COVID-19 And Kidney Disease Ⅱ

Minimal change disease. 

Minimal change disease (MCD) has also been reported in patients with COVID-19 (37, 46). The typical clinical presentation of MCD includes rapid onset of nephrotic range (>3.5 g/day) proteinuria, and kidney biopsy reveals normal glomeruli under light microscopy but severe podocyte injury by electron microscopy. It is unclear how COVID-19 may cause MCD, but since immune dysregulation is an important contributor to MCD, it is likely that immunologic factors are important. MCD is the most common glomerular lesion associated with SARS-CoV-2 vaccination in some series (38, 47); however, it remains unclear whether vaccination was causal in most cases. Most patients who develop MCD during COVID-19 or after vaccination has reduced proteinuria after treatment with glucocorticoids (38, 47). However, since these studies lacked controls, it remains unclear whether the treatment caused the resolution of proteinuria or if it would have resolved spontaneously.

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Membranous nephropathy. 

Membranous nephropathy (MN) is a common cause of primary nephrotic syndrome in adults and has also been reported to occur in some patients with COVID-19 (37, 48, 49). MN is caused by immunoglobulin G (IgG) deposition in the glomerular basement membrane, resulting in complement activation, which leads to podocyte injury. Though approximately 70% of cases of MN in the general population are caused by autoantibodies against the M-type phospholipase A2 receptor (50), these antibodies are variably present in patients with COVID-19 and MN (48, 49). De novo MN and relapsed MN have been reported after vaccination against SARS-CoV-2 (38, 45, 47, 51). The optimal approach to therapy for patients with MN during COVID-19 or after vaccination against SARS-CoV-2 is unknown.

Glomerulonephritis 

Glomerulonephritis presents clinically as increased proteinuria, and glomerular hematuria, and is often accompanied by reduced glomerular filtration, as reflected by increased serum creatinine. Kidney biopsy reveals glomerular inflammation and injury (52). Below, we summarize the most common types of glomerulonephritis occurring during COVID-19 and/or after vaccination against SARS-CoV-2.

IgA nephropathy.

Immunoglobin A nephropathy (IgAN) is diagnosed by the detection of pre-dominantly mesangial IgA deposits in kidney biopsies. IgAN is usually chronic and slowly progressive glomerulonephritis, but it can also manifest as a rapidly progressive GN (53). The majority of cases of IgAN reported related to COVID-19 have occurred after vaccination against SARS-CoV-2 and can also present as de novo or as a relapsing disease (45, 47). The optimal treatment for IgAN occurring during COVID-19 or after vaccination is unclear and aggressive immunosuppression has been reserved for rare cases with crescentic glomerulonephritis and AKI (47).

Systemic lupus erythematosus. 

Kidney disease is a common complication of SLE, and SLE can cause numerous histologic patterns of injury (54). There have been reports of exacerbations of lupus nephritis in patients with COVID-19 and several case reports of lupus nephritis (de novo or flare) after vaccination against SARS-CoV-2 (37, 38, 51, 55–57). The severity of CKD is strongly associated with clinical outcomes in patients with SLE and COVID-19 (58).

Other Glomerulopathies Related to COVID-19

De novo or relapsing ANCA (antineutrophil cytoplasmic antibody)–associated vasculitis (AAV) with rapidly progressive glomerulonephritis has been reported both during and after COVID-19 (38, 59–61). There have also been numerous case reports of AAV with glomerulonephritis occurring after vaccination against SARS-CoV-2 (38, 47, 51, 62). Patients with AAV after vaccination may have antibodies against myeloperoxidase, proteinase-3, or both antigens. Several other forms of glomerular injury have been reported in patients with COVID-19 and/or after vaccination against SARS-CoV-2, including anti-glomerular basement membrane disease (63–66) and thrombotic microangiopathy (36, 47, 67).

