key: cord-0699324-mzosdrd5 authors: Basic‐Jukic, Nikolina; Coric, Marijana; Bulimbasic, Stela; Dika, Zivka; Juric, Ivana; Furic‐Cunko, Vesna; Katalinic, Lea; Kos, Jelena; Fistrek, Margareta; Kastelan, Zeljko; Jelakovic, Bojan title: Histopathologic findings on indication renal allograft biopsies after recovery from acute COVID‐19 date: 2021-10-01 journal: Clin Transplant DOI: 10.1111/ctr.14486 sha: 886072060395f96d3afc864b26ed8bc4c77c0462 doc_id: 699324 cord_uid: mzosdrd5 Current knowledge on histopathological changes occurring after COVID‐19 in transplanted kidneys is limited. Herein, we present renal allograft pathology findings in patients recovered from COVID‐19. Six patients underwent indication biopsy, and one required allograft nephrectomy after acute COVID‐19. Demographic data, clinical characteristics, and laboratory findings were recorded. The histopathological analysis included light microscopy, immunostaining, and electron microscopy. Five patients were hospitalized for acute COVID‐19, and all were diagnosed with imaging‐confirmed pneumonia, one requiring mechanical ventilation, and two requiring dialysis. Two patients had mild form. Histopathologic examination of renal allograft specimens revealed collapsing, perihilar, tip‐lesion and secondary FSGS in one patient each. One patient had borderline acute cellular rejection, and two had chronic antibody‐mediated rejection. Histopathologic changes of glomerular tufts were accompanied by acute tubular injury in four patients. None of our patients had signs of viral inclusions in kidney cells. One patient died and one remained dialysis‐dependent after the good initial response to treatment. Patients with collapsing and perihilar FSGS had further progression of their chronic allograft nephropathy still without need for dialysis. In conclusion, diverse kidney pathology may be found in SARS‐CoV‐2–infected renal transplant patients. It seems that viral infection may affect the immune system with triggering of glomerular diseases, while the acute tubular injury is of multifactorial etiology. Direct viral effect is less likely. Kidney transplant recipients (KTR) are a vulnerable group that might be particularly susceptible to SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection and subsequent complications. Immunosuppressive state, direct kidney infection, disturbance of the renin-angiotensin-aldosterone homeostasis, and the pro-inflammatory cytokine milieu may contribute to kidney injury. The hypothesis that the kidney might be a target of the SARS-CoV-2 virus is supported by the findings of isolated virus from the urine of infected patients and the fact that ACE 2 is abundantly present in kidney tissue, mostly in podocytes and in the brush border of the proximal tubule. 1,2 Controversy on the renal tropism of SARS-CoV-2 is going on while some of the authors observed viral elements in kidney tissue and others did not. [3] [4] [5] However, direct viral effects were proposed, and collapsing glomerulopathy, coagulopathy, endothelial damage, complement activation, and inflammation were suggested as possible etiopathogenetic pathways. 6 All patients who met the criteria for discontinuation of quarantine after acute COVID-19 (afebrile with two negative real-time reverse transcriptase-polymerase chain reaction tests for SARS-CoV-2 24 h apart) continued with regular follow-up at our outpatient clinic. Patients with acute allograft dysfunction and/or proteinuria at the regular outpatient visit after the acute COVID-19 underwent percutaneous renal allograft biopsy. At the time of presentation, all patients had peripheral edema, and patient 3 had anasarca. Baseline (the last value before COVID-19) and post-COVID-19 kidney allograft function parameters are shown in Table 2 . D-dimers were increased in four patients and three had hypogammaglobulinemia. Patients 3 and 6 had low serum C3 with C4 level within the normal range which suggested complement alternative pathway activation. Viral reactivations were common, with the Epstein-Barr virus being the most frequent (four patients) ( Table 2 ). The light microscopic appearance of glomerular lesions included focal segmental glomerulosclerosis (collapsing, perihilar, tip-lesion, and secondary in one patient each), transplant glomerulopathy in two patients and mesangial proliferation in one patient. Acute tubular injury was recorded in four patients. All patients had degenerative lesions, including interstitial fibrosis, tubular atrophy and arteriosclerosis of diverse severity ( Figure 1 , Table 3 ). Virus particles were not identified in available specimens. (Table 4 ). KTRs are a specific group of patients exposed to immunosuppressive therapy and with preexisting changes within kidneys. Histopathology significantly differ between native and transplanted kidneys (Table 5 ). More data is available on biopsy findings from native kidneys. Kidney thrombotic microangiopathy was found in a subset of cases. A few cases of the glomerular disease have been reported, most commonly collapsing glomerulopathy. Other cases included minimal change disease, anti-GBM disease, infection-associated glomerulonephritis, membranous glomerulopathy, ANCA-associated vasculitis and other less frequent findings, summarized in Table 5 Decreased C3 with normal C4 may indicates activation of the alternative complement pathway which is common in post-infectious glomerulonephritis. High EBV load after acute COVID-19 may indicate immunomodulatory action of the SARS-CoV-2. These findings will require additional evaluations with careful follow-up due to increased risk of malignancy associated with the EBV infection. We will continue to follow trends in EBV viral load and carefully balance the immunosuppression. Interestingly, a case of MPGN (patient 6) may present a C3 glomerulonephritis given the lack of immunoglobulin and light chain staining. She had a severe disease course with low systemic C3 and extensive reactivation of both CMV and EBV which may both contribute to development of MPGN. [39] [40] [41] [42] The absence of viral inclusion bodies in the biopsy findings support the secondary effect of viral infection on kidney allograft cells, and goes against direct SARS-CoV-2 related allograft endothelial cell inflammation and dysfunction. Still, delay between initial SARS-CoV-2 infection and renal allograft biopsy may be associated by viral clearance from the kidney and the absence of viral particles from the biopsy specimens. Collapsing glomerulopathy is associated with various conditions, including viral infections, autoimmune diseases, hemophagocytic syndrome, glomerular ischemia and drug exposure such as interferon and pamidronate. The presence of the apolipoprotein L1 (APOL1) high-risk genotype is a major risk factor for collapsing glomerulopathy in African Americans. 43 renal allograft histopathology findings present to date. We could not determine the expression of SARS-CoV-2 in biopsy samples. Additionally, we had no possibility to determine the APOL1 genotype in our patient of Roma origin with collapsing FSGS. All patients underwent indication biopsies, which disable the generalization of our results. Finally, all but one patient had preexisting kidney allograft pathology, which may bias our results, while fortuitous associations with COVID-19 cannot be ruled out. In conclusion, diverse kidney pathology may be found in SARS-CoV- N.B.J. initiated the study, participated in study planning, designed data collection tools, and questionnaire, monitored data collection, drafted and revised the paper. I.J., V.F.C., L.K., J.K., Z.D., M.F. contributed to study planning, administered and monitored data collec-tion, and revised the paper. B.J. participated in study planning, analysis, and revising the paper. M.C. and S.B. performed histopathology. Z.K. contributed to study conception, study planning, data collection and monitoring, analysis and revised the paper. All authors reviewed and approved the final version. Data available on request from the authors. 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