key: cord-0909316-24dubnp7 authors: Chen, Shirui; Kowalewska, Jolanta; McCune, Thomas R. title: COVID-19 Associated Collapsing FSGS in an APOL1 Homozygous Transplant Recipient After Successful COVID Vaccination, a Case Report date: 2021-11-12 journal: Transplant Proc DOI: 10.1016/j.transproceed.2021.11.001 sha: c27636a785a4818b05c9804d16b7eb0a02f0d383 doc_id: 909316 cord_uid: 24dubnp7 Organ transplant recipients exhibit lower rates of immune response to COVID-19 vaccination. Even when they do mount a demonstrable antibody response, it is unclear what degree of protection is conferred against the myriad potential complications of COVID-19 infection. We present here a case of a kidney transplant recipient who was homozygous for APOL-1 risk alleles on low-dose immunosuppression who developed an antibody response to COVID-19 vaccination and subsequently acquired COVID-19 infection. Although she experienced relatively minor effects in other organ systems, she developed severe collapsing FSGS that left her dependent on hemodialysis on hospital discharge. This suggests that COVID-19 vaccination may not provide protection from infection-associated FSGS in patients with APOL-1 risk alleles. Vaccination against COVID-19 has played a primary role in reducing the spread of the novel coronavirus infection and in reducing the associated morbidity and mortality. 1 However, it is clear that COVID-19 vaccination does not confer protection equally to all populations. Organ transplant recipients have exhibited lower rates of immune response to COVID-19 vaccination in comparison to the general population. 2, 3 This is particularly the case for patients who have recently had a transplant and those transplant patients on higher doses of immunosuppression at the time of COVID-19 vaccination. 4 However, even in patients with an antibody response to vaccination, it is not known if vaccination confers protection against all complications of COVID-19 infection, such as FSGS associated with APOL1 risk alleles. Collapsing FSGS has been reported in association with COVID-19 infection in patients with the APOL1 risk alleles. There have been multiple case reports of patients with two APOL1 G1 risk alleles, and a patient who had the G1 and G2 risk alleles who developed native kidney collapsing FSGS associated with COVID-19 infection. [5] [6] [7] Collapsing FSGS has also been described in association with COVID-19 infection in a patient who was heterozygous for wild type and G1 alleles of APOL1. 8 Among renal transplant recipients, a patient with primary FSGS who received a kidney transplant was reported to develop proteinuria and biopsy-proven FSGS in association with COVID-19 infection and positive staining of SARS-CoV-2 spike protein RNA in renal tubular epithelial cells. 9 COVID-19 infection may act as a "second hit" for the development of FSGS in patients with APOL1 risk alleles. Other viral syndromes have been associated with the second hit in transplant recipients of kidneys from donors with two APOL1 risk alleles. 10, 11 We previously reported on a patient who was identified as homozygous for the APOL1 G1 and G2 risk alleles and developed FSGS 18 years after renal transplantation from an identical twin sibling. 12 Here we report a case of rapid onset collapsing FSGS associated with COVID-19 infection in the same patient after successful COVID-19 vaccination. A 57 year old female with a history of renal transplantation from her identical twin, two risk alleles for APOL1, and FSGS in the transplant kidney was admitted with shortness of breath, cough, nausea, and vomiting and was diagnosed with COVID-19 infection based on nucleic acid amplification test. She had a history of end-stage renal disease due to biopsy-proven FSGS prior to receiving a preemptive kidney transplant from her identical twin sister 23 years before this presentation. She received reduced immunosuppression with no induction therapy However, 18 years after transplantation, she was noted on routine follow up laboratory testing to have a UPCR of 1.8 gm/d. Serum creatine also increased to 1.5 mg/dl. She underwent allograft biopsy at this time which was negative for rejection but showed focal global (30%) and segmental glomerulosclerosis (NOS type; Figure 1 ), patchy interstitial fibrosis and tubular atrophy (30%) with associated nonspecific inflammation, mild arteriosclerosis, and hyaline arteriolosclerosis. Immunofluorescence was negative. Electron microscopy showed 30-40% foot process effacement. Genetic testing revealed that she and her twin donor carried both a G1 and a G2 risk allele for APOL1. The patient was treated with losartan and spironolactone and UPCR improved to 0.26 by 1 year post biopsy. Serum creatinine remained at 1.5 mg/dL on regular follow-up testing, the last of which was 3 months earlier, and last UPCR 6 months earlier was 0.74 gm/d prior to presentation. The patient had received the second dose of the Moderna SARS-CoV-2 vaccine approximately 6 weeks prior to presentation. On presentation, the patient's oxygen saturation was 98% on room air, and throughout her hospitalization for COVID-19, her oxygen saturation fluctuated between 92% to 98%, and she required at maximum 2 liters per minute supplemental oxygen via nasal cannula. Her blood pressure was 122/60 on admission, and she did not experience hypotension, with. Respiratory rate was 20 breaths per minute and heart rate 91 on presentation. Chest X-ray on hospital day 1 showed small bilateral pleural effusions and possible faint parenchymal opacities at the lung bases, which did not significantly change on repeat X-ray on hospital days 3 and 4. On presentation she had a serum creatinine of 12.6 mg/dL. UPCR was 32 gm/d. Other pertinent laboratory findings are presented in table 1. She was initially treated with methylprednisolone 1 gram daily for three days for possible acute rejection. Mycophenolate was discontinued due to COVID-19 infection. The patient underwent a second allograft biopsy, which showed acute tubular injury, collapsing glomerulopathy (involving 55% of glomeruli; Figure 2 In a case series of 42 patients who died of COVID-19, acute tubular injury was the primary finding in patients with acute kidney injury, and one patient had FSGS. 15 Both direct viral and cytokine-induced, immune-mediated damage is thought to contribute to kidney injury in COVID-19 infection. 16 While acute tubular injury might be associated with overall systemic illness and the severity of the sepsis response, our patient in this case presented with renal failure far out of proportion to the severity of her illness in other organ systems, and this was reflected in her kidney biopsy which demonstrated injury more consistent with FSGS rather than acute tubular injury. The mechanism of FSGS associated with COVID-19 infection and APOL1 risk status is unclear. COVID-19, like other viral infections, may act as a "second hit" in patients with APOL1 risk alleles, and our experience with this patient suggests that the mechanism of this second hit is not dependent on the overall severity of the infection. Proposed mechanisms of the increased susceptibility to kidney damage in APOL1 risk allele homozygous patients include reduced mitochondrial function and cellular respiratory reserve, altered lysosomal function leading to dysregulated autophagy, and activation of various pro-inflammatory pathways. 17 Potential second hits that may induce the development of FSGS include pharmaceutical and recreational drugs, infections such as human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus, and reduced nephron mass. 18 Our patient's infection may have acted as an immunologic trigger in an already vulnerable kidney to an inflammatory cascade that lead to cell death, and reduced metabolic reserve in her kidney may have led to further damage in the setting of increased metabolic demands of the proinflammatory state. Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. 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