A Case of COVID-Associated Nephropathy (COVAN).

Collapsing glomerulopathy is a variant of focal segmental glomerulosclerosis (FSGS) causing rapid renal failure. There has been an emergence of these cases among African American patients with COVID-19, especially those with the apolipoprotein L1 (APOL1) allele. We present a case of an African American patient with COVID-19 who tested positive for the APOL1 allele in the setting of acute renal deterioration. This provides a partial explanation for the increased burden of kidney failure in this population. As cases of COVID-19 persist, COVID-associated nephropathy (COVAN) should be suspected in patients with acute kidney injury and treatment tailored accordingly.

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.

APOL1 Risk Variants and Acute Kidney Injury in Black Americans with COVID-19.

BACKGROUND AND OBJECTIVES: Black Americans have a higher incidence of kidney disease compared with populations that do not have recent African ancestry. Two risk variants in the APOL1 are responsible for a portion of this higher risk. We sought to assess the odds of AKI conferred by APOL1 risk alleles in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Black Americans who tested positive for coronavirus disease 2019 (COVID-19) were genotyped to determine APOL1 risk allele status. We assessed the incidence of AKI, persistent AKI, and AKI requiring KRT within 21 days of the PCR-based diagnosis. Outcomes were adjusted for age, sex, body mass index, hypertension, eGFR, and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. RESULTS: In total, 126 cases of SARS-CoV-2 infection were included within a 5-month period, with 16 (13%) and 110 (87%) cases with two and zero/one APOL1 high-risk alleles, respectively. AKI occurred in 11 (69%) patients with two APOL1 high-risk alleles and 39 (35%) patients with zero/one high-risk alleles (adjusted odds ratio, 4.41; 95% confidence interval, 1.11 to 17.52; P=0.04). Persistent AKI occurred in eight (50%) patients with two APOL1 high-risk alleles and 21 (19%) of those with zero/one high-risk alleles (adjusted odds ratio, 3.53; 95% confidence interval, 1.8 to 11.57; P=0.04). AKI KRT occurred in four (25%) of those with two APOL1 high-risk alleles and eight (7%) of those with zero/one high-risk alleles (adjusted odds ratio, 4.99; 95% confidence interval, 1.02 to 24.4, P=0.05). CONCLUSIONS: APOL1 high-risk alleles are associated with greater odds of AKI in Black American patients with COVID-19.

An APOL1 genotype associated with adverse Covid- 19 outcomes: UK-Biobank data, September 2021

Introduction/ Background: The risk of hospitalisation/death from Covid-19 in the UK is disproportionately high in black populations. In people of African ancestry, variants of the APOL1 gene (G1 and G2) are associated with risk of noncommunicable diseases, and sleeping sickness. We hypothesise that adverse Covid-19 outcomes are also associated with these variants. Methods: The UK Biobank contains genetic, lifestyle, and health information from 7,643 individuals who self-report as being of black ethnicity. Within this cohort there had been 142 hospitalisations and 36 deaths attributed to Covid-19 as of September 2021. Taking risk factors previously associated with poor Covid-19 outcomes (age, sex, chronic kidney disease, atrial fibrillation, hypertension, depression, chronic obstructive pulmonary disease, dementia, type 2 diabetes, obesity, and Townsend deprivation index) as covariates, we used Firth's Bias Reduced Logistic Regression in R to identify APOL1 genotypes that were associated with hospitalisation and death. Results: Individuals who are heterozygous for variants at both the G1 and the G2 loci are termed G1/G2 compound heterozygotes. G1/G2 compound heterozygosity was associated with hospitalisation (odds ratio = 2.4, 95% confidence interval: 1.2-4.5, p = 0.010) and death (odds ratio = 5.4, 95% confidence interval: 1.8-15.4, p = 0.004). This association has not previously been detected in genome wide association studies, as they usually examine individual loci separately rather than considering combinations of loci. Impact: This has implications at the individual and population level by identifying those at higher risk of severe Covid-19 who would benefit from early vaccination and treatment. This is especially relevant to geographical regions where APOL1 G1 and G2 variants are common, such as West and Central Africa and their diaspora. Conclusion: This data supports hypotheses proposing APOL1 genotype (and specifically G1/G2 compound heterozygosity) as a significant contributory factor in the increased rates of poor Covid-19 outcomes observed in people of African ancestry.

