To evaluate the impact of surgical intervention on long-term renal outcomes for adult patients with congenital ureteropelvic junction obstruction (UPJO). We queried service members diagnosed with UPJO from the United States Military Health System electronic health records from 2005 to 2020. We assessed demographic, laboratory, radiology, surgical intervention, and outcome data. We evaluated the impact of surgical intervention on renal function based on the estimated glomerular filtration rate (eGFR), hypertension (HTN, defined as any prescription for blood pressure [BP] medication and/or average of two BP readings ≥ 130/80 mmHg more than 2 weeks apart), and changes in renal excretory function on radionuclide scans. We identified 108 individuals diagnosed with congenital UPJO; mean follow-up of 7 years. Mean age at diagnosis was 25 years; 95

Key Points The entire extracellular domain of thrombospondin type-1 domain 7A (THSD7A) in the luciferase immunoprecipitation system immunoassay was required to detect autoantibodies with high sensitivity in membranous nephropathy (MN). In THSD7A-seropositive MN patients, changes in antibody levels precede changes in clinical status. Seropositive THSD7A antibodies were detected in some patients with MN considered to be secondary to autoimmunity or cancer. Background Pathogenic autoantibodies against thrombospondin type-1 domain 7A (THSD7A) are present in approximately 3% of patients with membranous nephropathy (MN). Compared with PLA2R antibodies, less is known about THSD7A autoantibodies (ABs) because of the relative rarity and the lack of a commercially available quantitative immunoassay. Methods In this study, we describe the development and validation of a highly quantitative luciferase immunoprecipitation system (LIPS) assay for detecting THSD7A ABs and used it to study dominant THSD7A epitopes, disease associations, and monitoring disease activity. The Department of Defense Serum Repository (DODSR) was then used to analyze THSD7A AB in 371 longitudinal serum samples collected before clinical diagnosis of MN from 110 PLA2R-negative MN subjects. Results LIPS analysis demonstrated that a near full-length THSD7A (amino acids 1–1656) detected robust autoantibody levels in all known seropositive MN patients with 100% sensitivity and specificity compared with ELISA and/or Western blotting. Most of the THSD7A-seropositive subjects in our pilot cohort had evidence of coexisting autoimmunity or cancer. Moreover, three THSD7A-seropositive patients undergoing immunosuppressive therapy showed longitudinal autoantibody levels that tracked clinical status. Additional epitope analysis of two smaller protein THSD7A fragments spanning amino acids 1-416 and 1-671 demonstrated lower sensitivity of 32% and 44%, respectively. In the DODSR cohort, THSD7A seropositivity was detected in 4.5% of PLA2R-negative MN patients. In one primary and in one secondary MN-associated with cancer, THSD7A ABs were detectable <1 month before biopsy-proven diagnosis. In addition, three patients with lupus membranous nephropathy had detectable THSD7A ABs years before hypoalbuminemia and biopsy-proven diagnosis. Conclusions Although further studies are needed to explore the significance of THSD7A ABs in lupus membranous nephropathy, this study describes a novel, highly sensitive LIPS immunoassay for detecting THSD7A ABs and adds to the existing literature on THSD7A-associated MN. Clinical Trial registry name and registration number: NCT00977977; registration date: September 16, 2009.