COVID-19 IN PATIENTS WITH KIDNEY FAILURE REQUIRING REPLACEMENT THERAPY Epidemiology and Risk Factors 

Patients with KFRT are at increased risk of acquiring COVID-19 (68). In an analysis of studies published by June 2020, the overall pooled prevalence for COVID-19 in KFRT patients from 12 countries was 22-fold higher than the average global prevalence (68). This is likely explained in part by the fact that patients receiving in-center dialysis are unable to self-isolate and must travel three or more times or more per week, often using public or group transportation to and from dialysis centers. Conversely, patients receiving KRT at home have a lower of incidence of COVID-19 than those receiving in-center KRT (69). Other risk factors for COVID-19 in patients with KFRT include living in a congregational residence, Black race, Hispanic ethnicity, lower income, and residing in more densely populated neighborhoods (70, 71). KFRT patients are also at risk of infection due to impaired innate and adaptive immunity (72). Since up to 50% of patients with KFRT develop asymptomatic infection and only 47% present with fever, compared to 90% in the general population, a high degree of clinical suspicion for COVID-19 is needed (73).

Early in the pandemic, approximately 50% of KFRT patients diagnosed with COVID-19 required hospitalization, and mortality rates were approximately 20–30% (74). Patients receiving in-center hemodialysis were 3–4 times more likely to be hospitalized with COVID-19 than patients receiving peritoneal dialysis (75). Factors associated with increased risk of death in patients with KFRT are similar to those in the general population, but these risk factors are enriched in the KFRT population (73, 76). Though it is likely that clinical outcomes in persons with KFRT and COVID-19 have improved significantly since the widespread availability of vaccination and other advances in the care of patients with COVID-19, recent data on outcomes in persons with KFRT and COVID-19 are lacking.

Preventing COVID-19 in Patients with KFRT

Since patients receiving in-center KRT are at particularly high risk of COVID-19, infection control measures have been implemented at dialysis units to reduce the risk of exposure and spread among patients and staff. These measures include screening for symptoms and/or exposure to COVID-19, strict use of personal protective equipment, adequate spacing between patients, isolation of those with symptoms or recent exposure, and disinfection of potentially contaminated surfaces (77). Increased use of home modalities, telehealth, eliminating group travel, and prolonged contact, may prevent the spread of the virus to other patients and staff.

Patients with KFRT have reduced innate and adaptive immunity, and most clinical trials testing the efficacy of vaccines against SARS-CoV-2 excluded patients with severe kidney disease. However, a systematic review reported that 41% of patients with KFRT developed antibodies after the first vaccine dose and 89% after the second dose (overall immunogenicity rate of 86%), which was lower than controls without kidney disease (78). Since evidence indicating the optimal number and timing of vaccine doses is rapidly evolving, clinicians should consult current guidelines for patients with KFRT. Vaccine hesitancy is a significant problem in persons with KFRT, especially among younger patients, women, and Black, Native American, and Pacific Islander patients, and the most stated reason for vaccine hesitancy is safety concerns (79). Vaccine education is needed to support this at-risk population.

COVID-19 IN KIDNEY TRANSPLANT RECIPIENTS

The COVID-19 pandemic has significantly impacted the community of KTRs, kidney donors, and wait-listed patients. Initial studies of KTRs with symptomatic COVID-19 reported mortality of approximately 30% (80, 81). More recent studies have reported much lower mortality (82) in KTRs but still significantly higher than in the general population. Risk factors for death in KTRs with COVID-19 are similar to those in the general population. AKI is a common complication in hospitalized patients and is strongly associated with mortality (81, 83). Early in the pandemic, up to 89% of KTRs required hospital admission, and ICU admission was associated with a twofold increase in mortality (84).

Nearly half of KTRs have minimal or no symptoms during SARS-CoV-2 infection, with evidence of prior infection detectable only by serologic testing (85). Despite impaired immune responses, most KTRs with infection detected by RT-PCR subsequently develop anti-SARS-CoV-2 antibodies (86). There is a delay in the development of anti-S IgG but no difference in the development of anti-nucleocapsid IgG compared to normal controls (87).