Presentation and Variability of APOL1-Related Kidney Disease

Inheritance of the APOL1 G1 or G2 risk alleles in the homozygous or compound heterozygous state, are associated with a ~7-30X increased risk of development of chronic kidney disease (CKD), and with collapsing glomerulopathies in individuals with viral infections including COVID-19 or HIV. Identification of APOL1 high risk genotypes (HRG) can impact patient treatment, prognosis and kidney donor selection. Approximately 13% of African Americans (AA) have an APOL1 HRG, indicating genetic testing in this population can identify those at-risk for CKD development, leading to appropriate patient counseling and management. Here we sought to understand the clinical presentation and variability among patients with APOL1 HRGs, following the implementation of genetic testing for kidney disease with a broad panel at a Louisiana Nephrology clinic. Clinical genetic testing of patient samples was performed using a >380 kidney gene panel (the RenasightTM test, Natera, Inc.) A retrospective review of clinical data for individuals positive for an APOL1 HRG (G1/G1, G2/G2, G1/G2) was performed. We identified 12 patients that were positive for an APOL1 HRG, with all genotypes represented: G1/G1 (n=8), G1/G2 (n=3), and G2/G2 (n=1). Among this cohort, 100% (12/12) were of AA descent. At the time of testing 91% (11/12) of the patients were diagnosed with CKD or ESRD with proteinuria. Biopsy confirmed focal segmental glomerulosclerosis (FSGS) in two patients and collapsing glomerulopathy in one patient. The most common comorbidities among this cohort were hypertension (9/12) and diabetes mellitus (2/12). Four patients had a history of infection with COVID-19 (n=3) or HIV (n=1), three of whom had renal involvement (acute kidney injury or CKD and proteinuria). Use of a broad kidney gene panel enabled the identification of APOL1 HRGs in individuals for which hypertension or diabetes may have otherwise been attributed as the primary cause of CKD. APOL1 HRGs could also provide context for the renal involvement seen in the patients with COVID-19 or HIV infection. Broad panel genetic testing provides an accessible tool for nephrology clinics to help identify individuals at risk for positivity for an APOL1 HRG, including those of AA descent with hypertensive, proteinuric CKD.

COVID-19 ASSOCIATED COLLAPSING VARIANT OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS: A CASE SERIES OF 7 PATIENTS FROM A SINGLE UK CENTRE

BACKGROUND AND AIMS: Cases of collapsing glomerulopathy in association with COVID-19 infection have been reported worldwide, frequently referred to as COVAN (COVID-19 Associated Nephropathy). Affected patients are almost exclusively of Black ethnicity, likely associated with APOL-1 renal risk variants. There remains a paucity of data on patient outcomes, however, and it is unclear how the natural history of this disease may vary from HIV-associated nephropathy (HIVAN) and other non-viral causes of collapsing FSGS. Here, we present a case series of seven patients with presumed COVAN from a single tertiary UK renal centre;highlighting patient demography, biopsy findings, clinical management and short-term renal outcomes. METHOD: We identified all adult patients presenting to our centre with nephrotic syndrome and a renal biopsy demonstrating collapsing glomerulopathy, in association with a positive COVID-19 PCR swab result. Detailed case note reviews were undertaken using electronic health records to extract data relevant to patient demography, co-morbidities, COVID -19 symptoms, renal biopsy findings, treatment and biochemical parameters, both at the time of presentation and during follow-up at 1, 3, 6 and 12 months respectively (where available). RESULTS: In total, we identified seven patients with presumed COVAN. Three of the seven patients were male, median age was 60 years (range 25-80 years). Six of the seven patients were of Black ethnicity and one patient was of South Asian ethnicity (renal transplant recipient with donor ethnicity unknown). All seven patients had a background of hypertension, 5/7 had known chronic kidney disease (CKD), 5/7 had type 2 diabetes mellitus (T2DM) and 4/7 were obese (BMI > 30). In the vast majority of cases, associated COVID-19 symptoms were mild. All patients had profound nephrotic syndrome at the time of renal biopsy, with median urine ACR 1085 mg/mmol (range 682-1380 mg/mmol) and median serum albumin 15 g/L (range 8-20 g/L). Two of seven patients had mild AKI (stage 1) and 5/7 patients had severe AKI (stage 3), with 3 of these patients receiving acute haemodialysis therapy. Management of glomerulopathy was supportive in all cases, including diuresis and anticoagulation (two patients received a short course of oral dexamethasone for their COVID-19 symptoms). ACE inhibitors/angiotensin receptor blockers were re-introduced in two patients and newly commenced in two further patients during follow-up. At 6 months follow-up, one patient remained dialysis dependant and one patient had ongoing decline in renal function (renal transplant recipient);all other patients achieved at least partial remission, with > 50% reduction in urine ACR and some (but not complete) recovery in renal function (Fig. 1). There were no viral particles identified on direct examination of renal biopsy specimens, but 4/7 biopsies exhibited tubulo-reticular inclusions, suggesting an interferon-driven systemic inflammatory process. CONCLUSION: In this case series of seven COVAN cases from a single tertiary UK centre, we noted that in keeping with reports from North America, Black ethnicity patients were disproportionately affected. Partial remission was achieved in most of our cases with supportive treatment only;however, ongoing monitoring of this cohort is required to better understand longer-term patient outcomes. Testing for APOL-1 gene mutations and molecular testing of biopsy samples for this cohort is also ongoing to facilitate better insights into pathophysiology and risk factors associated with this novel disease. (Figure Presented).