Introduction Atypical hemolytic uremic syndrome (aHUS) is associated with dysregulation of the alternative complement pathway and causes significant morbidity and mortality when undiagnosed or inappropriately treated. C5 inhibitors (C5i) improve thrombotic microangiopathy (TMA) response and renal recovery, but significant morbidity may remain. This study described the clinical characteristics and treatment patterns associated with readmission after index hospitalization using real-world evidence from one of the largest, most diverse cohorts of presumed incident aHUS in the United States (US). Methods This was a retrospective cohort study of 634 incident cases among hospitalized adult patients with presumed aHUS derived from the US Premier Healthcare Database, an electronic healthcare records database that contains ~25% of all US hospitalizations (January 1, 2011-June 30, 2021). aHUS was defined as the presence of an International Classification of Diseases (ICD)-9-CM/ICD-10-CM diagnostic code for TMA (446.6, M31.1, M31.10, M31.19) or HUS (283.11, D59.3) and a treatment code (standard charge, HCPCS, ICD-10-PCS) for a C5i, in the absence of a diagnostic code for secondary causes of TMA/HUS or other C5i indications. The proportion of patients readmitted following the index hospitalization was assessed at 30 days and 365 days following discharge, among other timepoints. The time from index hospitalization discharge to all-cause hospital readmission was defined as the number of days from the discharge date of the index hospitalization to the date of all-cause readmission. Readmission for aHUS was defined as a hospitalization lasting ≥2 days to avoid the inclusion of in-hospital infusion clinic visits for C5i treatment. Demographic and clinical characteristics were analyzed using a t-test, Wilcoxon rank test, Fisher's exact test, or Chi-squared test, as appropriate. Results Overall, 78/634 patients (12.3%) died during index hospitalization. Among the 556 patients who survived until discharge, 23.4% and 39.7% had a readmission within 30 days and 365 days, respectively. During the first 365 days, 20.1% of patients required multiple hospitalizations. The median time to first readmission was 27.5 days (interquartile range [IQR]: 9-102 days). Infection was a common cause of readmission (25.6%). Readmission within either 30 or 365 days was associated with longer median time between index admission and therapeutic plasmapheresis (TPE) (3 vs 2 days, p=0.0002, and 3 vs 2 days, p<0.0001, respectively), longer median time between index admission and C5i (10 vs 8 days, p=0.0441, and 10 vs 8 days, p=0.0005, respectively), and longer median time between index admission and renal replacement therapy (RRT; 4 vs 2 days, p=0.0030, and 3 vs 2 days, p=0.0053, respectively). Only readmission within 365 days was associated with median age (52 vs 46 years of age, p=0.0124) or a history of hypertension (80.5% vs 64.5%, p<0.0001), atrial fibrillation (9.5% vs 4.8%, p=0.0363), or heart failure (21.7% vs 14.6%, p=0.0395) at index hospitalization. Readmission within 30 or 365 days was not associated with sex, race, ethnicity, insurance type, geographical region, hospital size or location (rural vs urban), diabetes, chronic kidney disease, myocardial infarction history, TPE, TPE duration, corticosteroids (CS), CS duration, time to CS, RRT requirement, or TMA remission at discharge. Conclusions aHUS readmission rates remain high, despite treatment with C5i, and infection is a common cause of readmission. Delayed TPE, RRT, and C5i treatment for aHUS during index hospitalization, even if only for 1-2 days, were associated with increased readmission within 30 and 365 days. Future efforts should be made to examine the causal relationship between treatment delays and outcomes.

OBJECTIVE:Scleroderma renal crisis (SRC) is a rare and severe manifestation of systemic sclerosis (SSc). Although it is well documented that Black patients with SSc have worse morbidity and mortality than non-Black patients, racial predilection for SRC is underreported. We examine the association of race and future development of SRC in an SSc cohort.METHODS:Using the electronic health record of the US Military Health System, we conducted a comprehensive chart review of each patient with SSc from 2005 to 2016. The final study cohort was comprised of 31 SRC cases and 322 SSc without SRC controls. We conducted logistic regression of SRC as the outcome variable and race (Black versus non-Black) as the primary predictor variable, adjusted for age, estimated glomerular filtration rate, hypertension, and proteinuria at SSc diagnosis.RESULTS:Of 353 patients, 294 had identifiable race (79 Black, 215 non-Black). Thirteen of 79 Black patients (16.5%) versus 16 of 215 (7.4%) non-Black patients developed SRC (P = 0.02). On adjusted analysis, Black patients had a significantly higher risk of developing SRC than non-Black patients (odds ratio 6.4 [95% confidence interval 1.3-31.2], P = 0.02). Anti-Ro antibody was present in a higher proportion of Black SRC patients versus Black patients without SRC (45% versus 14%, P = 0.01). Conversely, older age, thrombocytopenia, and anti-RNA polymerase III antibody at SSc diagnosis were significantly associated with future SRC in the non-Black cohort.CONCLUSION:Black race was independently associated with a higher risk of future SRC. Further studies are needed to elucidate the mechanisms that underlie this important association.

