key: cord-1012013-frh2besk
authors: Uppal, Nupur N.; Kello, Nina; Shah, Hitesh H.; Khanin, Yuriy; De Oleo, Ivan Ramirez; Epstein, Edward; Sharma, Purva; Larsen, Christopher P.; Bijol, Vanesa; Jhaveri, Kenar D.
title: De Novo ANCA-associated Vasculitis with Glomerulonephritis in COVID-19
date: 2020-08-20
journal: Kidney Int Rep
DOI: 10.1016/j.ekir.2020.08.012
sha: 8e3c9218949cfc0644ec4a0d42859c50048539a7
doc_id: 1012013
cord_uid: frh2besk

nan

Coronavirus Disease 2019 (COVID-19) is a pandemic, caused by a novel coronavirus that has been identified to belong to the beta-coronavirus family. 1 As the COVID-19 pandemic continues to evolve, more aspects of this illness are being defined and described. In the US, the incidence of acute kidney injury (AKI) in patients hospitalized with COVID-19, has been reported to be around 37%. 2 Different autopsy and kidney biopsy series have revealed acute tubular injury (ATI) to be the most common renal pathology lesion in these patients. 3 ,S1

Although cases of collapsing glomerulopathy and thrombotic microangiopathy (TMA) with COVID-19 have been reported, 4, 5 an association between COVID-19 and crescentic glomerulonephritis (GN) has rarely been described. 6 Herein, we report two cases of pauci immune GN with Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, who clinically improved with treatment of COVID-19 and cautious use of immunosuppressants.

A 64-year-old African American male with remote history of cryptogenic organizing pneumonia, presented to the hospital with two weeks of progressive shortness of breath and dry cough. There was no history of fever or sick contacts. He was noted to be in hypoxic respiratory failure, with respiratory rate of 23, and low oxygen saturation of 83% on room air, that improved to 100% on 10 liter non-rebreather mask. Otherwise, the patient was hemodynamically stable and afebrile. Laboratory findings revealed AKI with elevated serum creatinine (Scr) of 7.87mg/dL, baseline Scr was unknown, and elevated inflammatory markers; D-J o u r n a l P r e -p r o o f dimer:1353ng/mL, Ferritin:1985ng/mL, and CRP:14.53mg/dL. He was diagnosed with COVID-19 using reverse transcriptase polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on a nasopharyngeal swab; chest x-ray showed bilateral patchy opacities. Urinalysis revealed an active sediment with 55 RBC/hpf, 65 WBC/hpf, and significant proteinuria, with spot urine protein to creatinine ratio elevated at 5. Serum albumin was low at 2.8g/dL. His respiratory status and kidney function progressively worsened, despite use of high dose intravenous diuretics. The patient was initiated on intermittent hemodialysis treatment to optimize him for kidney biopsy, as well as to assist with volume overload and electrolyte derangements. was not detected. A kidney biopsy was subsequently performed.

Kidney Biopsy findings: A total of 10 glomeruli were seen on light microscopy; four showed small cellular crescents and/or segmental necrosis and three contained fibrocellular (healing) crescents. There was moderate acute tubular necrosis. Immunohistochemistry staining for SARS-CoV-2 was negative. Immunofluorescence (IF) microscopy revealed non-specific findings Clinical Outcome: Patient did not require mechanical ventilation. The kidney function started to improve after use of pulse dose corticosteroids, and hemodialysis was discontinued. Scr initially decreased and stabilized at 3.5mg/dL, however hospital course was complicated by methicillin sensitive staphylococcus aureus bacteremia with new AKI, when Scr peaked at 4.89mg/dL. He remained non-oliguric, with a decrease in Scr to 4.1mg/dL and MPO titer to 14 units/ml upon discharge. His Scr continues to decrease and has improved to 2.41mg/dL approximately a month after receipt of rituximab. He is scheduled to receive second dose of rituximab at completion of antibiotic therapy for bacteremia.

A 46-year-old South Asian male, with diabetes mellitus, presented with fever, cough, diffuse purpuric rash and AKI with a Scr of 2.9 mg/dL on admission. A few days prior, he was treated for pneumonia with Azithromycin. RT-PCR for SARS-CoV-2 was positive on nasopharyngeal swab, confirming the diagnosis of COVID-19, and he was initiated on hydroxychloroquine. Urinalysis had 100 mg/dL of protein and moderate blood. Serum albumin was low at 2.1g/dL. A skin biopsy revealed leukocytoclastic vasculitis. Kidney function worsened with a peak Scr of 4.0 mg/dL. Serological evaluation for glomerular disease showed normal serum C3 and C4, elevated Proteinase 3 (PR3) level of 57.3units/ml, elevated rheumatoid J o u r n a l P r e -p r o o f factor (320 IU/ml), and IgG kappa monoclonal band on serum immunofixation. A kidney biopsy was performed.

