[Diagnosis and Treatment of IgA Nephropathy-2023]. / Diagnostik und Therapie IgA Nephropathie ­ 2023.

Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis. It leads to end-stage kidney disease in about a third of the patients within 10 to 20 years. The pathogenesis of IgAN is incompletely understood. It is believed that a dysregulation of the mucosal immune system leads to undergalactosylation of IgA, followed by formation of IgG autoantibodies against undergalactosylated IgA, circulation of these IgG-IgA immune complexes, deposition of the immune complexes in the mesangium, ultimately resulting in glomerular inflammation. IgAN can occasionally be triggered by other diseases, these secondary causes of IgAN should be identified or ruled out (chronic inflammatory bowel disease, infections, tumors, rheumatic diseases). Characteristic findings of IgAN of variable extent are a nephritic urinary sediment (erythrocytes, acanthocytes, erythrocyte casts), proteinuria, impaired renal function, arterial hypertension, or intermittent painless macrohematuria, especially during infections of the upper respiratory tract. However, the diagnosis of IgAN can only be made by a kidney biopsy. A histological classification (MEST­C score) should always be reported to be able to estimate the prognosis. The most important therapeutic measure is an optimization of the supportive therapy, which includes, among other things, a consistent control of the blood pressure, an inhibition of the RAS, and the administration of an SGLT2 inhibitor. A systemic immunosuppressive therapy with corticosteroids is discussed controversially, should be used restrictively and only administered after an individual benefit-risk assessment under certain conditions that speak for a progressive IgAN. New promising therapeutics are enteral Budesonide or the dual angiotensin-II-receptor- and endothelin-receptor-antagonist Sparsentan. Rapidly progressive IgAN should be treated with corticosteroids and cyclophosphamide like ANCA-associated vasculitis.

[Diagnosis and treatment of Minimal Change Disease in adults-2023]. / Diagnostik und Therapie der Minimal Change Glomerulopathie beim Erwachsenen ­ 2023.

Minimal change disease is a glomerulopathy that clinically manifests as acute onset nephrotic syndrome. A diagnosis is made by renal biopsy, implying the absence of glomerular lesions on light microscopy but detection of extensive podocyte foot process effacement on electron miscroscopy. Considering the typically excellent response to immunosuppressive measures (especially to glucocorticoids), an autoimmune pathogenesis is assumed. Although general prognosis is overall beneficial, steroid-dependent, steroid-resistant and frequently-relapsing disease courses may complicate the management of these patients and necessitate the use of alternative immunosuppressive treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides a consensus on how to best diagnose and manage adult patients with minimal change disease.

[Diagnosis and treatment of focal-segmental glomerulosclerosis-2023]. / Diagnostik und Therapie der Fokal-Segmentalen Glomerulosklerose ­ 2023.

The histopathological term focal-segmental glomerulosclerosis comprises different pathogenic processes with the unifying features of a high proteinuria and the name-giving glomerular lesion pattern seen on light microscopy. A differentiation according to the underlying cause into primary, secondary and genetic forms is therefore of utmost importance. The pathogenesis of primary focal-segmental glomerulosclerosis remains unknown but, like minimal-change disease, an autoimmune-mediated process leading to podocyte damage is assumed. Consequently, the unifying term "podocytopathy" is increasingly being used for both entities. Supportive treatment measures to preserve kidney function are important in all subtypes. In contrast, immunosuppressive treatment is only indicated in primary focal-segmental glomerulosclerosis. Steroid-dependence, steroid-resistance and frequently relapsing disease often complicate disease management and necessitate alternative treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides consensus recommendations on how to best diagnose and manage patients with focal-segmental glomerulosclerosis.

[Diagnostic and therapy of lupus nephritis - 2023]. / Diagnostik und Therapie der Lupusnephritis ­ 2023.

The manuscript summarizes the consensus of the Austrian Society of Nephrology on the diagnosis and therapy of lupusnephritis, which is built on existing studies and literature. We discuss in detail the immunosuppressive treatment in proliferative forms of lupusnephritis (III and IV ± V) and in pure lupusnephritis V with nephrotic-range proteinuria. Furthermore, the supportive medication in lupusnephritis is summarized in the consensus. The figures were designed to provide the reader a guidance through the therapeutical approach in lupusnephritis for the daily practice.

[Diagnosis and treatment of glomerular diseases with a membranoproliferative glomerulonephritis (MPGN) pattern of injury]. / Diagnose und Therapie glomerulärer Erkrankungen mit einem membranoproliferativen Läsionsmuster (MPGN) ­ 2023.