Few studies have reported clinical outcomes in vaccinated KTRs with COVID-19. In one study of 55 KTRs who developed COVID-19 after receiving two doses of mRNA vaccine, 27% required hospitalization, 6 required ICU admission, and 3 died. Of the 25 with available serologic data, 24 had no detectable anti-S antibodies and 1 had weak antibody titers, strongly suggesting that poor antibody responses to vaccination may increase risk of severe COVID-19 in KTRs (88).

MANAGEMENT OF IMMUNOSUPPRESSION

Though protocols at individual transplant centers vary, changes to immunosuppressive medications largely depend upon the severity of COVID-19. Many authors recommend reducing antimetabolite dose in outpatient KTRs with mild disease and withdrawal in inpatients with moderate or severe disease. Doses of calcineurin inhibitor (CNI) and/or mechanistic target of rapamycin inhibitor (mTORi) are also often reduced in hospitalized patients with moderate–severe disease and discontinued in severely ill KTRs requiring ICU care (89–91). Clinicians must be vigilant for severe drug interactions between immunosuppressants, especially CNI, and many medications including some SARS-CoV-2 medications (reviewed below). Glucocorticoids improve clinical outcomes in patients with severe COVID-19, and most hospitalized patients receive dexamethasone as per guidelines for the general population (91, 92). Most KTRs can then be returned to their baseline glucocorticoid dose if/when appropriate.

Vaccination in Kidney Transplant Recipients

KTRs have significantly reduced antibody response to vaccination against SARS-CoV-2 (91). Only 30–54% of KTRs develop detectable antibodies after two doses of mRNA vaccine, and approximately 70% develop antibodies after a third dose. The use of antimetabolites and belatacept is associated with reduced immune response to SARS-CoV-2 vaccination (91). Guidelines, therefore, state that KTRs should be vaccinated with at least three doses of an mRNA vaccine at least 2 weeks prior to transplantation (92). The US Centers for Disease Control and Prevention (CDC) currently recommends immunocompromised persons receive a fourth vaccine dose at least 3 months after the previous dose.

Though some centers temporarily ceased performing kidney transplants during periods of extremely high COVID-19 prevalence, reduced rates of community transmission, widespread availability of vaccination, and improved treatment protocols have allowed centers to safely resume kidney transplantation (93). However, additional research is needed to define optimal approaches to prevent and treat COVID-19 in KTRs.

COVID-19 Treatment in Patients with Kidney Disease

As noted above, patients with severe kidney disease were excluded from nearly all COVID-19 treatment trials, severely limiting the availability of data to support evidence-based treatment recommendations (94). Decisions regarding treatment with antiviral and immunomodulatory medications in KFRT patients and KTRs with COVID-19 depend on the availability of medications; duration and degree of symptoms; and risk factors including age, comorbidities, and vaccine status. CKD patients and KTRs are defined by the CDC as persons with high-risk medical conditions and are therefore prioritized for access to COVID-19 therapeutics. Since treatment guidelines are rapidly evolving as new treatments and evidence become available, clinicians are encouraged to consult updated guidelines, including those maintained by the US National Institutes of Health (NIH) (92). Below, we highlight important information for clinicians considering the use of specific therapies for COVID-19 in KTRs and in patients with severely reduced kidney function due to AKI or CKD.

Several antiviral medications, including molnupiravir, ritonavir-boosted nirmatrelvir, and remdesivir, have been approved for use in patients with COVID-19. At this time, NIH/CDC guidelines only endorse the use of molnupiravir and ritonavir-boosted nirmatrelvir in some outpatients with COVID-19 (92). Molnupiravir is a cytidine analog that inhibits viral RNA replication,and since it is not cleared by the kidneys, no dose adjustment is necessary in patients with kidney disease (92).

