key: cord-0877113-bw6nxduy
authors: Daniel, Emily; Sekulic, Miroslav; Kudose, Satoru; Kubin, Christine; Ye, Xiaoyi; Shayan, Katayoon; Patel, Ankita; Cohen, David J.; E. Ratner, Lloyd; Santoriello, Dominick; Barry Stokes, M.; Markowitz, Glen S.; Pereira, Marcus R.; D’Agati, Vivette D.; Batal, Ibrahim
title: Kidney allograft biopsy findings after COVID‐19
date: 2021-09-03
journal: Am J Transplant
DOI: 10.1111/ajt.16804
sha: 59bd88e8c15f0b1496b45f05422539b02462fc42
doc_id: 877113
cord_uid: bw6nxduy

COVID‐19 has been associated with acute kidney injury and published reports of native kidney biopsies have reported diverse pathologies. Case series directed specifically to kidney allograft biopsy findings in the setting of COVID‐19 are lacking. We evaluated 18 kidney transplant recipients who were infected with SARS‐CoV‐2 and underwent allograft biopsy. Patients had a median age of 55 years, six were female, and five were Black. Fifteen patients developed COVID‐19 pneumonia, of which five required mechanical ventilation. Notably, five of 11 (45%) biopsies obtained within 1 month of positive SARS‐CoV‐2 PCR showed acute rejection (four with arteritis, three of which were not associated with reduced immunosuppression). The remaining six biopsies revealed podocytopathy (n = 2, collapsing glomerulopathy and lupus podocytopathy), acute tubular injury (n = 2), infarction (n = 1), and transplant glomerulopathy (n = 1). Biopsies performed >1 month after positive SARS‐CoV‐2 PCR revealed collapsing glomerulopathy (n = 1), acute tubular injury (n = 1), and nonspecific histologic findings (n = 5). No direct viral infection of the kidney allograft was detected by immunohistochemistry, in situ hybridization, or electron microscopy. On follow‐up, two patients died and most patients showed persistent allograft dysfunction. In conclusion, we demonstrate diverse causes of kidney allograft dysfunction after COVID‐19, the most common being acute rejection with arteritis.

COVID-19-infected transplant recipients have been published as case reports (n = 9) or as part of series containing predominantly native kidney biopsies (n = 6). 1, [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] These reports (summarized in Table S1 ) demonstrate a variety of etiologies of allograft dysfunction in the transplanted kidney, including podocytopathies, 6, [9] [10] [11] [12] [13] acute rejection, 1, 15 allograft infarction, 14 thrombotic microangiopathy (TMA), 7 and acute tubular injury (ATI). 1, 8, 15 Direct viral invasion of kidney parenchyma was suggested in two reported cases. 8, 9 Because individual case reports may be subject to publication bias and the timeline relative to COVID-19 infection was not provided consistently, detailed case series devoted to kidney allograft biopsy findings are needed to elucidate the range of kidney manifestations and inform clinical management. Herein, we report the first case series of kidney allograft biopsy findings from recipients with COVID-19.

From the archives of the Renal Pathology Laboratory at Columbia University Irving Medical Center (CUIMC), we retrospectively identified kidney allograft biopsies from SARS-CoV-2-infected patients procured between 3/2020 and 5/2021. All biopsies were "for-cause" biopsies, largely reflecting elimination of protocol biopsies during the pandemic. Patients were required to have either a positive SARS-CoV-2 PCR by nasal swab within 60 days of biopsy or more than 60 days before biopsy plus no documentation of a subsequently negative PCR test result performed prior to the allograft biopsy (n = 18). We chose this arbitrary period because transplant patients are known to have a prolonged COVID-19 course 16, 17 and the potential duration of COVID-19-related histologic manifestations is unknown.

To be more precise regarding the effects of COVID-19, we divided patients into those who had recent infection (positive PCR ≤1 month of biopsy, n = 11), and those with more "remote" infection (positive PCR >1 month of biopsy, n = 7). These allograft biopsies were reviewed at CUIMC and included 17 biopsies processed at CUIMC and one biopsy referred to CUIMC for immunostaining for SARS-CoV-2. Three of these biopsies were previously reported by our group. 1 Clinical and laboratory data were extracted from chart review or provided by the referring physician.

