Biomarkers of renal injury as early predictors of COVID-19 associated AKI: a prospective observational trial (BRICOAKI-trial)

Introduction: Early prediction by the use of serum and urinary biomarkers for the detection of acute kidney injury (AKI) may be very valuable to optimize the management and helps in improving the outcomes. This study aims to investigate whether daily measurement of urinary and plasma renal biomarkers have a role in earlier predicting COVID-19 associated AKI. Method(s): The study was conducted as a single-center, prospective, observational cohort study between August 2020 and December 2020 in hospitalized COVID-19 patients. A total of 65 moderate and severe COVID-19 positive adult (>= 18 years) patients were enrolled for this study. We measured serum creatinine, cystatin C, NGAL, KIM-1, Urine-Klotho, TIMP-2, IL-6 level, and urinary microalbumin/urinary creatinine on various days. The receiver operating characteristic curve (ROC) analysis was used to find the sensitivity and specificity of various markers to predict the incidence of AKI. Result(s): A total of 24 moderate and 41 severe COVID-19 patients were included. Out of which 47 patients developed (72.3%) acute kidney injury (AKI) over the course of COVID-19. Among these subjects, 18/47 (38.2%) developed severe AKI (KDIGO 2 + 3), and 5/47 (10.6%) required RRT. NGAL was found to be the best marker to predict the probability of AKI (Area under curve AUC of 0.713-0.786) with a sensitivity of 76-90% and specificity of 56-79% on different days of assessment from Day 1 to Day 7. IL-6 had moderate accuracy of prediction and cystatin C, KIM-1, Urine-Klotho, TIMP-2, IL-6 had poor accuracy for predicting the incidence of AKI. Conclusion(s): Urinary biomarkers like NGAL have good predictability for AKI.

Association of urinary mitochondrial DNA with COVID-19 related acute kidney injury, mitochondrial stress, and inflammation in renal transplant recipients

Introduction: ACE-receptors are profusely expressed in the renal cell, making it highly susceptible for severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) infection. After entering the cells, the virus induces high levels of cytokines, chemokines, and inflammatory responses, resulting neutrophilic infiltration, activation, and profuse reactive oxygen species (ROS) formation, leading to cellular necrosis and acute tubular injury. Proximal convoluted tube cell are rich in mitochondria and susceptible for developing acute kidney injury (AKI) due to mitochondrial stress. Early detection of AKI may helpful in its management, limiting the severity, avoiding nephrotoxic medicines and modifying the drug dose depending on renal function. Therefore, in the current study, we have determined the utility of urinary mitochondrial DNA (umt-DNA) and neutrophil gelatinase-associated lipocalin (NGAL) in predicting COVID-19-associated acute kidney injury (AKI) and mitochondrial stress and demonstrated the inflammatory response of urinary mt-DNA. Method(s): Live-related RTRs(n=66), who acquired SARS-CoV-2 infection and were admitted to a COVID hospital were included and subclassified into AKI (N=19) with > 25% spike in serum creatinine level from the pre-COVID-19 serum creatinine level, and non-AKI (N=47) whose serum creatinine value remained stable similar to the baseline value, or a rise of < 25% of the baseline values of pre-COVID-19. A 50ml urine sample was collected and umt-DNA and N-GAL was determined by the RT-PCR and ELISA methods respectively. A 10ml blood sample from 10 healthy volunteers was also collected for PBMC isolation and inflammatory response demonstration. A 1x106 PBMC was stimulated for 24hrs. with 1microg/ml of urinary DNA or TLR9 agonist CpG oligodeoxynucleotide (5'-tcgtcgttttcggcgc:gcgccg-3') in duplicate. Unstimulated PBMCs served as control. The gene expression of IL-10, IL-6, MYD88 was analyzed by the RT-PCR and IL-6, IL-10 level in supernatants by the ELISA. Result(s): Both the urinary mitochondrial gene ND-1 and NGAL level was significantly higher in AKI group compared to non-AKI. The mean ND-1 gene Ct in AKI group was (19.44+/-2.58 a.u) compared to non-AKI (21.77+/-3.60;p=0.013). The normalized ND-1 gene Ct in AKI was (0.79+/-0.11 a.u) compared to non-AKI (0.89+0.14;P=0.007). The median urinary NGAL level in AKI group was (453.53;range, 320.22-725.02, 95% CI) ng/ml compared to non-AKI (212.78;range, 219.80-383.06, 95%CI;p=0.015). The median urine creatinine normalized uNGAL was 4.78 (0.58-70.39) ng/mg in AKI group compared to 11.26 ng/mg (0.41-329.71) in non-AKI group. The area under curve of ND-1 gene Ct was 0.725, normalized ND-1 Ct was 0.713 and uNGAL was 0.663 and normalized uNGAL was 0.667 for detecting the AKI and mitochondrial stress. The IL-10 gene expression was downregulated in umt-DNA treated PBMCs compared to control (-3.5+/-0.40vs1.02+/-0.02, p<0.001). IL-6 and Myd88 gene expression was upregulated. The culture supernatant IL-10 and IL-6 level in umt-DNA treatment PBMCs vs control was 10.65+/-2.02 vs 30.3+/-5.47, p=0.001;and 200.2+/-33.67 vs 47.6+/-12.83, p=0.001 pg/ml respectively. Conclusion(s): Urinary mt-DNA quantification can detect the Covid19 associated AKI and mitochondrial distress with higher sensitivity than uNGAL in RTRs. Urinary mt-DNA also induces a robust inflammatory response in PBMCs, which may exacerbate the Covid19 associated allograft injury. No conflict of interestCopyright © 2023