Kidney biopsy findings: Focal necrotizing glomerulonephritis with segmental glomerular thrombi, diffuse severe tubular epithelial injury, mild interstitial fibrosis and moderate arteriosclerosis. IF microscopy showed trace segmental finely granular and mostly mesangial staining for IgA, IgM and C3. No significant staining for IgG, C1q, kappa or lambda light chains was noted. Rare mesangial dense deposits were seen on EM, but no viral particles were noted.

Clinicopathologic diagnosis: PR3-ANCA associated vasculitis (AAV) with focal necrotizing, pauci-immune glomerulonephritis.

Treatment: Patient was initiated on pulse dose corticosteroids (IV methylprednisolone, given as 1 gram daily for 3 days) and received first dose of rituximab (375mg/m2 intravenously) during the hospital stay. Subsequently, he was transitioned to oral prednisone and completed his rituximab treatment after discharge.

Clinical Outcome: Two weeks after the initial dose of rituximab, PR3 titer decreased to 28.8units/ml, and Scr improved to 2.0mg/dL. Most recent urinalysis has been negative for protein, with mild hematuria. Scr has decreased to 1.27mg/dL, at 12 weeks after initial diagnosis. Table 1 summarizes clinical findings, demographics and treatment strategies of our two cases and the already published case 6 of ANCA-associated GN with COVID-19.

Several mechanisms for development of kidney injury in COVID-19 patients, including hemodynamic factors, viral tropism towards kidney tissue, 8 We describe two patients with ANCA-associated GN and severe AKI associated with COVID-19. Both patients are non-obese males, without any prior history of kidney disease or known ANCA vasculitis. The pulmonary findings in our two patients were deemed associated with COVID-19 illness and volume overload. Clinically, pulmonary ANCA disease was not suspected. Another case of cytoplasmic (c)-ANCA associated with glomerulonephritis in the setting of COVID-19 has been reported in a 25-year-old male from Iran. 6 While the association between SARS-CoV-2 infection and our patients with GN remains obscure, it is possible that cytokine storm, with immune system related dysregulation in a uremic state may have led to an altered response to infection (similar to the mechanism previously postulated for SARS-CoV infection) S5 further giving rise to AAV. In addition, it is possible that a specific host is prone to a certain type of kidney pathology in response to a "second hit". Here, we postulate the second hit is COVID-19. Immunosuppression with cyclophosphamide or rituximab during COVID-19 infection is rightfully of large concern in the medical community, and there is limited knowledge on outcomes of COVID-19 in patients on these background therapies. Rituximab leads to B-cell depletion and can abrogate a prompt and efficient antibody response to facilitate faster recovery from the virus. Additionally, use of rituximab can lead to inability to mount antibodies to a potential vaccine as well. However, for our patients, rituximab was considered as the choice of therapy based on its better tolerability and lesser side effects. Emerging reports of COVID-19 patients who had been receiving rituximab (or other anti-CD20 monoclonal antibodies) for their underlying immune-mediated conditions, have demonstrated that these patients do not seem to have a worse course or outcome compared with the general population, with some even suggesting that rituximab may forestall the cytokine storm seen in COVID-19 and improve outcomes. S9-S11 Furthermore, early and higher levels of anti-viral antibody titers have been correlated with increased mortality in COVID-19 patients S12 and patients with X-linked agammaglobulinemia (XLA) who suffer from full B-cell deficiency have shown full recovery from COVID-19 infection. S13 Anders et al, S14 suggests to postpone maintenance rituximab during the surge of the pandemic to avoid not only the unnecessary immunosuppression, but also unnecessary contact with other potentially infected patients and health personnel during the rituximab administration.

Regardless, treatment might be still indicated in certain clinical settings. While our first patient J o u r n a l P r e -p r o o f received rituximab after his COVID-19 PCR turned negative (to promote recovery and ensure immunological memory from COVID-19), the second patient received it concurrently with corticosteroid therapy. Both of the patients had improvement in their COVID-19 related symptoms, as well as kidney recovery.

In summary, ANCA-associated GN can be associated with COVID-19. Due to the lack of scientific evidence related to COVID-19, management of diverse pathological entities arising in its setting is challenging. The existing literature on viral infection related ANCA vasculitis reveals favorable outcomes with treatment of virus and ANCA disease using antiviral agent and immunosuppression concurrently, however our major concern was worsening of infection with use of immunosuppression, since no specific agent has been proven to be beneficial in treating COVID-19. All three patients with COVID-19 (two in this series and one prior published case 6 ) who developed ANCA glomerulonephritis responded well to immunosuppressive agents ( Table  Table 1 

Coronavirus Disease

Acute kidney injury in patients hospitalized with COVID-19

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

COVID-19-Associated Collapsing Glomerulopathy: An Emerging Entity

Thrombotic microangiopathy in a patient with COVID-19

Newly Diagnosed Glomerulonephritis During COVID-19 Infection Undergoing Immunosuppression Therapy, a Case Report

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

Multiorgan and Renal Tropism of SARS-CoV-2