All biopsies were processed for light microscopy and immunofluorescence staining for C4d. A full immunofluorescence panel (IgG, IgM, IgA, C3, C1q, kappa, lambda, fibrinogen, albumin) was performed on all but three patients with minimal proteinuria (<0.2 g/g). In an attempt to identify histologic correlates of COVID-19 in the kidney allograft, we compared biopsy findings in our cohort with recent COVID-19 to these of 14 kidney transplant recipients who had non-COVID pneumonia within 1 month before allograft tissue collection (13 autopsies and 1 "for-cause" biopsy), 13 native kidney biopsies obtained within 1 month of COVID, and all pre-COVID "forcause" kidney allograft biopsies (protocol biopsies were excluded) reviewed at CUIMC between January 1, 2019 and December 31, 2019 (n = 538). Pneumonia was defined by an infectious disease specialist (MRP) based on a combination of clinical symptoms, and radiographical and microbiological findings. 

The 18 patients included in this study had a median age of 55 (IQRs: 50, 61) years. Six of the patients were female and five were Black.

Underlying etiologies of native kidney failure included immune complex-mediated glomerulonephritis (n = 5), ANCA-associated glomerulonephritis (n = 1), diabetic nephropathy (n = 4), hypertension (n = 2), smoking-related nodular glomerulosclerosis (n = 1), cystic kidney disease (n = 2), calcineurin inhibitor toxicity following liver transplantation (n = 1), congenital abnormalities (n = 1), and neurogenic bladder (n = 1). Six allografts were from living donors. All patients had comorbidities, including hypertension in 17 and diabetes mellitus in eight (Table 1) .

Fifteen patients had developed COVID-19 pneumonia. Using the World Health Organization classification of COVID-19 severity, 18 one patient was asymptomatic, two were mild, six moderate, four severe, and five critically severe, requiring intubation and mechanical ventilation (Table 1) . Allograft biopsies were performed for AKI with proteinuria (n = 4), AKI alone (n = 11), isolated proteinuria (n = 2), and transplant nephrectomy after allograft failure (n = 1). Table 2 , excluding the three patients who were dialysis-dependent prior to biopsy, the median baseline serum creatinine was 1.5 mg/dL (IQRs: 1.3, 2.2) and the median serum creatinine at biopsy was 2.4 (IQRs: 2.1, 2.8). Five patients had nephrotic range proteinuria. Although serial SARS-CoV-2 PCR by nasal swab was not performed for all patients, at least one patient had prolonged PCR positivity for over 6 months (patient #8).

Most kidney transplant recipients with COVID-19 were treated by lowering immunosuppression (n = 13; of which three were lowered following allograft biopsy) and/or initiation of therapy with corticosteroids (n = 8), tocilizumab (n = 3), remdesivir (n = 3), and/or bamlanivimab monoclonal antibody (n = 2) ( On analysis of histology results in the biopsies taken within 1 month of positive PCR (n = 11), the most common finding was acute rejection (n = 5, 45%, Table 3 , Figure 1A ) (Table 2) .

Moreover, three of these five patients had no previous episodes of acute rejection and appeared adequately immunosuppressed (one with tacrolimus levels of 11-16.5 ng/mL within 2 weeks prior to biopsy and the other two were on regular belatacept infusion with no missed doses) ( Table 3) .

Two biopsies revealed podocytopathy, one with collapsing glomerulopathy ( Figure 1C ) and one with recurrent lupus nephritis with diffuse foot process effacement, consistent with lupus podocytopathy ( Figure 1D ). Calcineurin inhibitor (CNI) levels were assessed between the time of SARS-CoV-2 detection (by polymerase chain reaction) and allograft kidney biopsy, or 2 weeks before the biopsy if SARS-CoV-2 was detected less than 2 weeks before biopsy; tacrolimus levels measured in ng/mL; if the patient was maintained on cyclosporine, then this is mentioned and the levels are reported (ng/mL); if the patient was maintained on belatacept, then this is mentioned together with any missing doses. b Did not miss any belatacept infusion subsequent to detection of SARS-CoV-2.

c Considered positive since multiple prior values were positive for class-II DSA with high MFI (24,000 5 months prior to the current biopsy). (Table S2 ).

In an attempt to confirm the above findings, the incidence of Table S3 ).

In contrast to biopsies performed within 1 month of COVID-19, biopsies performed >1 month after positive SARS-CoV-2 PCR tended to show more chronic and nonspecific changes (Table 3) .

