key: cord-1044798-xhft6ye6
authors: Nasr, Samih H.; Alexander, Mariam Priya; Cornell, Lynn D.; Herrera, Loren Hernandez; Fidler, Mary E.; Said, Samar M.; Zhang, Pingchuan; Larsen, Christopher P.; Sethi, Sanjeev
title: Kidney Biopsy Findings in Patients With COVID-19, Kidney Injury, and Proteinuria
date: 2020-11-18
journal: Am J Kidney Dis
DOI: 10.1053/j.ajkd.2020.11.002
sha: b9270fac323ce6a11b65a20be80a097c0b276ad1
doc_id: 1044798
cord_uid: xhft6ye6

nan

Acute tubular injury (AKI) develops in up to 37% of hospitalized COVID-19 patients and its pathophysiology has not been fully elucidated. Recent kidney biopsy and postmortem series revealed that the most common pathology in COVID-19 patients is acute tubular injury (ATI), but a variety of pathologies have also been described. [1] [2] [3] [4] Here, we report the clinicopathologic characteristics and outcome of 13 COVID-19 patients with kidney injury and proteinuria. The methods are described in Item S1.

The demographics and clinical characteristics are shown in Table S1 . The cohort consisted of 12 men and 1 woman, with a median age of 52 years. Nine patients were black, 2 Hispanic, and 2 white. All patients except 1 had one or more co-morbid conditions, most commonly hypertension (85%), diabetes (46%), and obesity (54%).

Twelve patients presented with pulmonary symptoms and 11 of them were diagnosed with COVID-19 pneumonia. Most patients had hypoxic respiratory failure and required supplemental oxygen, including 1 needing intubation. One patient presented with COVID-19 Guillain-Barré-like syndrome without pneumonia.

Patients presented with AKI on or during admission, superimposed on underlying CKD in 44%. The kidney injury was severe (peak creatinine >3 mg/dl) in all patients except 1, and 10 (77%) required hemodialysis during admission. The median peak and admission creatinine was 8.9 and 3.9 mg/dL, respectively. One or more potential contributing factors to AKI, aside from pneumonia, were present in 6 including ARB or ACE I use in 5, vomiting in 2, and NSAIDs use in 1. All patients had proteinuria (median 5.5 g/day), including 11 (85%) with nephrotic range proteinuria (NRP). Hypoalbuminemia was present in 975%, edema in 15%, nephrotic syndrome (NS) in 8%, and microhematuria in 77%.

The 8 collapsing glomerulopathy (CG) patients were black, all except 1 were men, and had a median age of 55 years. All presented with severe AKI (requiring dialysis in 7) and NRP (=7) or near NRP (n=1), with a median proteinuria of 5.5 g. Only 4 had hypoalbuminemia and none had edema.

The pathologic findings are shown in table 1. Kidney biopsy in 8 (#1-8) revealed CG ( Fig  1A) , accompanied by diffuse ATI, tubular microcystic dilation (=6, Fig 1B) , tubular protein reabsorption droplets, interstitial fibrosis/ tubular atrophy (IFTA), and interstitial inflammation. Ultrastructurally, podocyte foot process effacement was extensive (≥90%) in 63%. Endothelial tubuloreticular inclusions (TRIs) were seen in 38%. APOL1 genotyping in 1 of these patients revealed the presence of 2 risk alleles (G1/G2). Concurrent pre-existing glomerulopathy was present in 3 including PLA2R-negative membranous nephropathy (MGN) in 1, mild IgA nephropathy in 1, and diabetic glomerulosclerosis (DGS) in 1.

Kidney biopsy in 5 patients did not show CG. Patient #9 had stage I-II PLA2R&THDS7A-negative MGN (Fig 1C) . Patient #10 presented with RPGN and a purpuric skin rash temporally associated with COVID-19. His creatinine was 1.5 (baseline 0.9) which progressively increased to 4.2 10 days later, accompanied by NS and hematuria. Urinalysis done 10 days prior to COVID-19 showed negative blood and trace protein. He had negative ANCA and anti-GBM antibody. Biopsy revealed diffuse crescentic HSP nephritis ( Fig 1D) and ATI without IFTA. Patients #11-13 had DGS with superimposed ATI (Fig 1E) . No biopsy showed thrombotic microangiopathy or peritubular capillary thrombi.

