key: cord-0927158-ur9rboxe
authors: Yamada, Masaaki; Rastogi, Prerna; Ince, Dilek; Thayyil, Abdullah; Adela Mansilla, M.; Smith, Richard J.H.; Kuppachi, Sarat; Thomas, Christie P.
title: A Case Report: Minimal Change Disease with Nephrotic Syndrome Associated with COVID-19 after APOL1 risk variant Kidney Transplantation
date: 2020-08-20
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2020.08.012
sha: 319cc65987d303d39650e4755efc3fd278c64e9d
doc_id: 927158
cord_uid: ur9rboxe

Abstract Kidney injury is a well-known complication in people with coronavirus disease 2019 (COVID-19). In kidney transplant recipients with COVID-19, presentation with nephrotic syndrome has not been well described. We report on a 49-year-old African American female kidney transplant recipient who presented 25 years after transplantation with clinical features of nephrotic syndrome following a diagnosis of COVID-19. Histological examination showed acute tubular injury with unremarkable glomeruli on light microscopy and diffuse foot process effacement of podocytes on electron microscopy, consistent with minimal change–like podocyte injury. Apolipoprotein L1 (APOL1) genetic testing confirmed two high-risk APOL1 alleles in the kidney donor. We speculate that COVID-19-induced systemic or local cytokine release could serve as a second hit in the presence of APOL1 risk alleles and mediate a podocytopathy manifesting as nephrotic syndrome. The presented case with minimal change like disease, occurring in the context of the donor high-risk APOL1 genotype, extends the spectrum of clinical manifestations in COVID-19-associated nephropathy.

Acute kidney disease can be seen with coronavirus disease 2019 caused by severe 2 acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The kidney manifestations range from 3 simple abnormalities on urinalysis to severe acute kidney injury (AKI) requiring renal replacement 4 therapy. The development of AKI is associated with higher mortality in people with 5 2) Initial presentation with nephrotic syndrome in COVID-19 is rare but has been reported in 6 patients without a prior history of chronic kidney disease.(3-5) Although a number of kidney 7 transplant recipients have developed COVID-19, there are scarce data on the occurrence of 8 nephrotic syndrome in kidney transplantation.(6-8) 9

We report a case of a long-term kidney transplant recipient with COVID-19 who presented with 10 nephrotic syndrome attributable to minimal change-like podocytopathy in the context of donor 11 homozygosity for apolipoprotein L1 (APOL1) risk allele, G1. 12

The patient is a 49-year-old African American female with a prior history of preeclampsia who 14 developed end-stage kidney disease (ESKD). She underwent kidney transplantation from a sibling 15 donor in December of 1995 at an outside hospital. Since 2003, when she relocated to our center, 16 her maintenance immunosuppression has been tacrolimus (target trough level 3-8 ng/mL) and 17 prednisone 5 mg daily. She takes atenolol 25 mg twice daily and losartan 75 mg daily. She had a 18 baseline serum creatinine (SCr) ranging from 1.4 to 1.6 mg/dL [estimated glomerular filtration rate 19 (eGFR) 45-50 mL/min/1.73m 2 ] and minimal proteinuria until her diagnosis of COVID-19 in April 20 2020 (shown in Table 1) . 21

At presentation, she reported fever (up to 38.6 °C), dry cough, myalgia, and anorexia in the context 22 of exposure to SARS-CoV-2 (her spouse had been diagnosed with COVID-19). She confirmed 23 positive for SARS-CoV-2 from a nasopharyngeal swab on reverse transcription-polymerase chain 24 reaction (RT-PCR) (cycle threshold values of nucleocapsid protein 1 and 2 were 21 and 20, 25 J o u r n a l P r e -p r o o f respectively, with a positive threshold of 40 or less). Initially, her renal function was stable, and she 26 was treated conservatively with antipyretics. Her symptoms gradually improved except an episode 27 of low blood pressure with lightheadedness that prompted discontinuation of losartan. Repeat 28 laboratory work 2 weeks later showed significant deterioration in renal function with a SCr of 4.4 29 mg/dL (eGFR 13 mL/min/1.73m 2 ). She denied any use of non-steroidal anti-inflammatory drugs. 30

Pre-renal AKI was suspected because of her poor oral intake, and her SCr improved to 3.7 mg/dL 31 with intravenous fluids. Three weeks after the initial detection of SARS-CoV-2, she noticed bilateral 32 pedal edema along with chest discomfort. She had persistent poor renal function with a SCr of 3.4 33 mg/dL (eGFR 17 mL/min/1.73m 2 ), a urine protein dipstick test of 4+, and a urine protein 34 creatinine ratio (UPCR) of 8.0 g/g Cr (shown in Table 1 ). She was admitted to the hospital for 35 further evaluation. 36