MINIMAL CHANGE DISEASE SECONDARY TO SARS-COV-2 (COVID-19) INFECTION: A REPORT OF 2 CASES AND REVIEW OF RELATED LITERATURE

BACKGROUND AND AIMS: The COVID-19 pandemic has brought to the forefront a wide spectrum of renal injuries that included glomerulopathies, some of which were recently highlighted in various case reports. These consist of focal and segmental glomerulosclerosis (FSGS) and minimal change disease (MCD).1 These changes were found among seemingly vulnerable populations such as the African American and Caucasian ethnicities with paucity of reports among other races. We present two cases of biopsy-confirmed MCD secondary to COVID-19 infection among adult Filipino patients. METHODS: Case Report RESULTS: Case 1 A 40-year-old Filipino female with a history of right total mastectomy 2 years prior for a low-grade phyllodes tumor and no other medical comorbidities was admitted due to stillbirth. She was noted to have bipedal edema with a positive COVID-19 RT-PCR swab. Further workup revealed a serum creatinine 1.04 mg/dL, urine RBC 1/HPF and a 24-h urine protein of 9.22 g with hypoalbuminemia and dyslipidemia. Serologic workup was noted to be negative. She was started on Losartan, Atorvastatin, and Furosemide. A kidney biopsy was performed which demonstrated unremarkable light microscopy and immunofluorescence and widespread podocyte-foot process effacement. These biopsy findings were interpreted to be consistent with minimal change disease. She was started on Prednisone at 1 mg/kg/day with continuation of both Losartan and Atorvastatin. Six weeks after, the patient achieved complete remission with resolution of both hypoalbuminemia and dyslipidemia. She also reports no further recurrence of edema. Case 2 A 61-year-old Filipino male with a history of type 2 diabetes mellitus, hypertension, dyslipidemia and mild COVID-19 infection 4 months prior now presented with diarrhea. A routine COVID-19 RT-PCR swab revealed a re-infection. Physical examination noted bipedal edema. Further workup demonstrated a serum creatinine 3.39 mg/dL, urine RBC 2/HPF and urine ACR 2.6 g/g. Serologic tests were negative. He was diagnosed with Nephrotic Syndrome and underwent kidney biopsy. Findings showed an unremarkable light microscopy and immunofluorescence with widespread podocyte-foot process effacement. These findings were found to be consistent with minimal change disease and acute tubular injury. He was started on Prednisone (1 mg/kg/day), Losartan, Furosemide and Atorvastatin. Eight weeks later, the patient achieved complete remission with resolution of edema. CONCLUSION: It is currently suspected that APOL1 risk variants found in reported cases of COVID-19-associated glomerulopathies are underlying toxic gain-of-function mutations that drive kidney disease.2 It is interesting to note that APOL1 renal risk variants are found exclusively in African-derived chromosomes and are rarely found among European or Asian chromosomes.3 Even though an APOL1 genotyping was not performed, our case reports provide the first examples of MCD among individuals without a high-risk genotype (APOL1) by epidemiology and enlarge the literature on MCD in COVID-19. We posit that there may be other underlying predispositions or mechanisms that may be driving glomerulopathy formation among COVID-19 patients aside from their inherent APOL 1 risk. Both of our patients were started on steroid therapy with a tapering regimen and achieved complete remission on subsequent follow-up. Existing reports suggest that most cases of COVID-19-associated MCD will often achieve resolution of AKI and proteinuria with steroid therapy, even in those with high-risk APOL1 genotype, emphasizing the need for an accurate histologic classification.4 (Figure Presented).