Immunogenicity and Safety of Homologous Chadox1 Ncov-19 and Heterologous Prime-Boost of Coronavac and Chadox1 Ncov-19 among Kidney Transplant Recipients: An Observational Prospective Cohort Study

Introduction: Kidney transplant recipients (KTRs) are at risk for substantial morbidity and mortality during COVID-19 infection. Vaccination for this group of patients is reccommended. However, immunogenicity and safety data after COVID-19 vaccination among KTRs remains limited. Method(s): We conducted an observational prospective trial involving KTRs at Chiang Mai University hospital, Chiang Mai, Thailand. The participants were received homologous ChAdOx1 nCoV-19 (AZ-AZ), or the heterologous prime-boost of CoronaVac,followed by AZ (SV-AZ). The immunogenicity was assessed by measuring antibodies against the S1 receptor-binding domain (anti-RBD), and SARS-CoV-2 surrogate virus neutralization test (sVNT) at specific timepoints. The primary outcome was the seroconversion rate of sVNT at day 28 after complete vaccination. The secondary outcomes were the seroconversion rate of sVNT at day 28 after the first dose of vaccination, the level of sVNT and anti-RBD at specific timepoints, and the adverse events of each vaccine regimen. Result(s): A total of 18 KTRs were recruited. Among those, 13 (72.2%), and 5 (27.8%) patients were received AZ-AZ, and SV-AZ regimen, respectively. The seroconversion rate of sVNT at day 28 after the second dose were 23.1%, and 20.0% for AZ-AZ, and SV-AZ, respectively (P>0.99). The level of sVNT and the level of anti-RBD at day 28 after the first and at day 28 after the second dose were not different between groups (Figure 1). There were no serious adverse events reported in any vaccine groups. However, AZ-AZ showed sign of tubular dysfunction demonstrated by increasing of fractional excretion of magnesium after complete course of vaccination which correlated to the trend of urine albumin and urine protein creatinine ratio (r=0.720, P=0.013;and r=0.726, P=0.011, respectively). [Formula presented] [Formula presented] Figure 1 Percentage of neutralization inhibition (a) and level of anti-RBD antibody (b) at each visit of homologous ChAdOx1 nCoV-19 (AZ-AZ), and heterologous prime-boost of CoronaVac, followed by AZ (SV-AZ) regimen Conclusion(s): Immunogenicity after COVID-19 vaccination with either homologous or heterologous prime-boost regimen among KTRs was compromised. Homologous replication-defective viral vectors vaccine regimen seemed to affect renal tubular function, and further follow-up should be warranted. No conflict of interestCopyright © 2023

Overview Of Proteinuria Among Hospitalized Patients With COVID-19

COVID-19 was thought to be primarily a respiratory disease, progressing in some patients to serious respiratory symptoms, pneumonia, severe respiratory distress syndrome and even death.Patients infected with SARS-CoV-2 might have a variety of clinical presentations, ranging from no symptoms to life-threatening sickness. Later analysis revealed entire systems were compromised, affecting other vital organs, including the kidneys, and a correlation was observed between chronic kidney disease (CKD) and COVID-19 severity. A large percentage of affected patients present with acute kidney injury. However, specific phenotypic aspects of acute kidney injury or other renal manifestations of COVID-19 remain sparsely characterized. Urine proteincreatinine ratio (UPCR) in single-voided urine samples correlates well with measurements of 24-hour urinary protein when properly interpreted by taking into consideration the different rates of creatinine excretion. Arguably, knowing the baseline status of proteinuria can be equally important in the assessment of AKI in a hospitalized patient. Many reports indicate that proteinuria can be detected in acute kidney injury associated with COVID-19 despite being largely described as a form of acute tubular injury. Therefore, this study aimed to review acute kidney injury among hospitalized patients with COVID 19.Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Covid-19 Vaccination Induced Minimal Changed Disease

Introduction: Minimal change disease (MCD) accounts for approximately 15% of adults with idiopathic nephrotic syndrome (NS). We report the case of minimal change disease in a patient who presented with signs and symptoms of NS following Covid-19 immunisation vaccine. Method(s): Case: A 58-year-old male with negligible past medical history developed generalised swelling 2 days following receiving the Pfizer Covid-19 booster. On examination, he had a blood pressure of 130/80 and anasarca. Relevant laboratory results include a creatinine of 123, estimated glomerular filtration rate (eGFR) of 55, albumin of 9, urine protein: creatinine ratio of 713, and hyaline casts of moderate quantity. A kidney biopsy revealed glomerular sclerosis appropriate for age, and normal vessels and tubules. Immunofluorescence showed negative serology. A diagnosis of minimal change disease was made. The patient was treated with high dose prednisone at 1mg/kg/day and went into remission. The patient was followed up 2 months after admission, and investigations revealed a creatinine of 70, eGFR of >90, albumin of 34 and urine protein:creatine ratio of 58. Result(s): / Conclusion(s): Discussion and conclusion: This is the first case of Covid-19 vaccination induced NS reported in New Zealand. Theorised mechanism of injury includes T-cell mediated immune dysregulation, leading to glomerular disease (Sahin et al., 2020). Different glomerular diseases have been reported to occur for the first time following the Covid-19 vaccination (Klomjit et al., 2021). There has also been reports of reactivation of disease following Covid-19 immunisation (Hartley et al., 2022 and Leong et al., 2021). mRNA vaccination induced NS should be considered in all patients presenting with apparent idiopathic NS. This is especially important as we continue to learn more about the Covid-19 vaccination. No conflict of interestCopyright © 2023