Nirmatrelvir is an inhibitor of the SARS-CoV-2 MPRO protease. Since nirmatrelvir is metabolized by the liver via cytochrome P450 (CYP) 3A4, it is formulated with ritonavir, a potent CYP3A4 inhibitor, to prolong nirmatrelvir half-life. Nirmatrelvir/ritonavir dosage should be reduced by 50% in adults with eGFR 30–60 mL/min/1.73 m2 and is not recommended for use in patients with eGFR < 30 mL/min/1.73 m2 (92). Since CNI and mTORi are metabolized by CYP3A4, nirmatrelvir/ritonavir should be avoided in most KTRs

Remdesivir, an adenosine analog inhibitor of the viral RNA polymerase, is currently a treatment option for selected outpatients and inpatients with COVID-19 (92). Remdesivir is administered as an intravenous infusion, and though redeliver is not cleared by the kidneys, the vehicle formulated with it [sulfobutylether-B-cyclodextrin (SBECD)] is eliminated by the kidneys. Since high levels of SBECD can cause liver toxicity, it is recommended that clinicians use reconstituted lyophilized remdesivir (contains less SBECD), rather than the solution formulation of remdesivir, in patients with eGFR < 30 mL/min/1.73 m2 (92). Though the US Food and Drug Administration (FDA) does not currently recommend redelivering in patients with eGFR < 30 mL/min/1.73 m2, the CDC recommends that clinicians consider it in patients in whom the benefits may outweigh the risks (92). Recent case series have reported the use of redelivering in patients with severe kidney disease, including those with KFRT, suggesting it can be used in these patients without causing liver toxicity, but the risks and benefits of redelivering in this population require further study (95, 96)

Several anti-S monoclonal antibody formulations have been approved for use by the FDA and other regulatory agencies around the world. Since the efficacy of these antibodies can be strongly affected by mutations in S, recommendations regarding the use of specific monoclonal antibodies for the prevention and treatment of COVID-19 change rapidly as new SARS-CoV-2 variants emerge (92). We, therefore, do not discuss indications for specific monoclonal antibodies, and clinicians are encouraged to review the most current guidelines in making treatment decisions. Since antibodies are not cleared by the kidneys, kidney disease is not a contraindication to monoclonal antibody treatment, and dose adjustment is not required for patients with kidney failure. It is no longer recommended to delay SARS-CoV-2 vaccination in patients who have been treated with monoclonal antibodies.

Immunomodulatory medications including tocilizumab (a monoclonal antibody inhibitor of the interleukin-6 receptor) and baricitinib (an orally available JAK1/JAK2 inhibitor) are recommended as treatment options in selected patients with COVID-19 (92). Since tocilizumab is a monoclonal antibody, no dose adjustment is necessary in patients with kidney disease. However, baricitinib is primarily cleared by the kidneys. Dose adjustment is necessary for patients with eGFR < 60 mL/min/1.73 m2, and baricitinib is not recommended in those with eGFR < 15 mL/ min/1.73 m2 (92).

CONCLUSION 

COVID-19 can cause many forms of kidney injury, which occurs primarily due to systemic immune activation and/or ischemic injury. Though kidney cells express proteins that may allow infection by SARS-CoV-2, it remains controversial how often kidney cells are infected in patients with COVID-19 and whether infection of kidney cells contributes to kidney disease. COVID-19 has had a disproportionate impact upon persons with CKD and KTRs, who are at markedly increased risk of morbidity and mortality due to COVID-19. Further research is needed to determine the optimal approach to prevent COVID-19 in persons with kidney disease and to improve clinical outcomes in persons with COVID-19 and kidney disease.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS The authors thank our colleagues in the Division of Nephrology at the Albert Einstein College of Medicine/Montefiore Medical Center, whose selfless and heroic efforts have saved countless lives during the COVID-19 pandemic.

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