eP270: Incorporating genetic services into adult kidney disease care

Introduction: Chronic kidney disease (CKD) is a debilitating disorder associated with significant morbidity and mortality. CKD diagnoses can have overlapping, non-specific clinical symptoms and histology findings, and the underlying etiology can remain unknown. Recent studies have shown that 1 in 10 adults with CKD has a genetic component to their disease. However, genetic services are limited in this patient population and disproportionally impact those from medically underserved communities. Therefore, an adult kidney genetics clinic was developed within the Division of Nephrology at a large urban academic medical center to increase access to genetic services and testing in adults with kidney disease. Methods: In June 2019, the Division of Nephrology at Columbia University Irving Medical Center created a Kidney Genetics Clinic staffed by genetic counselors (GC) and nephrologists. Initially, appointments were held in-person but transitioned to telemedicine beginning in May 2020 due to the COVID-19 pandemic. The clinic utilized two appointment types: full genetic consults (staffed by a GC and nephrologist) and genetic counseling visits (staffed by a GC only). Genetic counselors implemented several genetic education initiatives to increase clinic referrals and increase provider interest. These included bi-monthly genetic case seminars, monthly genetic research sign-out rounds, a continuing education course focusing on clinical genetics, and genetic counseling student rotations. Results: Between June 2019 and June 2021, the clinic received 277 referrals, averaging 11 per month. Of those referred, 83% were scheduled, and 212 patients underwent genetic evaluation. The median wait time from referral to appointment was 37 days, and the no-show rate was 8%. The majority (89%) of appointments were via telehealth, either by phone or video, while the rest occurred in person. Genetic counseling visits accounted for 21% of patient appointments, and the remaining ones were full genetic consults. Most patients who attended their genetics appointment were in the NY tri-state area (87%), but 12% resided in nine additional states, three other countries, and one US territory. The primary insurance was Medicare in 10% of patients and Medicaid in 17%. Most patients described themselves as white (n=126), while 47 patients reported Hispanic or Latino ethnicity, 36 identified as Black, 15 Asian, and 4 Native Hawaiian or Pacific Islander. The average age of the patient population was 44 years old (ranging from 18 to 87). Patients seen in the genetics clinic were referred for a variety of indications and included several different kidney diagnoses, including: CAKUT (n=6), tubulointerstitial disease (n=26), suspected or clinical diagnosis of a collagenopathy (n=38), focal segmental glomerulosclerosis (FSGS) (n=28), tubulopathy or electrolyte disorder (n=16), cystic kidney disease (including PKD) (n=24), hematuria and/or proteinuria (n=31), complement dysregulation (n=8), tumor or cancer (n=4), and CKD of unknown etiology (n=23). Six patients had a known genetic diagnosis, and 23 were healthy relatives of individuals with a known genetic diagnosis or potential kidney donors. Of patients seen in the kidney genetics clinic, 42% reported a family history of CKD or a personal or family history of a genetic diagnosis. A total of 186 clinical genetic tests were ordered on 174 patients;nine tests still have results pending, and ten were canceled. Genetic tests that were ordered included: small (>50) and large gene panels (n=146), exome sequencing (n=6), microarrays (n=4), and single gene and targeted variant testing (n=20). In patients that did not undergo genetic testing, reasons included: not clinically indicated, testing already ordered, and financial concerns. A diagnostic or candidate diagnostic positive result was reported in 29% of patients, involving 18 different genes. Pathogenic or likely pathogenic variants were most common in COL4A4 (n=11), followed by PKD1 (n=8). Similarly, the highest diagnostic yield was in patients with a referral ndication of a suspected collagenopathy (diagnosis in 50%) or cystic disease (diagnosis in 50%). A non-diagnostic positive finding was identified in 9% of patients and included results such as secondary findings (n=1), carrier status (n=5), and risk factors, such as an APOL1 high-risk genotype (n=9). The identification of a genetic diagnosis in patients impacted several areas of clinical care, including referrals to specialists, kidney donor selection, clinical trial eligibility (for example, in patients with a genetic Alport diagnosis), and increased access to medications (such as tolvaptan in patients with PKD1 variants). In addition, those with non-diagnostic findings were referred to ongoing research studies at the medical center to elucidate the genetics of kidney disease. Conclusion: Here, we describe the successful creation and implementation of an adult kidney genetics clinic at a large medical center. By utilizing a combination of in-person appointments and telemedicine, the clinic was able to provide access to genomic services across a broad geographic region and to a diverse patient population of adults with kidney disease. Genetic education efforts were an integral component of the clinic's success, as it increased visibility and helped providers identify patients who would benefit from genetic services, as evidenced by the high percentage of referred patients scheduling appointments and high diagnostic yield in patients undergoing testing. Identifying genetic diagnoses in this patient population has several clinical implications, including changes in management, eligibility for genetically stratified clinical trials, and treatment decisions. Continued and ongoing access to genomic services is a fundamental component of patient care in adults with kidney disease.