A case report of IgA vasculitis following CoronaVac vaccination in a Filipino patient

Introduction: Coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV- 2) are emerging. There is an urgent need for COVID-19 vaccines to control disease outbreaks by herd immunity. Vaccines can trigger immunity as many vaccine-related immunological adverse events have been described. Case Presentation: A case of a 32 years old Filipino female with no known co-morbidity who presented with rashes on bilateral lower extremities one day after receiving her second dose of CoronaVac-Sinovac vaccine. These were non-pruritic nor painful, which appeared to be initially well-defined round erythematous macules, papules, and plaques, mostly raised. It was associated with colicky abdominal pain and inflammatory arthritis affecting the both knees and ankles. She has no vices but known to have allergy with seafood. There were multiple well defined erythematous round to irregularly shaped purpuric macules, papules and plaques, non-blanching, flat and raised, on arms near the antecubital fossa, abdomen and lower extremities. She underwent skin biopsy and direct immunofluorescence showed interface dermatitis with leukocytoclastic vasculitis and IgA +1 vessel wall, and fibrinogen +2 vessel wall, respectively. There was microscopic hematuria and proteinuria. The Urine protein creatinine ratio was normal at 0.193 gm/gm. She was managed as a case of IgA vasculitis and was given moderate dose of steroid (0.5mg per kilogram per day prednisone equivalent) and omeprazole. She was discharged improved with resolution of rashes evident during follow up at the out-patient consultation. Conclusion(s): We report a case of an adult Filipina developing IgA vasculitis following CoronaVac COVID-19 vaccination. She responded well following initiation of steroid therapy. Autoimmune phenomenon following immunization is possible through different mechanisms. These include molecular mimicry, a hyper-stimulated inflammatory state, and autoimmune syndromes induced by adjuvants. While no strategies have been found to prevent autoimmunity following vaccination, it should be emphasized that vaccine recipients should seek medical care for any untoward events following receipt of any immunization.

Elevated Urinary Mitochondrial DNA Induces Inflammation and Associated with Acute Kidney Injury in Sars-Cov-2 Infected Renal Allograft Recipient

BACKGROUND: Severe acute respiratory coronavirus-2 (SARS-CoV-2) affected multiple organs including kidney. SARSCoV- 2 open reading frame protein 3a induces necroptosis in infected cell leading release of mtDNA which binds to TLR9 and trigger innate immunity which may lead to acute allograft injury. AIM OF THE STUDY: To determine the specificity and sensitivity of urinary mitochondrial DNA (umt-DNA) and neutrophil gelatinase-associated lipocalin (NGAL) in predicting COVID-19-associated acute kidney injury (AKI) mitochondrial stress and inflammation. METHOD(S): Live-related RTRs (n = 66) who acquired SARSCoV- 2 infection and were admitted to a COVID hospital were included and subclassified into AKI (N = 19) with >25% spike in serum creatinine level from the pre-COVID-19 serum creatinine level and non-AKI (N = 47) whose serum creatinine value remained stable similar to the baseline value or a rise of < 25% of the baseline values of pre-COVID-19. A 50 ml urine sample was collected and umt-DNA and N-GAL was determined by the RT-PCR and ELISA methods respectively. A 1 x 106 PBMCs were stimulated for 24 hrs. with 1mug/ml of urinary DNA or CpG oligodeoxynucleotide (5) in duplicate. Unstimulated PBMCs served as control. The gene expression of IL-10 IL-6 and MYD88 was analyzed by the RT-PCR and IL-6 IL-10 level in supernatants by the ELISA. RESULT(S): Both the urinary mitochondrial gene ND-1 and NGAL level were significantly higher in AKI group compared to non-AKI. The mean ND-1 gene Ct in AKI group was (19.44 +/- 2.58 a.u) compared to non-AKI (21.77 +/- 3.60;p = 0.013). The normalized ND-1 gene Ct in AKI was (0.79 +/- 0.11 a.u) compared to non- AKI (0.89+0.14;P = 0.007). The median urinary NGAL level in AKI group was (453.53;range, 320.22-725.02, 95% CI) ng/ml compared to non-AKI (212.78;range, 219.80-383.06, 95%CI;p = 0.015). The median urine creatinine normalized uNGAL was 4.78 (0.58-70.39) ng/mg in AKI group compared to 11.26 ng/mg (0.41-329.71) in non-AKI group. The area under curve of ND-1 gene Ct was 0.725, normalized ND-1 Ct was 0.713, and uNGAL was 0.663 and normalized uNGAL was 0.667 for detecting the AKI and mitochondrial stress. The IL-10 gene expression was downregulated in umt-DNA-treated PBMCs compared to control (-3.5 +/- 0.40 vs 1.02 +/- 0.02, p < 0.001). IL-6 and Myd88 gene expression was upregulated. The culture supernatant IL-10 and IL-6 level in umt-DNA treatment PBMCs vs control was 10.65 +/- 2.02 vs 30.3 +/- 5.47, p = 0.001 pg/ml;and 200.2 +/- 33.67 vs 47.6 +/- 12.83pg/ml, p = 0.001 respectively. CONCLUSION(S): Urinary mt-DNA quantification can detect the Covid-associated AKI and mitochondrial distress with higher sensitivity than uNGAL in RTRs and induces inflammation in PBMCs.