While viral-like particles were observed in some cases, no definitive SARS-CoV-2 virions were seen in glomerular or tubular cells on electron microscopy. Further, In situ hybridization for SARS-CoV-2 RNA done in 1 case was negative.

Follow up was available in 12 patients. Therapies given are listed in Table S1 . Patient #9 who was on dialysis died 10 days post-biopsy due to COVID-19 ARDS. The median follow up in the remaining 11 was 68 days (range 35-95). Of the 9 who required dialysis during admission, 6 (including 4 CG patients) remained on dialysis and 3 (all CG) came off dialysis. The 2 patients who were not on dialysis (#11 with DGS and ATI, #7 with CG) had improvement of creatinine. The severity of IFTA correlated with better renal outcome (ie, recovery in 5 of 7 of those with <30% IFTA vs. in 0 of 4 of those with >30% IFTA). Steroids did not correlate with recovery in CG patients on dialysis (recovery in 2 of 5 steroid-treated patients vs. in 1 of 2 non-steroid treated patients).

Our findings substantiate those described by other recent COVID-19 biopsy and autopsy series 1-4 and provide additional insights and longer follow up. Thus, patients presented with severe AKI and NRP, and ATI was a universal pathologic finding. CG was the most common glomerulopathy, present in 8 (62%) patients. Interestingly, despite the presence of NRP, just over half of our CG patients had hypoalbuminemia and none had peripheral edema. Therefore, NS is not a typical presentation of CG associated with COVID-19 (similar to HIVAN). All CG patients were black, and most exhibited tubular cystic dilation (a histologic feature of APOL1 nephropathy) including 1 with genetically confirmed APOL1 risk alleles. As all patients with CG associated with COVID-19reported thus far were of African descent and when tested had APOL1 risk alleles 5 , 1,2,6 , it is likely that COVID-19 acts as a "second hit" that leads to podocyte dysregulation and injury resulting in CG, analog to CG associated with HIV and other viruses. We note that, contrary to HIVAN, only 38% of our CG cases showed TRIs and thus mechanisms other than high interferon states could play a role. Similar to some studies 1,2,6 and contrary to others 7 , extensive ultrastructural search for SARS-CoV-2 virions was unrevealing, providing evidence against direct viral infection of kidney cells.

Two COVID-19 patients in this series had PLA2R-negative MGN, including 1 with concurrent CG and 1 with prominent TRIs without underlying autoimmune disease. A third patient presented with crescentic HSP nephritis temporally associated with COVID-19. It is possible that COVID-19-associated exaggerated immune response may have exacerbated underlying MGN and triggered a crescentic transformation of HSP nephritis.

A notable limitation of this study is potential selection bias as patients had significant proteinuria and thus were likely selected for kidney biopsy; therefore, the study cohort may not be representative of all COVID-19 patients with AKI.

In conclusion, CG is the most common glomerulopathy in COVID-19 black patients undergoing kidney biopsy for AKI and proteinuria, typically presents with severe AKI and NRP but without full nephrotic syndrome, and is associated with poor prognosis. Further studies are needed to uncover its pathophysiology, determine the optimal strategies for prevention and treatment, and long-term prognosis. Lastly, the possibility that COVID-19 may exacerbate underlying autoimmune conditions should be investigated. 

Kidney Biopsy Findings in Patients with COVID-19

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings

Postmortem Kidney Pathology Findings in Patients with COVID-19

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

Collapsing Glomerulopathy in a Patient With COVID-19

AKI and Collapsing Glomerulopathy Associated with COVID-19 and APOL 1 High-Risk Genotype

Ultrastructural Evidence for Direct Renal Infection with SARS-CoV-2