Recurrent Focal Segmental Glomeruloscleosis Progressing to Collapsing Glomerulopathy in Renal Graft of an Autopsy study

Introduction/Objective Collapsing glomerulopathy (CGN) mainly occurs in patients of African descent because a majority of these patients have APOL-1 gene mutations that results in damage of terminally differentiated podocytes, diffuse fusion of foot processes, and podocyte hyperplasia. Idiopathic FSGS is associated with high rates of recurrent FSGS in renal transplants and can be seen in patients with APOL-1 gene mutations as well, but recurrent FSGS progressing to CGN is not reported. Here we report an autopsy case with renal transplant showing recurrent FSGS progressing to CGN. Methods/Case Report Our patient was a 32 year old African American man who had a native renal biopsy which showed primary FSGS (with no infectious history) 8 years ago. Last year he received a renal transplantation (complex donor kidney from a deceased 25 year old man with pre-mortem serum creatinine (sCr) at 0.7 mg/dl). His initial post- transplant sCr level was as low as 1.17 mg/dl. However, in 4 months his sCr went up and he began to have higher levels of proteinuria. Sequential biopsies indicated that the patient developed a recurrent FSGS that progressed to show features of CGN. In his autopsy kidney graft, approximately 50% of glomeruli show collapsed loops with various degrees of hyperplasic podocytes, confirmed by positive CD133 staining (a progenitor cell marker). In addition, the hyperplastic podocytes lost WT-1 expression and were positive for Ki-67 staining. Distal tubules showed obvious cystic dilation. Overall findings were consistent with a severe form of CGN. Results (if a Case Study enter NA) NA Conclusion The clinical presentation of recurrent FSGS progressing to collapsing FSGS in our patient suggests that CGN and idiopathic FSGS may share a common pathophysiologic mechanism of disease.

Glomerular Disease in Temporal Association to SARS-CoV-2 Vaccination - A Series of 29 Cases

Background: Immune responses to vaccination are a known trigger for a new onset of glomerular disease or disease flare in susceptible individuals. Mass immunization against SARS-CoV-2 in the COVID-19 pandemic provides a unique opportunity to study vaccination-associated autoimmune kidney diseases. In the recent literature, there are several case reports demonstrating a temporal association of SARS-CoV-2 immunization and kidney diseases. Methods: Here, we present a series of 29 cases of biopsy-proven glomerular disease in patients recently vaccinated against SARS-CoV-2 and identified patients who developed a new onset of IgA nephropathy, minimal change disease, membranous nephropathy, ANCA-associated glomerulonephritis, collapsing glomerulopathy, and diffuse lupus nephritis diagnosed on kidney biopsies post-immunization, as well as recurrent ANCA-associated glomerulonephritis. This included 28 cases of de novo glomerulonephritis within native kidney biopsies and one disease flare in an allograft. Results: The patients with collapsing glomerulopathy were of African American descent and had two APOL1 genomic risk alleles. A brief literature review of case reports and small series is also provided to include all reported cases to date (n=52). The incidence of induction of glomerular disease in response to SARS-CoV-2 immunization is unknown, however, there was no overall increase in incidence of glomerular disease when compared to the two years prior to the COVID-19 pandemic diagnosed on kidney biopsies in our practice. Conclusions: This suggests that glomerulonephritis in response to vaccination is rare, although should be monitored as a potential adverse event.

Digital Spatial Profiling of Collapsing Glomerulopathy

ABSTRACTCollapsing 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 and 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 from HIV and SARS-CoV-2 infected patients with biopsy confirmed collapsing glomerulopathy. The increased resolution of DSP uncovered 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. Therefore, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

Acute Kidney Injury in COVID-19

COVID-19 is mainly considered a respiratory illness, but since SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2) to enter human cells, the kidney is also a target of the viral infection. Acute kidney injury (AKI) is the most alarming condition in COVID-19 patients. Recent studies have confirmed the direct entry of SARS-CoV-2 into the renal cells, namely podocytes and proximal tubular cells, but this is not the only pathomechanism of kidney damage. Hypovolemia, cytokine storm and collapsing glomerulopathy also play an important role. An increasing number of papers suggest a strong association between AKI development and higher mortality in COVID-19 patients, hence our interest in the matter. Although knowledge about the role of kidneys in SARS-CoV-2 infection is changing dynamically and is yet to be fully investigated, we present an insight into the possible pathomechanisms of AKI in COVID-19, its clinical features, risk factors, impact on hospitalization and possible ways for its management via renal replacement therapy.

Evidence For and Against Direct Kidney Infection by SARS-CoV-2 in Patients with COVID-19

Despite evidence of multi-organ tropism of SARS-CoV-2 in patients with COVID-19, direct viral kidney invasion has been difficult to demonstrate. The question of whether SARS-CoV-2 can directly infect the kidney is relevant to the understanding of pathogenesis of acute kidney injury and collapsing glomerulopathy in COVID-19. Methodologies to document SARS-CoV-2 infection that have been used include immunohistochemistry, immunofluorescence, reverse transcriptase polymerase chain reaction (RT-PCR), in situ hybridization and electron microscopy. In our review of studies to date we found that SARS-CoV-2 in the kidney of patients with COVID-19 was detected in 18 of 94 (19%) by immuno-histochemistry, 71 of 144 (49%) by RT-PCR and 11 of 84 (13%) by in situ hybridization. In a smaller number of patients with COVID-19 examined by immunofluorescence, SARS-CoV-2 was detected in 10 of 13 (77%). In total, in kidneys from 102 of 235 patients (43.4%), the presence of SARS-CoV-2 was suggested by at least one of the methods used. Despite these positive findings, caution is needed as many other studies have been negative for SARS-CoV-2 presence and it should be noted that when detected it was only in kidneys obtained at autopsy. There is a clear need for studies from kidney biopsies, including those performed at early stages of the COVID-19 associated kidney disease. Development of tests to detect kidney viral infection in urine samples would be more practical as a non-invasive way to evaluate SARS CoV-2 infection during the evolution of COVID-19-associated kidney disease.