochrome 450, but due to its rapid in vivo degradation, it may not lead to clinically significant drug interaction.[49] Its formulation contains sulfobutylether-beta-cyclodextrin sodium (SBECD) which is cleared through kidneys, and hence there is concern about its accumulation in patient with reduced estimated GFR (eGFR). It was not used in the people with eGFR <30 mL/min, in the trials, so it is not recommended for use in the people with eGFR <30 mL/min.[47] However, it is also known that SBECD is rapidly and extensively eliminated by HD and hemodiafiltration.[50] Some authors have successfully used Remdesivir in patients on dialysis and eGFR <30 mL/min without any infusion-related adverse effects and any clinically significant ALT elevation.[51]

Immunosuppressant drugs

The use of immunomodulating/immuno-suppressants drugs is helpful in the management of COVID-19. They should be used at the right stage of the disease when there is dysregulated immune response inimical to the host. Dexamethasone is effective in lowering the mortality in the patient with severe to critical COVID-19, who required supplemental oxygen therapy or ventilatory support. Baricitinib (an inhibitor of oral JAK) along with remdesivir is another drug in various stages of development and approval in the management of COVID-19. NIH is neither for nor against, the use of baricitinib plus remdesivir in patients with COVID-19.[47] There has been a surge in the use of biologicals in the management of COVID-19, and it may be of concern in patients with reduced GFR. However, these monoclonal antibodies are relatively large molecules and are hence confined to vascular space. They are eliminated by proteolytic degradation at the site of absorption, and during transportation, target mediated drug disposition and intracellular catabolism. Because of their large size, they are not filtered by the kidneys and hence are not eliminated in the urine, except in pathological conditions.[52] Tocilizumab is one such biological agent, which has been used in severe COVID-19. It is a recombinant humanized anti-IL-6-receptor monoclonal antibody. NIH recommends against the use of tocilizumab for the treatment of COVID-19, except in a clinical trial.[47]

 Management of Acute Kidney Injury in Coronavirus Disease 2019



AKI is a clinical syndrome characterized by an abrupt decline in GFR leading to the accumulation of metabolic waste products. The initial approach for COVID-19 associated AKI should be to use an evidence-based approach to prevent further progression of AKI, as is being done in other non-COVID scenarios. Hemodynamics, volume status, serum creatinine, and urine output should be periodically monitored. Maintenance of euvolemia is important, as both dehydration and fluid overload are associated with adverse outcomes. Medical measures should be adopted to manage fluid overload and hyperkalemia. Kidney Diseases Improving Global Outcomes (KDIGO), guidelines advise for initiation of RRT in AKI, when there are life-threatening changes in fluid, electrolyte, and acid-base balance.[53] Delivery of RRT in pandemic like COVID-19 is challenging, because of the acute increase in the need for such therapies, which is overwhelming for any health care system and there is a risk of transmission of contagion to Health Care Workers and patients. RRT in COVID-19 should be delivered by adhering to strict epidemic control measures. Various modalities of RRT are: Intermittent HD, SLED, PIRRT, acute PD and CRRT. The first two have the advantage of intermittent therapy and may be less labor intensive. The latter two offer advantages of continuous slow convective clearance with better hemodynamic tolerability but may need more expertise and labor. In CRRT the pore size of CRRT hemofilter is 7–10 nm,[54] which is much smaller than the size of SARS-CoV2 (100 nm) which implies that passage of virus in CRRT effluent would be quite low. While delivering CRRT through a cytokine-absorbing polymethyl methacrylate membrane hemofilter, very weak but positive RT-PCR result for COVID-19 was detected in three of five effluent specimens.[55] COVID-19 creates a thrombogenic milieu, so clotting of CRRT filter becomes a major hindrance in the delivery of efficient, safe, and cost-effective dialysis in these patients. In one study, 83% of patients lost at least one filter with a median filter life of only 6.5 h.[56] Hence, anticoagulation needs to be meticulously monitored and individualized in the patients on extracorporeal therapy with COVID-19. CRRT can be successfully and safely incorporated and delivered with other extracorporeal therapies like: Cytokine reduction and extra corporeal membrane oxygenation.[57],[58] The main determinant for the type of RRT to choose, depends upon institutional expertise, overall clinical goals to be achieved with the RRT, and overall clinical suitability of the patient for a particular mode of RRT. In resource-poor areas acute PD fairs same as CRRT.[59] Epidemics like COVID-19 put a lot of strain on resources, and as such even an advanced and resource-rich health-care system can become resource-poor. Acute PD is under utilized in the management of AKI, mainly because of a lack of trained manpower. It has been also utilized in COVID-19 with successful outcomes.[60] Acute PD is a helpful complement to other modes of acute RRT and can be successfully administered with good outcomes in pandemic situations like this.[61] KDIGO guidelines suggest using CRRT, rather than standard intermittent RRT, for hemodynamically unstable patients and those with raised intracranial pressure. RRT should be provided to achieve the overall goals of electrolyte, acid-base, solute, and fluid balance. For intermittent and extended RRT, it recommends a Kt/V target of 3.9 per week and for CRRT it recommends delivering an effluent volume of 20–25 mL/Kg/h.[53] However, a patient’s overall clinical context should be taken into consideration while delivering RRT. COVID 19 does not appear to be one-time illness. Survivors of COVID 19 infection have reported various multisystem symptoms which persist from few weeks to few months. The symptoms which persist beyond a conventional threshold of four weeks (replication competent COVID-19 is usually not isolated beyond this period), which cannot be attributed to any other etiology has been defined as post-acute COVID-19 syndrome. It is also known to affect kidneys.[62] COVID-19 patients with RRT requiring AKI, experience high mortality on long-term follow-up. In one Chinese study around 13% of patients, with documented normal renal functions during acute COVID-19, developed new-onset reduction of eGFR, on long-term follow-up.[62],[63] Such patients with persistent renal impairment should be followed up closely.[62]