The mRNA coronavirus disease 2019 (COVID-19) vaccines induce an IgG response that prevents people from contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Interestingly, there are now at least 6 cases of gross hematuria reported in patients with a history of biopsy-proven IgA nephropathy (IgAN), involving both mRNA vaccines.1Negrea L. Rovin B.H. Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy.Kidney Int. 2021; 99: 1487Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 2Rahim S.E.G. Lin J.T. Wang J.C. A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccination.Kidney Int. 2021; 100: 238Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 3Perrin P. Bassand X. Benotmane I. Bouvier N. Gross hematuria following SARS-CoV-2 vaccination in patients with IgA nephropathy.Kidney Int. 2021; 100: 466-468Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar All of the previous patients were treated with supportive therapy with rapid resolution of hematuria and no acute kidney injury (AKI). It has been reported in preclinical trials that nasal shedding of SARS-CoV-2 still occurred after vaccination with both mRNA vaccines, suggesting a lack of a mucosal IgA response.1Negrea L. Rovin B.H. Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathy.Kidney Int. 2021; 99: 1487Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar,4Bleier B.S. Ramanathan Jr., M. Lane A.P. COVID-19 vaccines may not prevent nasal SARS-CoV-2 infection and asymptomatic transmission.Otolaryngol Head Neck Surg. 2021; 164: 305-307Crossref PubMed Scopus (101) Google Scholar We also cared for 2 patients who had prior biopsy-proven IgAN, who developed gross hematuria after their second dose of the Pfizer vaccine, without a preceding COVID-19 infection. Table 1 outlines the clinical data. Our first patient presented 5 days after his second dose, with nonspecific myalgias, chills, headache, dysuria, and gross hematuria within 24 hours of initial symptoms. Previous IgAN flares in this patient were precipitated by upper respiratory infections and were limited to gross hematuria with no AKIs and no requirement for steroids in the past. His postvaccine workup was notable for AKI, with a serum creatinine level of 3.53 mg/dl and a urine protein–creatinine ratio of 3.0. He was empirically started on steroids with recovery to baseline renal function at 1 month and recovery to baseline proteinuria within 2 months. Our second patient developed gross hematuria within 24 hours of receiving his second dose. His hematuria resolved after 3 days with supportive therapy only. To our knowledge, we are the first to report an IgAN flare that has led to an AKI that resolved with steroid therapy. We agree that it is not clear how a nonmucosal immune challenge led to an IgAN exacerbation; however, the delayed-type hypersensitivity reactions seen in our patients suggest a cell-mediated immune response, not an antibody response. We offer further evidence that patients with IgAN warrant close monitoring after receiving their second mRNA vaccine dose.Table 1Patient characteristics, treatment, and symptomsPatient characteristicsPatient 1Patient 2Year of IgAN diagnosis20182020Exacerbations since diagnosis1. February 2019: UPCR 3.2 after URI;None2. February 2020: UPCR 2.6 after URICurrent treatmentLisinopril and prednisoneLisinoprilBaseline serum creatinine level, mg/dl0.81.0Peak serum creatinine level after COVID-19 vaccine, mg/dl3.531.16Last UPCR (gm/g) before COVID-19 vaccine1.560.61Last UACR (mg/g) before COVID-19 vaccineNA341Gross hematuriaYesYesOther symptomsFevers, chills, body aches, dysuriaBody achesUPCR (gm/g) after COVID-19 vaccine4.970.92UACR (mg/g) after COVID-19 vaccine3160320Hematuria 5 days after COVID-19 vaccinePresentResolvedCOVID-19, coronavirus disease 2019; IgAN, IgA nephropathy; NA, not applicable; UACR, urine albumin–creatinine ratio; UPCR, urine protein–creatinine ratio; URI, upper respiratory infection. Open table in a new tab COVID-19, coronavirus disease 2019; IgAN, IgA nephropathy; NA, not applicable; UACR, urine albumin–creatinine ratio; UPCR, urine protein–creatinine ratio; URI, upper respiratory infection. The views expressed in this chapter are those of the authors and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or US government. The authors are military service members. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties. A case of gross hematuria and IgA nephropathy flare-up following SARS-CoV-2 vaccinationKidney InternationalVol. 100Issue 1PreviewWe read with great interest the report of Negrea and Rovin of 2 cases of IgA nephropathy with gross hematuria following the Moderna vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 We also cared for a 52-year-old Asian female with prior biopsy-proven IgA nephropathy who developed gross hematuria within 24 hours of receiving a second dose of the Pfizer vaccine. Table 1 summarizes clinical data. Her workup was notable for proteinuria of 4.2 g/g of creatinine with serum creatinine at baseline. Full-Text PDF Gross hematuria following vaccination for severe acute respiratory syndrome coronavirus 2 in 2 patients with IgA nephropathyKidney InternationalVol. 99Issue 6PreviewSeveral of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines use a nucleoside-modified, purified mRNA lipid nanoparticle-encapsulated platform. Compared with traditional inactivated viral and adjuvanted protein vaccines, this RNA platform elicits far higher neutralizing antibody titers, stronger antigen-specific cluster of differentiation (CD) 4+ and CD8+ T-cell responses, and stronger germinal center B and TFH cell activation in experimental animals.1 The activated CD4+ and CD8+ T cells produce several proinflammatory cytokines, including interferon-γ and tumor necrosis factor-α. Full-Text PDF Gross hematuria following SARS-CoV-2 vaccination in patients with IgA nephropathyKidney InternationalVol. 100Issue 2PreviewAfter the publication of the 2 letters by Negrea and Rovin1 and Rahim et al.,2 we herein describe 3 additional patients with IgA nephropathy (IgAN) who developed gross hematuria after receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA-based vaccines. The clinical data of our cases are summarized in Table 1. In line with the 3 previously reported cases, patient 1 had normal kidney function. However, patients 2 and 3 were treated with kidney transplantation (KT) and hemodialysis, respectively. Full-Text PDF Distinct glomerular disease association after vaccination with BNT162b2 and mRNA-1273: a VigiBase analysisKidney InternationalVol. 101Issue 2PreviewWith the worldwide rollout of coronavirus disease 2019 (COVID-19) vaccines, numerous reports of de novo or relapsing glomerular diseases have been published recently.1–4 It has been stressed that associations between vaccination efforts and the onset of disease do not prove causation, but the administration of vaccines and the induction of an immune response might trigger disease activity. Of note, most cases appear to be either IgA nephropathy (IgAN) or minimal change disease,1 with around 30 cases each reported to date. Full-Text PDF