A Case of Primary Membranous Nephropathy (MN) After Booster Injection of the BNT162b2 COVID-19 Vaccine (Pfizer-BioNTech)

Introduction: All currently authorized COVID-19 vaccines have proven to be safe, effective and reduce risk of severe illness. Glomerular disease have been reported after administration of COVID-19 messenger RNA (mRNA) vaccines. We report on the development of nephrotic syndrome from Primary Membranous nephropathy after third injection of the BNT162b2 COVID-19 vaccine. Case Description: 34 years old female with no significant past medical history except migraine headaches, presented to the outpatient setting reporting intermittent and gradually progressing lower extremities edema for 3 months;accompany by abdominal and lower back swelling, facial edema and foamy urine. She received her 3rd dose of COVID-19 vaccine 1-2 weeks before symptoms appearance. On evaluation, she was normotensive, preserved kidney function(Creatinine 0.85 BUN 9 eGFR >60), hypoalbuminemia (Alb 1.1 g/dL), nephrotic-range proteinuria (Spot urine protein 869.9 mg/dL, Urine Creatinine 79.9mg/dL, 24hr Urinary protein excretion estimation 11000mg/g [11g/day]), elevated cholesterol (572mg/dL) and triglycerides (220 mg/dL). She has negative ANA, ANCA, DNA Ds Ab, Hepatitis profile, HIV. Her Anti-phospholipase A2 receptor (anti- PLA2R) antibody came back positive (247 relative units/ml [<14, negative;>20, positive]) She underwent kidney biopsy showing global 3+ Subendothelial electron dense deposits (IgG, C3, Kappa, Lambda), 100 % foot process effacement, IF staining positive for PLA2R, consistent with Primary Membranous Nephropathy Stage II. She was started on High-dose steroids and later switched to Tacrolimus 2mg BID, and received Rituximab x 2 doses with major improvement in symptoms and proteinuria. Discussion(s): MN is more common in male in their early 50s. The fact our patient doesn't fit this category, her temporal association with vaccination and the exclusion of other explanatory factors, supports a potential connection between COVID-19 vaccination and glomerular disease. To our knowledge, this is only the second case reporting association of COVID-19 mRNA vaccine and MN. Together with a report from Relapse MN after vaccination and one case of Minimal Change disease, we highlight the possible role of COVID vaccination causing immune glomerular dysregulation. Further studies are needed to elucidate the early postvaccination immune response mechanism.

Collapsing Glomerulopathy in a Patient With Recent COVID-19 and APOL-1 High-Risk Genotype

Introduction: Collapsing glomerulopathy (CG) is an aggressive subtype of focal segmental glomerulosclerosis, associated with poor renal outcomes. Risk factors for CG include HIV infection, APOL1 high-risk genotypes, and CG has also recently been reported in patients with COVID-19. We report a case of CG with acute kidney injury (AKI) in a patient with a high risk APOL1 genotype, who had renal recovery after prednisone treatment. Case Description: A 43-year-old male with no past medical history presented with fever, myalgia, hemoptysis, vomiting, and diarrhea of 2 weeks duration. Initial exam was remarkable for temperature 103 degrees Fahrenheit, SpO2 95% on room air, and inspiratory crepitations without peripheral edema. Labs were notable for serum creatinine 2.6 mg/dL (unknown baseline), peak creatine kinase 4037 U/L, and urine protein creatinine ratio 19 g/g without RBCs. Chest CT was consistent with multilobar pneumonia. SARS-CoV2 PCR was repeatedly negative but COVID-19 spike and nucleocapsid IgG were positive. Extensive serologic workup for causes of glomerulonephritis and nephrotic syndrome was negative. He was empirically treated with antibiotics for pneumonia but cultures remained negative. Bronchoscopy revealed no evidence of alveolar hemorrhage. His renal function worsened, requiring hemodialysis. Kidney biopsy revealed collapsing glomerulopathy associated with thrombotic microangiopathy, few myoglobin casts suggestive of rhabdomyolysis, and acute tubular injury. Prednisone was initiated at 1mg/kg daily and tapered over 2 months. Lisinopril was initiated for proteinuria. After 5 months, serum creatinine was 1.3 mg/dL and urine protein creatinine ratio improved to 0.6g/g. Genetic testing revealed APOL1 G1/G1 genotype. Discussion(s): In this patient, SARS-CoV2 PCR was likely negative because he presented weeks after symptom onset but the clinical course and serologic evidence of prior SARS-CoV-2 infection supports the diagnosis of COVID-19 associated CG in the setting of APOL1 high-risk G1/G1. Proposed mechanisms of COVID-19-related CG include increased cytokines, that upregulate podocyte expression of toxic APOL1 variants and AKI with tubular injury is often found. Our patient improved with steroid treatment but the treatment of COVID-19 associated CG requires further study.