Upon admission, her body temperature was 36.9 °C, heart rate 84 bpm and regular, blood pressure 37 138/94 mmHg, respiratory rate 15 bpm, pulse oximeter 99% on room air, height 165 cm, weight 79 38 kg, and body mass index 29 kg/m 2 . Her physical exam was notable for bilateral pedal edema but no 39 periorbital edema. Admission laboratory studies revealed persistent positivity of a nasopharyngeal 40 sample for SARS-CoV-2 by RT-PCR (cycle threshold values for nucleocapsid protein 1 and 2 were 36 41 and 37, respectively), She had a SCr of 3.4 mg/dL, carbon dioxide of 16 mg/dL, and albumin of 2.5 42 mg/dL but no leukocytosis, lymphopenia, or hypercholesterolemia (shown in Table 1) . 43

Subsequently, nephrotic-range proteinuria of 6.3 g/day was confirmed by a 24-hour urine 44 collection. Additional tests for an autoimmune process, other viral infection, and paraproteinemia 45 were negative except for a reduced C3 level of 81 units/mL (normal reference 90-180) (shown in 46 Table 1 ). Her chest X-ray at admission was unremarkable and no ultrasonographic evidence of 47 hydronephrosis was seen. 48 A transplanted kidney biopsy performed 5 days after admission revealed acute tubular injury and 49 diffuse foot process effacement of podocytes in the absence of segmental glomerular sclerosis. 50

Light microscopy showed renal cortex with a total of 9 glomeruli of which 4 were globally sclerosed 51 in the single focal area of scar. The remaining non-sclerosed glomeruli were normocellular with no 52 crescents or podocyte hypertrophy (shown in Fig. 1. a) . No segmental lesion was identified. 53

Tubules showed evidence of acute tubular injury with luminal cell exfoliation and dilatation. There 54 was no tubulitis. There was moderate interstitial fibrosis and tubular atrophy, and moderate 55 arteriosclerosis and arteriolar hyalinosis. C4d stain was negative in the peritubular capillaries; SV-56 40 was negative by immunohistochemistry; and the Epstein-Barr encoding region was negative by 57 in situ hybridization. Electron microscopy showed glomerular capillary loop basement membrane 58 with preserved tri-laminar architecture. There was extensive foot process effacement (up to 90%) 59

with microvillous transformation (shown in Fig. 1. b) . Multiple tubulo-reticular inclusions were 60 noted in endothelial cells (shown in Fig. 1. c) , indicative of a viral etiology. The sample for 61 immunofluorescence examination did not contain any glomeruli. However, electron microscopy 62 examination did not show any deposits, essentially ruling out the possibility of immune-complex 63

A sample from her kidney tissue tested negative by immunohistochemistry and in situ hybridization 65 for SARS-CoV-2 (Arkana Laboratories, Little Rock, AR). Testing of her serum sample 5 weeks after 66 her initial presentation showed positive SARS-CoV-2 qualitative antibody by two assays (Elecsys ® 67

Anti-SARS-CoV-2, Roche Diagnostics, Indianapolis, IN and LIAISON ® SARS-CoV-2 S1/S2 IgG, 68

DiaSorin Inc., Stillwater, MN). Genetic testing (Iowa Institute of Human Genetics, Iowa City, IA) 69 confirmed that both the recipient and her donor were homozygous for the APOL1 renal risk allele, 70

Pertinent findings in this patient were acute tubular injury and diffuse foot process effacement of 72 podocytes with endothelial cell tubulo-reticular inclusions without evidence for an immune 73 complex-mediated process, graft rejection, or other infectious process. While her AKI was likely 74 J o u r n a l P r e -p r o o f secondary to acute tubular injury, her nephrotic syndrome was probably secondary to a viral 75 podocytopathy, manifesting as minimal change disease (MCD). 76

On day 6 after admission, the patient was discharged home with her maintenance 77

immunosuppression. Due to lack of improvement in proteinuria at 3 weeks after the discharge, oral 78 glucocorticoids (prednisone 60 mg daily) and angiotensin converting enzyme inhibitor (lisinopril 79 10 mg daily) were added. At her last follow-up, 9 weeks since discharge and after 6 weeks of oral 80 glucocorticoid therapy, she has clinically improved with a SCr of 3.4 mg/dL and UPCR of 2.6 g/g Cr 81 (cf. SCr of 4.4 mg/dL and UPCR of 8.0 g/g Cr at admission). Despite her improvement in 82 proteinuria, her glucocorticoid therapy was weaned down earlier than planned due to its adverse 83 effects. 84

Based on a thorough literature review, the presented case, to our knowledge, is the first to 86 demonstrate MCD-type podocyte injury with nephrotic syndrome in a kidney transplant recipient 87 with COVID-19. Our case with the podocytopathy, occurring in the context of the donor high-risk 88 APOL1 genotype, extends the spectrum of COVID-19-associated nephropathy. 89

Nephrotic syndrome refers to a constellation of clinical features that are usually seen with a variety 90 of glomerular diseases including the podocytopathies.(9) MCD is the most common cause of 91 nephrotic syndrome in children, whereas it is a less common cause in adults, and conditions like 92 focal and segmental glomerulosclerosis (FSGS) predominate in those patients.(10) It is pertinent to 93 differentiate MCD from FSGS to determine a therapeutic option and its prognosis; however, it is not 94 always an easy task in clinical practice because early FSGS can only present with diffuse foot 95 process effacement. In the presented case, the possibility of early FSGS cannot be completely 96 excluded this time, given the low number of glomeruli obtained and the limited follow-up. But, her 97 prompt response to glucocorticoids in reduction of proteinuria could support MCD-type podocyte 98 injury whereas her eGFR remains poor because of chronic scarring in the renal interstitium. 99