Only one additional case of a collapsing glomerulopathy (patient #12) was documented. In this case, the allograft kidney was ob- (Table 3) .

When risk factors for acute rejection 19 were compared between patients presenting more than 1 month from COVID-19 and those presenting within 1 month of diagnosis, no significant differences were noted in this small sample (Table S4) . were seen in all six biopsies studied by electron microscopy (Table 4 , Figure S1 ). (Table S5 ). There might be some differences between native and donor kidney disease with regard to the importance of APOL1 status. In the setting of COVID-19 in kidney transplant recipients, none of the two cases of collapsing glomerulopathy where the donor had been typed showed APOL1 high-risk genotypes. 6, 13 This is in contrast to COVID-19 in the native kidney where >90% of patients who developed collapsing glomerulopathy had APOL1 high-risk genotypes. 4, 13, 23 In our series, podocytopathies were identified in three (17%) patients.

While APOL1 genotypes of the donors were not tested in our cohort, we can assume that at least one of the two donors with collapsing glomerulopathy can be categorized as APOL1 low risk since he was White. However, it is worth noting that the kidney allograft biopsy in this particular patient also showed TMA, which is a known risk factor for collapsing glomerulopathy in the kidney allograft. 24 In our series, ATI was identified in three patients, of whom two had critically severe COVID-19 (management requiring intubation), a situation in which ATI is commonly observed. 3

While this case series is the first to describe biopsy findings in kidney transplant recipients with COVID-19, it has several limitations. Given the descriptive nature of this study, it is difficult to prove a definitive pathogenetic link between SARS-CoV-2 infection and the biopsy findings. Our sample size is small, underscoring the need for additional multicenter studies. Finally, because all the allograft biopsies were performed for cause, our study cannot address potentially important subclinical histologic changes.

In conclusion, this series provides new insight into the factors underlying kidney injury in the kidney transplant population after SARS-CoV-2 infection. The close temporal associations with acute rejection implicate roles for heightened adaptive and innate immune responses.

Kidney biopsy findings in patients with COVID-19

Histopathologic and ultrastructural findings in postmortem kidney biopsy material in 12 patients with AKI and COVID-19

Postmortem kidney pathology findings in patients with COVID-19

AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype

COVID-19-associated kidney injury: a case series of kidney biopsy findings

COVID-19-related collapsing glomerulopathy in a kidney transplant recipient

COVID-19 manifesting as renal allograft dysfunction, acute pancreatitis, and thrombotic microangiopathy: a case report

Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient

Lessons for the clinical nephrologist: recurrence of nephrotic syndrome induced by SARS-CoV-2

Collapsing glomerulopathy affecting native and transplant kidneys in individuals with COVID-19

Minimal change disease with nephrotic syndrome associated with coronavirus disease 2019 after apolipoprotein L1 risk variant kidney transplant: a case report

De novo focal and segmental glomerulosclerosis after COVID-19 in a patient with a transplanted kidney from a donor with a high-risk APOL1 variant

COVID-19-associated glomerular disease

COVID-19-associated graft loss from renal infarction in a kidney transplant recipient

Multicenter clinicopathologic correlation of kidney biopsies performed in COVID-19 patients presenting with acute kidney injury or proteinuria

Viral shedding prolongation in a kidney transplant patient with COVID-19 pneumonia

Viral clearance and serological response to SARS-CoV-2 in kidney transplant recipients

World Health Organization. COVID-19 clinical management: living guidance

The clinical significance of receiving a kidney allograft from deceased donor with chronic histologic changes

COVID-19 infection in kidney transplant recipients: disease incidence and clinical outcomes

Poor anti-SARS-CoV-2 humoral and T-cell responses after 2 injections of mRNA vaccine in kidney transplant recipients treated with belatacept

Weak anti-SARS-CoV-2 antibody response after the first injection of an mRNA COVID-19 vaccine in kidney transplant recipients

COVAN is the new HIVAN: the reemergence of collapsing glomerulopathy with COVID-19

Donor APOL1 highrisk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts

The authors thank Yuancheng Wang, Maria Lourdes Diaz Belvis, and the Immunohistochemistry Laboratory at Columbia University Irving Medical Center for their excellent technical assistance.

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

The data that support the findings of this study are available on request from the corresponding author after obtaining an IRB approval.The data are not publicly available due to privacy or ethical restrictions.