Voclosporin for Lupus Nephritis: Assessment of Long-Term Safety and Efficacy Including Renal Outcome Over 3 Years of Treatment in the Phase 3 AURORA 1 and AURORA 2 Studies

Background: In AURORA 1, adding voclosporin to mycophenolate mofetil (MMF) and low-dose steroids led to significant reductions in proteinuria at 1 year in patients with lupus nephritis (LN). We report on the recently completed AURORA 2 study evaluating voclosporin compared to placebo in patients treated for an additional 2 years after AURORA 1. Method(s): Patients with LN completing AURORA 1 were eligible to continue on the same double-blinded treatment of voclosporin or placebo in AURORA 2;all patients recieved MMF and low-dose steroids. Outcomes assessed over the 3 year treatment period of both studies included adverse events (AEs), eGFR, urine protein-creatinine ratio (UPCR), good renal outcome and renal flare. Good renal outcome was defined based on achievement of an adequate response (i.e. sustained reduction in UPCR to <=0.7 mg/mg) and without renal flare (i.e. an increase to UPCR >1 mg/mg from a post-response UPCR of <0.2 mg/mg or an increase to UPCR >2 mg/mg from a post-response UPCR of 0.2 to 1.0 mg/mg), as adjudicated by a blinded Clinical Endpoints Committee. Result(s): Overall rates of serious AEs in the voclosporin (26.7% of 116 patients) and control arm (28.0% of 100 patients) were similar. There were no deaths in the voclosporin arm during AURORA 2;four deaths occured in the control arm (pulmonary embolism, n=1;coronavirus infection, n=3). Mean corrected eGFR was within the normal range and stable over the study period. The reductions in UPCR achieved in AURORA 1 were maintained in AURORA 2 and significantly more patients in the voclosporin arm achieved a good renal outcome (66.4% in voclosporin vs 54.0% in control;p-value=0.045). Renal flare occurred in 24 of 101 patients with adequate response in the voclosporin arm and 19 of 73 patients in the control arm (23.8% in voclosporin vs 26.0% in control;p-value=0.662);69.8% of all patients with renal flares completed study treatment. Conclusion(s): Voclosporin was well-tolerated over three years of treatment. The significant reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2 and more patients in the voclosporin arm achieved a good renal outcome. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis.

IgA Vasculitis After COVID-19 Vaccination: A Rare but Significant Complication

Introduction: A 24 year old male presented with rash, gastrointestinal bleeding and nephrotic syndrome one week after first COVID vaccination. Renal biopsy revealed crescentic IgA nephritis. He was treated steroids and responded clinically but continues to have proteinuria. Case Description: A 24 year old male with history of cerebral palsy presented with a vasculitic rash, hematochezia and edema. He had no prior history of renal or autoimmune disease. Symptoms developed one week after first dose of Moderna mRNA-1273 vaccine. Serum albumin was 1.6 g/dL and urine protein-creatinine ratio 8.5. Endoscopy showed esophagitis and small bowel ulcerations. Renal biopsy showed focally crescentic and necrotizing proliferative glomerulitis with IgA dominant deposits consistent with IgA vasculitis with renal involvement. He received pulse dose solumedrol followed by prednisone taper. Cyclophosphamide was initiated but then stopped due to cytopenias. After several weeks GI bleeding resolved spontaneously and proteinuria improved but remained in the nephrotic range. The course was further complicated by positive COVID testing prior to discharge-he was asymptomatic and received sotrovimab. On followup three months later the patient's edema resolved and serum albumin normalized. He continues to have subnephrotic range proteinuria with 2.3 grams/24 hours and active urinary sediment with dysmorphic red cells. He remains on steroid taper with plan for repeat renal biopsy to inform decisions regarding further immune suppression. He has not been rechallenged with COVID vaccine. Discussion(s): Rare associations between COVID vaccination and both de-novo and relapsing glomerular lesions, including minimal change disease, IgA nephropathy, ANCA and anti GBM glomerulonephritis, have been reported. COVID infection itself has been associated with an FSGS type lesion termed COVID-associated nephropathy (COVAN). As highlighted by this case, unvaccinated or partially vaccinated patients are at increased risk for COVID infection. Thus even in those with known glomerular disease, vaccination should still be recommended. Studies are needed to determine if patients with off-target glomerulopathies can be safely rechallenged with COVID vaccine, whether the course of COVID vaccine-associated disease glomerular lesions mimic the primary glomerular disease and how to optimally manage these patients.

Subclinical Kidney Allograft Rejection Without Maintenance Immunosuppressive Therapy (mIST)

Introduction: Kidney transplant (KTx) generally requires mIST to prevent rejection and graft loss. A mother-to-son kidney recipient presents with preserved kidney function despite being off mIST for 26 years. Case Description: A 44-year-old man with diabetes mellitus, unknown congenital kidney disease requiring peritoneal dialysis for 3y and KTx from his mother at age 13, and status post COVID19 infection 2m prior, presents with diabetic ketoacidosis due to insulin nonadherence. Patient received unknown mIST until age 18 when he self-discontinued therapy. Initial studies: Serum: glucose1064 mg/dL, pH 7.28, +ketones, creatinine (Cr) 2.4 mg/dL (baseline Cr 1.1);Urinalysis 4-10 white blood cells/high power field, few bacteria;Urine protein/Cr 0.4 g/g, albumin/Cr 0.1 g/g Patient received insulin and fluid with Cr improved to 1.1 mg/dL. Fig 1 shows Cr timeline. Kidney biopsy was performed prior to discharge to determine the need for mIST reinitiation. While awaiting for pathology report as outpatient, Cr increased to 1.82 mg/dL. Pathology Fig 2: Chronic active T-cell-mediated tubulointerstitial rejection, active vascular rejection, and chronic active antibody-mediated rejection. Patient was readmitted for intravenous immunoglobulin & antithymocyte globulin with appropriate Cr improvement and discharged on prednisone, mycophenolate, & tacrolimus. Donor HLA-typing was not available for donor specificic antibody testing. Discussion(s): The case demonstrates 1) Subclinical rejection may occur in the setting of prolonged IST discontinuation and 2) Cr is insensitive in detecting rejection and raises the possibility of COVID19-induced exacerbation of ongoing low-level rejection. (Figure Presented).

