On the occasion of world kidney day 2023;renal impacts of COVID-19

World kidney day is an international campaign focused on bringing awareness to kidney health throughout the world and reducing the incidence of renal disease and its related medical complications. This mini-review sought to take a short look on the renal impact of SARS-CoV-2, with a particular focus on post-COVID-19 nephropathy as a new dilemma in the era of nephrology, which can be a new concern for nephrologists that requires more attention and particular strategies. Keywords: SARS-CoV-2 vaccine, Glomerulonephritis, Acute kidney injury, World kidney day, SARS-CoV-2, COVID-19-related nephropathy, APOL1 gene, Collapsing glomerulopathy, Podocyte.Copyright © 2023 The Author(s);Published by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Collapsing Glomerulopathy in a Patient With Recent COVID-19 and APOL-1 High-Risk Genotype

Introduction: Collapsing glomerulopathy (CG) is an aggressive subtype of focal segmental glomerulosclerosis, associated with poor renal outcomes. Risk factors for CG include HIV infection, APOL1 high-risk genotypes, and CG has also recently been reported in patients with COVID-19. We report a case of CG with acute kidney injury (AKI) in a patient with a high risk APOL1 genotype, who had renal recovery after prednisone treatment. Case Description: A 43-year-old male with no past medical history presented with fever, myalgia, hemoptysis, vomiting, and diarrhea of 2 weeks duration. Initial exam was remarkable for temperature 103 degrees Fahrenheit, SpO2 95% on room air, and inspiratory crepitations without peripheral edema. Labs were notable for serum creatinine 2.6 mg/dL (unknown baseline), peak creatine kinase 4037 U/L, and urine protein creatinine ratio 19 g/g without RBCs. Chest CT was consistent with multilobar pneumonia. SARS-CoV2 PCR was repeatedly negative but COVID-19 spike and nucleocapsid IgG were positive. Extensive serologic workup for causes of glomerulonephritis and nephrotic syndrome was negative. He was empirically treated with antibiotics for pneumonia but cultures remained negative. Bronchoscopy revealed no evidence of alveolar hemorrhage. His renal function worsened, requiring hemodialysis. Kidney biopsy revealed collapsing glomerulopathy associated with thrombotic microangiopathy, few myoglobin casts suggestive of rhabdomyolysis, and acute tubular injury. Prednisone was initiated at 1mg/kg daily and tapered over 2 months. Lisinopril was initiated for proteinuria. After 5 months, serum creatinine was 1.3 mg/dL and urine protein creatinine ratio improved to 0.6g/g. Genetic testing revealed APOL1 G1/G1 genotype. Discussion(s): In this patient, SARS-CoV2 PCR was likely negative because he presented weeks after symptom onset but the clinical course and serologic evidence of prior SARS-CoV-2 infection supports the diagnosis of COVID-19 associated CG in the setting of APOL1 high-risk G1/G1. Proposed mechanisms of COVID-19-related CG include increased cytokines, that upregulate podocyte expression of toxic APOL1 variants and AKI with tubular injury is often found. Our patient improved with steroid treatment but the treatment of COVID-19 associated CG requires further study.

Long-Term Renal Outcomes of COVID-19-Associated Nephropathy (COVAN)

Background: COVID-19-associated nephropathy (COVAN) is a type of collapsing glomerulopathy that leads to acute kidney injury (AKI) and overt proteinuria in individuals with apolipoprotein L1 (APOL1) polymorphism infected with SARS-CoV-2. Although the severity of the acute presentation of COVAN is well described, the long-term renal prognosis has not been clearly established. Method(s): We retrospectively identified native kidney biopsies from patients with diagnosis of COVAN discharged alive between January 2020 and March 2021. Time of biopsy pathological and clinical data were collected. We performed APOL1 genotyping for G1/G2 risk alleles. We examined the rate of end-stage kidney disease (ESKD), de novo or progressive chronic kidney disease (CKD) and death. Factors associated with those outcomes were assessed by logistic regression. Result(s): A total of 43 patients with COVAN with median follow-up at 244 days were included. Mean age was 53 +/- 12 years (range 30-78), 49% women, and 85% were of African descent. High-risk APOL1 genotypes were found in 86%. Most presented with AKI (91%) and nephrotic-range proteinuria (81%). Sixteen patients required dialysis at presentation (AKI-RRT), 8 of which reached ESKD and dialysis dependence at followup. Additionally, 6 patients without AKI-RRT developed ESKD and required dialysis at follow-up. Forty patients (93%) either developed de novo CKD or progressed to advanced stage of CKD [mean serum creatinine (sCr) 3.1 +/- 1.9 mg/dL]. Overall, 35% reached the combined endpoint of ESKD, progressive CKD or death. Predictive factors of ESKD included older age (59.1 +/- 13.9 vs. 50.4 +/- 10.7 years, p=0.03), increased sCr at time of biopsy (9.4 +/- 3.2 vs. 6.0 +/- 4.9, p=0.03), increased glomerular obsolescence (52.8 +/- 21.3 vs. 25.0 +/- 23.2%, p=0.0005), and IFTA [moderate-severe vs. mild, OR 9.8 (CI: 1.1-85.2), p=0.03]. AKI-RRT, sex, proteinuria at the time of biopsy, and absence vs. presence of an APOL1 high-risk genotype were not predictive of ESKD. Conclusion(s): COVAN is associated with ominous long-term renal sequelae. Serum creatinine at time of biopsy, patient age, glomerular obsolescence, and IFTA are associated with greater risk of ESKD.