 Management of Kidney Transplant Recipients with Coronavirus Disease 2019



KTR are another vulnerable group of patients for COVID-19. It is traditional to reduce the intensity of immunosuppression during infectious illness in KTR. On the same analogy, antimetabolites are usually withdrawn in most of the KTR with COVID-19, and a dose of CNI is reduced or stopped if further reduction in immunosuppressant drugs is warranted. In one study dose of the antiproliferative drug was reduced in 86% of the patients, and in 21% of the critically ill COVID-19 patients, tacrolimus was withheld.[64] In another study, the intensity of immunosuppression and degree of reduction following COVID-19 diagnosis were not associated with either survival or acute allograft rejection.[65] Profound lymphopenia is one of the important features of COVID 19 and correlates with poor outcomes.[66] The absolute lymphocyte count is also used as a marker for a therapeutic effect of anti-thymocyte globulin, used during induction in transplant.[67] So, the patients of COVID 19 may not be at increased risk of rejection, especially if they are lymphopenic. In a study of 30 KTRs with COVID-19 where CNI and antimetabolites were withheld, and 40% of patients continued baseline corticosteroids, and standard of care, it was found that the mortality in the cohort was 20%, four had RRT requiring AKI and there was no increased risk of acute allograft rejection.[68] As per the current understanding of COVID-19 pathogenesis, the initial assault of the disease is led by direct viral cytotoxic effect and later by immune hyperresponsiveness.

Hence, immunosuppression in COVID-19 may be modified as per the duration of illness, concomitant use of other drugs, and severity of the disease. It needs to be individualized and tailored as per the overall clinical context.[69]

 Coronavirus Disease 2019 Vaccine



The development of vaccine is a long and challenging process. However, in the case of COVID-19 concerted international efforts led to the rapid development and roll-out of various vaccines against it. Patients with kidney diseases are known to have a compromised immune system, and so live microbial replicating vaccines should be avoided in them.[70] Because of this immunocompromised state many patients with kidney diseases, especially those with reduced eGFR, and those on immunosuppressant drugs, are not able to develop an optimal immune response to various vaccines like hepatitis B, and influenza.[71] Hence, this sub-group of patients, may not be able to develop a sufficient immune response to the COVID-19 vaccine also. In some of the studies, around 97% of PD, and 90% of dialysis patients were found to have demonstrable anti spike antibodies after receiving a complete dose of mRNA vaccine.[71],[72] Most of KTR are on immunosuppressant drugs and exhibit subdued immune response to the COVID-19 vaccine. In one study anti-spike antibodies could be demonstrated in only 25% of KTR, after receiving full dose of mRNA vaccine.[73] However, seroconversion is known to increase in solid organ transplant recipients after administration of the second dose,[74] and despite lack of neutralizing antibodies vaccinees might be protected from severe COVID-19 disease by cellular immune response.[75] It is conventional to give higher and extra doses of hepatitis B vaccine to patients with reduced eGFR, and the same can also be explored for the COVID-19 vaccine. In patients on active immunosuppressants drugs, it is likely to be wise to postpone COVID-19 vaccination until dose of steroids have been reduced to below 20 mg prednisone equivalent a day, and six months have passed since the last dose of rituximab.[75] The currently available and widely used COVID 19 vaccines like killed whole virus vaccine, replication-defective viral-vectored vaccines ChAdOx1 nCoV-19 (Oxford-AstraZeneca), and the mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) are safe to use in these subgroups of the patients.[70],[71] Considering the vulnerability of these patients, they should be prioritized to receive COVID-19 vaccine. With the available evidence, it is inferred that the currently approved COVID-19 vaccines (mRNA and inactivated), are safe and efficacious in patients with various stages of CKD, patients on maintenance dialysis, patients with autoimmune diseases of the kidney and KTR.[70],[75]

 Conclusion



COVID-19 affects kidneys, mainly as a part of systemic illness and ARDS, although rarely it can also involve kidneys, irrespective of the systemic disease. It can lead to AKI, with poor immediate and long-term outcomes. It is important to prevent AKI, timely diagnose and treat it, and prevent its further progression. Patients with CKD, ESRD, and KTR, have the worst outcomes with COVID-19. Delivery of RRT is challenging for any health care system in a pandemic of this magnitude. So, it becomes important to protect the vulnerable population and appropriately channelize resources and human expertise, in situations like this. Epidemic control measures, appropriate use of drugs like dexamethasone and remdesivir, supportive care, and now rapid deployment of vaccine would prove effective, in mitigating the pandemic of COVID 19. All modalities of RRT are complementary to each other and can be used effectively in the management of patients with COVID-19 who require RRT. Appropriate use of specific antiviral drugs, identification of abnormal hyperimmune response, and timely introduction of immunosuppressant can throw a light, on the management of viral diseases in the future. This unprecedented pandemic has also seen, unprecedented, concerted international efforts, which has led to the rapid transmission of research and knowledge across the globe.

Conflict of interest: None declared.

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