Adverse Renal Events After BNT162b2 Pfizer/BioNTech COVID-19 Vaccine in Kidney Transplant Recipients

Purpose: Adverse events of a novel mRNA vaccine are not well described in Kidney Transplant Recipients(KTR), especially the risk of immune activation or recurrent glomerulonephritis(GN), which has been described in native GN after COVID-19 vaccines. Method(s): In this single-center prospective study, 147 KTR were enrolled after informed consent and administered 2 doses of Pfizer/BioNTech vaccine 21 days apart. Follow-up was 3 weeks after Dose2. Result(s): Mean age of KTR was 51 years;55.1% male;65.3% Chinese, 19% Malay, 11.6% Indian;69.5% Living donor, 29.9% Deceased donor, 0.7% Pancreas-kidney transplants;71.5% had biopsy-proven or presumptive chronic GN(CGN), 12.9% diabetic nephropathy, 15.6% other causes. 11(7.5%) KTR had delayed Dose2 administered at median 29 days(range 24-93) after Dose1. 7(4.8%)were delayed due to renal events: rise in creatinine(n=3), or proteinuria(n=2), or both creatinine and proteinuria with allograft biopsy showing acute T-cell and antibody-mediated rejection(n=1), new BK viraemia(n=1). Other reasons were possible anaphylaxis(n=1), intercurrent infection(n=2), and inability to attend due to quarantine(n=1). 27 KTR had new microhaematuria(MH) after Dose1;9 persisted after Dose2. Additional 18 had new MH after Dose2. Of 45 KTR with new MH, 7 had underlying IgAN, 5 had other biopsy-proven-CGN and 22 had presumed CGN, suggesting 34/45 with possible immune activation. 12 KTR had new onset proteinuria (rise in urine protein:creatinine ratio (UPCR) <=30 to >30mg/mmol);5/7 who developed a rise after Dose1 remained elevated;additional 5 had a rise after Dose2. 7 KTR had rise in proteinuria from UPCR <=100 to >100mg/mmol. Conclusion(s): Subclinical changes in allograft monitoring parameters are frequent after COVID-19 mRNA vaccines with up to 40.1% of KTRs showing rises in creatinine, proteinuria or new MH. Although overt recurrent GN and acute rejection are infrequent, high vigilance and monitoring for these occurrences should be undertaken in KTRs receiving mRNA vaccines.

VOCLOSPORIN for LUPUS NEPHRITIS: RESULTS of the TWO-YEAR AURORA 2 CONTINUATION STUDY

Background: Voclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN signifcantly increased rates of complete renal response at 52 weeks. Objectives: Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 study Methods: Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, I V, or V ± III/IV), proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular fltration rate (eGFR) >45 mL/min/1.73 m2. Patients who completed AURORA 1 and who elected and were eligible to enter AURORA 2 continued on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed. Results: In total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm receiving treatment to the end of AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%];Table 1). Eight patients in each arm experienced serious adverse events of infection;serious coronavirus infections were observed in 2 patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2;four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m2 at 4 weeks following study drug discontinuation (Figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation. Conclusion: Voclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period, and the signifcant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a longterm treatment beneft of VCS in patients with LN. Includes adverse events starting on or after the frst dose of study drug in AURORA 2 up to 30 days after the last dose and all events of death reported during study follow-up. Adverse events were aggregated by System Organ Class and Preferred Term and coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0. AE, adverse event.

Minimal Change Disease Relapse After SARS-CoV-2 Booster Vaccine

Immune dysregulation has been postulated as a pathogenetic mechanism for minimal change disease (MCD) and several vaccines have been reported to act as a trigger for relapse. While cases of both de-novo MCD and MCD relapse have been reported following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) mRNA vaccinations, we report, to the best of our knowledge, the first case of MCD relapse following booster dose of Pfizer-BioNTech SARS-CoV-2 vaccine. 63-year-old Italian male, with history of nephrotic syndrome secondary to kidney biopsy proven MCD, who had achieved complete remission with steroid therapy, had follow up labs done that showed spot urine protein: creatinine of 10.1 and albumin of 3.0g/dL. He had received the booster dose of Pfizer-BioNTech SARS-CoV-2 vaccine 2 weeks ago, and endorsed generalized weakness, puffiness over face, edema over upper extremities that appeared within a week after administration of the vaccine, and weight gain of 10 lbs over past week. Blood pressure was elevated (152/78 mmHg). He denied any recent infections, use of Nonsteroidal Anti-Inflammatory Drugs, or antibiotics. Other diagnostic work up revealed hypertriglyceridemia, normal serum creatinine. Serological work up for secondary causes of glomerular diseases was negative. He was initiated on oral prednisone therapy. Spot urine protein:creatinine decreased to 1.1, 2 weeks after initiation of steroids. Vaccination is a recognized trigger for relapse of nephrotic syndrome. mRNA vaccines are expected to produce a higher antibody response as well as increased production of cytokines and chemokines. This can lead to dysregulation in permeability factors that can result in relapsing glomerulonephritis. As data on adverse effects of SARS-CoV-2 vaccines continue to evolve, we suggest to closely monitor patients with history of nephrotic syndrome for relapse after receipt of the SARS-CoV-2 vaccine, including the booster dose. Further studies are needed to determine whether relapse of MCD is specific for SARS-CoV-2 mRNA vaccination and to decipher mechanisms for possible immune dysregulation in those patients. This may help in formulation of protocol for vaccination in patients with nephrotic syndrome and contribute to informed decision making.