Although the exact mechanism of MCD is not known, there could be a pathogenic association 100 between certain viral infections and the resulting T-lymphocyte activation with cytokine release 101 that may contribute to its pathogenesis. (11, 12) In some patients with nephrotic syndrome in 102 remission, respiratory infections including SARS-CoV-2 is associated with a relapse of 103 proteinuria. (13, 14) On the other hand, in hospitalized patients with moderate to severe 104 about 5% exhibited AKI upon admission and 10% had proteinuria defined by a urine protein 105 dipstick of 2+ or greater.(15) A higher rate of proteinuria, up to 42%, was observed in patients 106 with COVID-19 who developed AKI during hospitalization.(2) AKI in critically ill patients with 107 COVID-19 may be secondary to acute tubular injury resulting from hemodynamic instability, 108

although the cause of the reported proteinuria is not well described. Clearly, our recipient transplanted with a kidney bearing two APOL1 risk alleles was doing well for 142 25 years after transplantation, indicating that the high-risk APOL1 genotype alone is insufficient to 143 cause a proteinuric kidney disease. A second hit, such as HIV or, in our case, SARS-CoV-2, may have 144 been required for the development of disease. 145

This report describes MCD-like podocytopathy causing nephrotic syndrome in a patient with 147 COVID-19. This case extends the spectrum of COVID-19-associated nephropathy that can be seen in 148 transplant recipients. The podocytopathy occurred in a recipient who had received a kidney 149 bearing two high-risk APOL1 alleles and who had stable kidney allograft function for years after 150 transplantation. We speculate that cytokine activation within the podocytes following SARS-CoV-2 151 infection, in the presence of a susceptible APOL1 genotype, resulted in a clinical manifestation that 152 included MCD-like podocytopathy. 153

The authors would like to thank Mr. Paul J Casella for editorial assistance. 155

This research work does not contain human subject research material. 157

This research did not receive any specific grant from funding agencies in the public, commercial, or 159 not-for-profit sectors. 160

Written consent for publication has been obtained by the patient. 162

163 MY, SK, and CPT examined the patient, analyzed and interpreted the patient data, prepared the 164 manuscript, contributed to critical revisions, and finalized the manuscript. PR and AT performed 165 the histological examination of the transplanted kidney, and were major contributors in writing the 166 manuscript. DI analyzed and interpreted the patient data regarding the diagnostic tests for SARS-167

CoV-2 and contributed to the final manuscript. MAM and RJHS performed the genetic testing and 168 contributed to the final manuscript. All authors read and approved the final manuscript. 169 J o u r n a l P r e -p r o o f 

Clinical course and risk factors for mortality of adult 171 inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Acute kidney injury in patients 174 hospitalized with COVID-19

Collapsing Glomerulopathy in a Patient 176 With Coronavirus Disease 2019 (COVID-19)

Collapsing glomerulopathy in 178 a COVID-19 patient

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

COVID-19 in kidney 183 transplant recipients

Early Description of Coronavirus 2019 Disease in 185 Kidney Transplant Recipients in New York

Collapsing Glomerulopathy in a Kidney Transplant Recipient

Minimal change disease and idiopathic 189 FSGS: manifestations of the same disease

Adult minimal-change 191 disease: clinical characteristics, treatment, and outcomes

Molecular Mechanisms in the Pathogenesis of Idiopathic Nephrotic

Impact of Tauh1 and Tauh2 cytokines in the progression of idiopathic nephrotic syndrome due to focal 197 segmental glomerulosclerosis and minimal change disease

Role of respiratory viruses in 199 exacerbations of primary nephrotic syndrome

SARS-CoV-2 infection in 201 Spanish children with chronic kidney pathologies

Kidney disease is associated with in-203 hospital death of patients with COVID-19

Renal histopathological analysis of 26 205 postmortem findings of patients with COVID-19 in China

207 Multiorgan and Renal Tropism of SARS-CoV-2

Is the kidney a target of SARS-CoV-2?

Kidney Biopsy Findings in Patients 211 with COVID-19

The significance of tubuloreticular inclusions 213 as a marker of systemic stimulation by interferons in a case of focal and segmental glomerulosclerosis 214 associated with cytomegalovirus (CMV) infection

Clinical features of patients infected with 2019 216 novel coronavirus in Wuhan

Heightened Innate Immune Responses in the 218 Respiratory Tract of COVID-19 Patients

APOL1 polymorphisms and kidney disease: loss-of-function 220 or gain-of-function?

The Impact of APOL1 on Chronic Kidney Disease and Hypertension

HIV-associated nephropathies: epidemiology, 224 pathology, mechanisms and treatment

Reference range Baseline (Early April, 2020)

(Late April, 2020)