Terminal transplant failure due to Covid-19 associated nephrotic glomerulonephritis

Background: Covid 19 infection associated glomerulopathy has most often been described as collapsing FSGS and occurs almost exclusively in black patients carrying APOL1 risk genotypes. Methods: We report an acute, COVID19-associated nephrotic glome-rulonephritis in a caucasian transplant recipient which led to terminal graft failure. Results: This 67 y old white female had received a living donor kidney 31 years ago for medullary cystic disease. Her clinical course on cyclos-porin/MMF had been stable with an eGFR around 20 ml/min/1.73 m in the last years. On her 31st annual checkup, she presented with an unusually high blood pressure (171/108), but afebrile (36.9°C), with an eGFR or 21 ml/min/1.73 m, a protein/creatinine ratio (PCR) of 503 mg/mmol and normal serum albumin. Physical examination was unremarkable except for some pain from thoracic herpes zoster 2 months previously. Her husband had tested positive for Covid19 on the same morning. She developed fever (38.9 °C) and cough on the same evening and tested positive for Covid19 the next day. MMF was paused and low dose steroids were instituted. In the following weeks, full nephrotic syndrome developed (edema, PCR of 1350 mg/mmol, serum albumin ↓ to 28 g/l). eGFR decreased to 8-10 ml/min/1.73 m. Renal biopsy on day 42 showed several instances of focal segmental sclerosis with collapsing morphology (Figure 1, consistent with "collapsing glomerulopathy"). In addition there were signs of capsular proliferation and electron dense deposits in the GBM, consistent with glome-rulonephritis. Sequencing of Exon 6 of the APOL1 gene was negative for G1 and G2 risk alleles in the patient and her kidney donor. Nephrotic syndrome never remitted, and renal function did not recover. Peritoneal dialysis was initiated 9 months after the Covid 19 infection. Figure 2: Self-rated health status over time Conclusions: Higher mortality in older recipients complies with data from the general population. The non-linear relationship between age and graft loss and the higher scored self-rated health status at all follow-up time-points compared to the pre-transplant status-regardless of age-highlight that age alone might not be an accurate measure for risk prediction and clinical decision making in kidney transplantation. Exploring other independent predictors, such as frailty as an indicator for biological age should be considered. Conclusions: This case documents an unusal Covid19-associated glo-merulonephritis with "collapsing features" which led to the loss of a 31 years functioning living donor kidney.