De novo IgA Nephropathy Following mRNA COVID-19 Vaccine

In response to the COVID-19 pandemic, worldwide efforts contributed to the largest vaccination campaign in history. Thus far, 17 cases of IgA nephropathy (IgAN) following COVID-19 vaccine were reported in adults, all after mRNA vaccines. Most patients had gross hematuria (GH) and sub-nephrotic range proteinuria (SNRP) within 2 days after the second dose. A 23-year-old White female with recent mild COVID-19 infection developed asymptomatic GH with SNRP 2 days after receiving the first and the second dose of Pfizer-BioNTech vaccine. Laboratory studies showed normal kidney function and serum albumin. Negative rheumatologic workup. Urinalysis revealed proteinuria, dysmorphic red blood cells, and rare granular casts. Urine protein-creatinine ratio (UPr/Cr) was 1,4g/g. Within 1 week the GH self-resolved, however, she continued to have persistent microscopic hematuria and subnephrotic proteinuria. Kidney biopsy showed IgAN. The Oxford MEST-C score was M1E0S1T0C0. She was started on Lisinopril. Upr was 976mg/24h. Subsequently, 2 days after the booster vaccine she developed GH, Upr increased to 2063mg/24h and was started on Dapagliflozin. This is the first reported case of de novo IgAN following each dose of COVID-19 vaccine and booster presenting with recurrent GH and SNRP. This case illustrates the need for pharmacovigilance and whether we should use non-mRNA or a different vaccine schedule in this vulnerable population. The new-onset and recurrence of GH shortly after the COVID-19 vaccines suggests a potential association with the development of IgAN and relapses. Further studies are needed to understand the pathophysiology of the vaccine-associated glomerular diseases, optimize vaccine strategies and guide optimal therapeutic management. (Figure Presented)

Features of the course of acute pyelonephritis in children with an experience of a new coronavirus infection (COVID-19)

Purpose. To determine the clinical and laboratory features of the course of acute pyelonephritis in children with a history of COVID-19 and to determine the risk of developing chronic kidney disease. Material and methods. The main cohort consisted of 36 patients with the debut of acute pyelonephritis, who had previously suffered COVID-19, the average age was 7,5 years. The comparison group included 47 patients with the onset of acute pyelonephritis and a normal level of IgG antibodies to SARS-CoV-2, the average age was 7,0 years. Laboratory tests included full blood count and urinalysis, blood biochemistry, procalcitonin, urine microalbumin, urine creatinine, Zimnitsky urine test, bacteriological urine test, glomerular filtration rate, coagulogram, and Lipocalin-2 associated with neutrophil gelatinase (NGAL) in the urine. Results. Patients with a history of COVID-19, at the onset of acute pyelonephritis, demonstrated a higher incidence of apostematous pyelonephritis, a higher degree of damage to the tubulointerstitial kidney tissue, a high frequency and a higher level of hematuria, proteinuria, hyperfiltration, hypostenuria, as well as a more significant increase in fibrinogen, CRP, procalcitonin, and uNGAL/Cr levels than children of the comparison group. It was shown that almost half of the children with acute pyelonephritis who had had COVID-19 retained urinary syndrome during examination 3–4 months after the onset of the disease. Conclusion. Thus, long-term effects of the SARS-CoV-2 virus on the renal parenchyma were confirmed, even in asymptomatic children. The high level of uNGAL/Cr in children with acute pyelonephritis who had had COVID-19, which was almost 8 times higher than in the comparison group, reflects more pronounced damage to the tubulointerstitial kidney tissue. The risk of developing chronic kidney disease in this group was 3,5 times higher.

Leukocytoclastic vasculitis secondary to COVID-19 vaccine

We present the case of a severe cutaneous reaction following COVID-19 vaccination. A 60-year-old white woman presented to our service with an extensive painful, pruritic rash affecting her bilateral lower limbs. This was on a background of psoriasis, psoriatic arthritis and notably inoculation against COVID-19 with the Johnson & Johnson vaccine hours prior to onset. There was no history of new medications, illicit drug use or infections. On examination, extensive palpable purpura was noted circumferentially at both lower limbs from the knee distally. Tense bullae were described at her bilateral ankles. She was apyrexial. Her cardiopulmonary and gastrointestinal examinations were normal. A punch biopsy taken from her right lower limb demonstrated findings consistent with leucocytoclastic vasculitis (LCV). Direct immunofluorescence demonstrated IgA deposits within the vasculature. IgA LCV secondary to COVID-19 vaccination was proposed on the basis of histological and clinical findings. Treatment consisted of oral steroids, oral antibiotics for secondary infection and wound dressings. Opioid analgesia and nitrous oxide were implemented for severe pain associated with dressing changes. As her urinary protein creatinine ratio was in excess of 100 mg dL-1 and microscopic haematuria was noted on urine microscopy, she was referred to nephrology. We note case reports of patients diagnosed with LCV up to 2 weeks following COVID-19 vaccination (Cavalli G, Colafrancesco, De Luca G et al. Cutaneous vasculitis following COVID- 19 vaccination. Lancet Rheumatol 2021;3: E743-4). In this case, onset of symptoms occurred within hours. While this presentation may have been coincidental, the relationship between immune complex vasculitis, COVID-19 infection (Iraji F, Galehdari H, Siadat AH, Bokaei Jazi S. Cutaneous leukocytoclastic vasculitis secondary to COVID-19 infection: a case report. Clin Case Rep 2020;9: 830-4) and vaccination (Cavalli et al.) has been reported in the literature and represents the most likely diagnosis.