Introduction: Among kidney transplant recipients (KTRs) with end-stage kidney disease (ESKD) due to atypical hemolytic uremic syndrome (aHUS), recurrence is associated with poor allograft outcomes. We compared graft and patient survival of aHUS KTRs with and without prophylactic/early use of eculizumab, a monoclonal antibody that binds complement protein C5, at the time of transplantation. Methods: We conducted a retrospective cohort study using the United States Renal Data System. Out of 123 624 ESKD patients transplanted between January 1, 2008, and June 1, 2016, we identified 348 (0.28%) patients who had “hemolytic uremic syndrome” as the primary cause of ESKD. We then linked these patients to datasets containing the Healthcare Common Procedure Coding System (HCPCS) code for eculizumab infusion. Patients who received eculizumab prior to or within 30 days of transplant represented the exposure group. We calculated crude incidence rates and conducted exact logistic regression, adjusted for recipient age and sex, for the study outcomes of graft loss, death-censored graft loss, and mortality. We also estimated the average treatment effect (ATE) by propensity-score matching, to reduce the bias in the estimated treatment effect on graft loss. Results: Our final study cohort included 335 aHUS KTRs (23 received eculizumab, 312 did not), with a mean duration of follow-up of 5.8 ± 2.7 years. There were no significant differences in baseline demographic and clinical characteristics between the eculizumab versus non-eculizumab group. Patients who received prophylactic/early eculizumab were less likely to experience graft loss compared with those who did not receive eculizumab (0% vs 20%, P = .02), with an adjusted odds ratio of 0.13 ( P = .02). In the propensity-score-matched sample, the ATE (eculizumab vs non-eculizumab) was −0.20 (95% confidence interval [CI] = −0.25 to −0.15, P < .001); thus, treatment was associated with an average of 20% reduction in graft loss. There was no significant difference in the risk of death between the 2 groups. Conclusions: Although there was no significant difference in the risk of death, prophylactic/early use of eculizumab was significantly associated with improved graft survival among aHUS KTRs. Given the high cost of eculizumab, randomized controlled trials are much needed to guide prophylactic strategies to prevent graft loss.

Biotin (vitamin B7) is a dietary supplement that can lead to falsely abnormal endocrine function tests. The impact of biotin on both 25-hydroxyvitamin D [25(OH)D] and intact parathyroid hormone (iPTH) have not been previously described in end-stage renal disease (ESRD). A woman with ESRD on hemodialysis taking biotin 10mg daily had a 25(OH)D spike from 25 to >100 ng/mL and an iPTH decrease from 966 to 63 pg/mL. After discontinuation of biotin, her 25(OH)D and iPTH returned to baseline. Biotin can cause erroneous 25(OH)D and iPTH results in ESRD that could adversely affect patient care.