IgA Vasculitis After COVID-19 Vaccination: A Rare but Significant Complication

Introduction: A 24 year old male presented with rash, gastrointestinal bleeding and nephrotic syndrome one week after first COVID vaccination. Renal biopsy revealed crescentic IgA nephritis. He was treated steroids and responded clinically but continues to have proteinuria. Case Description: A 24 year old male with history of cerebral palsy presented with a vasculitic rash, hematochezia and edema. He had no prior history of renal or autoimmune disease. Symptoms developed one week after first dose of Moderna mRNA-1273 vaccine. Serum albumin was 1.6 g/dL and urine protein-creatinine ratio 8.5. Endoscopy showed esophagitis and small bowel ulcerations. Renal biopsy showed focally crescentic and necrotizing proliferative glomerulitis with IgA dominant deposits consistent with IgA vasculitis with renal involvement. He received pulse dose solumedrol followed by prednisone taper. Cyclophosphamide was initiated but then stopped due to cytopenias. After several weeks GI bleeding resolved spontaneously and proteinuria improved but remained in the nephrotic range. The course was further complicated by positive COVID testing prior to discharge-he was asymptomatic and received sotrovimab. On followup three months later the patient's edema resolved and serum albumin normalized. He continues to have subnephrotic range proteinuria with 2.3 grams/24 hours and active urinary sediment with dysmorphic red cells. He remains on steroid taper with plan for repeat renal biopsy to inform decisions regarding further immune suppression. He has not been rechallenged with COVID vaccine. Discussion(s): Rare associations between COVID vaccination and both de-novo and relapsing glomerular lesions, including minimal change disease, IgA nephropathy, ANCA and anti GBM glomerulonephritis, have been reported. COVID infection itself has been associated with an FSGS type lesion termed COVID-associated nephropathy (COVAN). As highlighted by this case, unvaccinated or partially vaccinated patients are at increased risk for COVID infection. Thus even in those with known glomerular disease, vaccination should still be recommended. Studies are needed to determine if patients with off-target glomerulopathies can be safely rechallenged with COVID vaccine, whether the course of COVID vaccine-associated disease glomerular lesions mimic the primary glomerular disease and how to optimally manage these patients.

Digital spatial profiling of collapsing glomerulopathy.

Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV or SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli isolated from formalin fixed paraffin embedded sections from HIV or SARS-CoV-2-infected patients with biopsy-confirmed collapsing glomerulopathy and used normal biopsy sections as controls. Even though glomeruli with collapsing features appeared histologically similar across both groups of patients by light microscopy, the increased resolution of DSP uncovered intra- and inter-patient heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Thus, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

Coronavirus Disease (COVID)-19 and Diabetic Kidney Disease.

The present review describes COVID-19 severity in diabetes and diabetic kidney disease. We discuss the crucial effect of COVID-19-associated cytokine storm and linked injuries and associated severe mesenchymal activation in tubular epithelial cells, endothelial cells, and macrophages that influence neighboring cell homeostasis, resulting in severe proteinuria and organ fibrosis in diabetes. Altered microRNA expression disrupts cellular homeostasis and the renin-angiotensin-system, targets reno-protective signaling proteins, such as angiotensin-converting enzyme 2 (ACE2) and MAS1 receptor (MAS), and facilitates viral entry and replication in kidney cells. COVID-19-associated endotheliopathy that interacts with other cell types, such as neutrophils, platelets, and macrophages, is one factor that accelerates prethrombotic reactions and thrombus formation, resulting in organ failures in diabetes. Apart from targeting vital signaling through ACE2 and MAS, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are also associated with higher profibrotic dipeptidyl transferase-4 (DPP-4)-mediated mechanisms and suppression of AMP-activated protein kinase (AMPK) activation in kidney cells. Lowered DPP-4 levels and restoration of AMPK levels are organ-protective, suggesting a pathogenic role of DPP-4 and a protective role of AMPK in diabetic COVID-19 patients. In addition to standard care provided to COVID-19 patients, we urgently need novel drug therapies that support the stability and function of both organs and cell types in diabetes.