VOCLOSPORIN FOR LUPUS NEPHRITIS: RESULTS OF THE TWO-YEAR AURORA 2 CONTINUATION STUDY

BACKGROUND AND AIMS: Voclosporin, a novel calcineurin inhibitor, was approved in the USA in January 2021 for the treatment of adult patients with active lupus nephritis in combination with background immunosuppressive therapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring. Previously reported results from the Phase 2 AURA-LV and Phase 3 AURORA 1 studies showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids in patients with lupus nephritis significantly increased rates of complete renal response at 48 weeks (AURA-LV) and 52 weeks (AURORA 1). Here we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of voclosporin compared with placebo in patients with lupus nephritis receiving treatment for an additional 24 months following completion of the AURORA 1 study. METHOD: Key inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV), proteinuria ≥ 1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2. Patients who completed AURORA 1 were eligible to enroll in AURORA 2 and continued with the same blinded treatment of voclosporin (23.7 mg BID) or placebo in combination with MMF (target dose 2 g/day) and lowdose oral steroids. Safety and tolerability were evaluated by monitoring adverse events and laboratory assessments including eGFR;changes in urine protein creatinine ratio (UPCR) were also assessed. RESULTS: In total, 116 patients in the voclosporin arm and 100 patients in the control arm enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm completing treatment to the end of AURORA 2. There were no new or unexpected safety signals detected in patients who continued on treatment with voclosporin compared to control-treated patients. Rates of serious adverse events in the voclosporin (19.0%) and control arms (24.0%) were similar, with eight serious adverse events of infection in each arm. Estimated glomerular filtration rate remained stable through the end of AURORA 2 (Figure 1). The slopes of the least-squares (LS) mean change in corrected eGFR from AURORA 2 baseline to end of study were -0.2 [95% confidence interval (CI) -3.0 to 2.7' in the voclosporin arm and -5.4 (95% CI -8.4 to -2.3) in the control arm. There were no deaths in the voclosporin arm during AURORA 2;four deaths were reported in the control arm due to pulmonary embolism (n = 1) and coronavirus infection (n = 3). The LS mean reductions in UPCR observed in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation (Figure 2). CONCLUSION: Voclosporin was well-tolerated over three years of treatment with a similar safety profile to control and no unexpected safety signals detected. Further, the significant and meaningful reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis. (Figure Presented).

ANCA-ASSOCIATED VASCULITIS AFTER SARS-COV-2 VACCINATION IN A PATIENT WITH HLA-DRB1∗09: 01 ALLELE: A CASE REPORT AND LITERATURE REVIEW

BACKGROUND AND AIMS: A Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with severe pneumonia and fatal systemic complications. Currently, SARS-CoV- 2 vaccines are effective in reducing the risk of onset and severity of the disease. However, autoimmune diseases, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), have been reported as rare complications of the COVID-19 vaccine. Although the mechanism of ANCA vasculitis remains unknown, the genetic background, environmental factors and infections are involved in the development of the disease. Genome-wide association studies have identified several AAV-related haplotypes, including the human leukocyte antigen (HLA)-DRB1∗09: 01 allele. Here, we report a case of AAV with a risk HLA allele after SARS-CoV-2 vaccination (Pfizer-BioNTech) and a literature review. METHOD: Case report: A 71-year-old woman visited a clinic complaining of fever (37.0-37.5°C) and malaise, 1 week after receiving second dose of COVID-19 vaccine (Pfizer-BioNTech). Two months after her first dose, her serum creatinine (Cr) level had increased from 0.86 mg/dL to 1.2 mg/dL with high titer of MPO-ANCA (280 IU/mL, normal value <3.5 IU/mL). Urinary microscopy revealed a red blood cell count of 30-49/high power field and a urinary protein-creatinine ratio of 1.06 g/gCr. We diagnosed MPO-AAV with manifestations of renal involvement, general symptoms and the presence of ANCA, as a cause of renal progressive glomerulonephritis. A course of corticosteroids and intravenous cyclophosphamide was initiated. After treatment, her general symptoms and urinary abnormalities disappeared, and renal insufficiency was improved as well. Three months later, the MPO-ANCA titer decreased to 27.4 IU/mL. We examined a human leukocyte antigen (HLA) haplotype and her allele was HLA-DRB1∗09:01, which is a known risk allele of MPO-ANCAassociated vasculitis. RESULTS: Review: Until November 30, 2021, we searched PubMed, including the case report study and seven cases have been reported as De novo AAV after SARS-CoV-2 vaccination. The mean age of patients was 72.5 years (three women and four men). The onset of symptomatic symptoms, such as fever, headache and malaise, ranged from the day after the first dose to 2 weeks after the second dose;consequently, renal dysfunction was detected. In six patients (except for our case), histological findings showed pauci-immune crescentic glomerulonephritis. Most patients received initial induction immunosuppressive therapy, including corticosteroids and cyclophosphamide, followed by maintenance therapy. The renal involvement of six patients improved, but one patient with severe renal dysfunction developed end-stage renal disease. Information on HLA allele was not available in any case. CONCLUSION: This is the first case report of De novo AAV after SARS-CoV-2 vaccination in a patient with AAV susceptible HLA-DRB1∗09:01 allele. (Table Presented).