Objectives: To determine whether Seraph-100 (Exthera Medical Corporation, Martinez, CA) treatment provides clinical benefit for severe coronavirus disease 2019 cases that require mechanical ventilation and vasopressor support. Data Sources: The first two patients in the United States treated with the novel Seraph-100 device. These cases were reviewed by the Food and Drug Administration prior to granting an emergency use authorization for treatment of coronavirus disease 2019. Study Selection: Case series. Data Extraction: Vasopressor dose, mean arterial pressure, temperature, interleukin-6, C-reactive protein, and other biomarker levels were documented both before and after Seraph-100 treatments. Data Synthesis: Vasopressor dose, temperature, interleukin-6, and C-reactive protein levels declined after Seraph-100 treatments. Severe acute respiratory syndrome coronavirus 2 viremia was confirmed in the one patient tested and cleared by the completion of treatments. Conclusions: Seraph-100 use may improve hemodynamic stability in coronavirus disease 2019 cases requiring mechanical ventilation and vasopressor support. These findings warrant future study of a larger cohort with the addition of mortality and total hospital day outcomes.

BackgroundFSGS is a heterogeneic glomerular disease. Risk factors for kidney disease ESKD and the effect of immunosuppression treatment (IST) has varied in previously published cohorts. These cohorts were limited by relatively small case numbers, short follow-up, lack of racial/ethnic diversity, a mix of adult and pediatric patients, lack of renin-angiotensin-aldosterone system (RAAS) inhibition, or lack of subgroup analysis of IST.MethodsWe compared demographics, clinical characteristics, histopathology, and IST to long-term renal survival in a large, ethnically diverse, adult cohort of 338 patients with biopsy-proven FSGS with long-term follow-up in the era of RAAS inhibition using data from the US Department of Defense health care network.ResultsMultivariate analysis showed that nephrotic-range proteinuria (NRP), eGFR <60 ml/min per 1.73 m2, hypoalbuminemia, interstitial fibrosis and tubular atrophy, and interstitial inflammation at diagnosis and the absence of remission were all associated with worse long-term renal survival. IgM, C3, and a combination of IgM/C3 immunofluorescence staining were not associated with reduced renal survival. IST was not associated with improved renal survival in the whole cohort, or in a subgroup with NRP. However, IST was associated with better renal survival in a subgroup of patients with FSGS with both NRP and hypoalbuminemia and hypoalbuminemia alone.ConclusionsOur study suggests that IST should be reserved for patients with FSGS and nephrotic syndrome. It also introduces interstitial inflammation as a potential risk factor for ESKD and does not support the proposed pathogenicity of IgM and complement activation.

Scleroderma Renal Crisis (SRC) is associated with significant morbidity and mortality. While prednisone is strongly associated with SRC, there are no previous large cohort studies that have evaluated ace inhibitor (ACEi) calcium channel blocker (CCB), angiotensin receptor blocker (ARB), endothelin receptor blocker (ERB), non-steroidal anti-inflammatory drug (NSAID), fluticasone, or mycophenolate mofetil (MMF) use in systemic sclerosis (SSc) and the risk of SRC. In this retrospective cohort study of the entire military electronic medical record between 2005 and 2016, we compared the use of ACEi, ARB, CCB, NSAID, ERB, fluticasone, and MMF after SSc diagnosis for 31 cases who subsequently developed SRC to 322 SSc without SRC disease controls. ACEi was associated with an increased risk for SRC adjusted for age, race, and prednisone use [odds ratio (OR) 4.1, 95% confidence interval (CI) 1.6–10.2, P = 0.003]. On stratified analyses, ACEi was only associated with SRC in the presence [OR 5.3, 95% CI 1.1–29.2, p = 0.03], and not the absence of proteinuria. In addition, a doubling of ACEi dose [61% vs. 12%, p < 0.001) and achieving maximum ACEi dose [45% vs. 4%, p < 0.001] after SSc diagnosis was associated with future SRC. CCB, ARB, NSAIDs, ERB, fluticasone, and MMF use were not significantly associated with SRC. ACEi use at SSC diagnosis was associated with an increased risk for SRC. Results suggest that it may be a passive marker of known SRC risk factors, such as proteinuria, or evolving disease. SSC patients that require ACEi should be more closely monitored for SRC.