Membranoproliferative glomerulonephritis (MPGN) represents a heterogeneous group of diseases. The common feature of a membranoproliferative lesion pattern in the kidney biopsy can either be idiopathic/primary or-much more frequently-have a secondary cause. The historical classification into MPGN types I to III has largely been abandoned and replaced in recent years by a pathogenesis-oriented classification. A MPGN with C1q, C3 and/or C4 deposits on light microscopy is referred to as immune complex GN (IC-GN), while a MPGN with dominant C3 deposits is referred to as C3 glomerulopathy (C3G). C3G is further divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These diagnoses can only be made by a kidney biopsy. Possible causes of MPGN are chronic infections (especially hepatitis B and C, bacterial infections, infections with protozoa), autoimmune diseases (especially lupus, rheumatoid arthritis) or malignancies (especially hematological malignancies). Particularly in the case of C3G a comprehensive analysis of the complement system components is strongly recommended. Due to the low incidence and the heterogeneous clinical appearance of MPGN therapeutic decisions must be made individually; an optimal general therapy is unknown, except that supportive treatment as with other glomerular diseases should be optimized. In the case of a secondary MPGN it is generally recommended to treat the potential cause of the MPGN. If significant proteinuria persists and eGFR remains > 30 ml/min/1.73 m2, treatment with systemic steroids and mycophenolate mofetil is recommended. Other treatment options on an individual level after evaluation and discussion of the risk-benefit ratio with the patient are rituximab and eculizumab. Rapidly progressive MPGN should be treated like ANCA-associated vasculitis. The recurrence rates after kidney transplantation are very high and treatment is challenging.

[General recommendations for the management of glomerular diseases-2023]. / Allgemeine Empfehlungen für die Behandlung glomerulärer Erkrankungen ­ 2023.

Glomerular diseases are associated with extrarenal complications, such as thromboembolism, cardiovascular events and particularly infections. A thorough knowledge of the various immunosuppressants and their associated toxicity profile is therefore of great importance. While nephrologists usually have extensive experience with calcineurin inhibitors and antimetabolites, two other compounds (rituximab, in severe cases cyclophosphamide) are used comparatively infrequently and will be discussed in more detail. Moreover, practical recommendations for the prevention of thromboembolism in states of nephrosis and for the prophylaxis of Pneumcystic jirovecii pneumonia are provided.

[Diagnosis and therapy of granulomatosis with polyangiitis and microscopic polyangiitis-2023: consensus of the Austrian society of nephrology (ÖGN) and Austrian society of rheumatology (ÖGR)]. / Diagnose und Therapie der Granulomatose mit Polyangiitis und mikroskopische Polyangiitis ­ 2023: Konsens-Empfehlungen der Österreichischen Gesellschaften für Nephrologie (ÖGN) & Rheumatologie (ÖGR).

ANCA-associated vasculitides (AAV) are rare, complex systemic diseases that are often difficult to diagnose, because of unspecific clinical symptoms at presentation. However, the clinical course may be very dramatic and even life-threatening, necessitating prompt diagnosis and treatment.Therefore, it is important to increase disease awareness among physicians and support colleagues who are not confronted with these rare diseases on a regular basis. Here, the Austrian Society of Nephrology (ÖGN) and the Austrian Society of Rheumatology (ÖGR) provide a joint consensus on how to best diagnose and manage patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).

Evaluation of two fully automated ADAMTS13 activity assays in comparison to manual FRET assay.

INTRODUCTION: The objective of the present study was to evaluate and compare the validity and utility of two fully automated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity assays for clinical diagnostic decision-making and to compare their performance. METHODS: Two automated ADAMTS13 activity assays (Werfen HemosIL® AcuStar ADAMTS13 Activity, Technoclone Technofluor ADAMTS13 Activity) were compared with a manual FRET assay (BioMedica ACTIFLUOR ADAMTS13 Activity). The following samples were used: 13 acute phase TTP (thrombotic thrombocytopenic purpura) samples from 11 different patients, one sample from a patient with congenital ADAMTS13 deficiency, 16 samples from control patients, three follow-up samples from TTP patients in long-term remission and one sample from a patient with stem cell transplantation related thrombotic microangiopathy (TMA). The WHO 1st International Standard for ADAMTS13 and several dilutions of normal plasma with ADAMTS13-depleted normal plasma were also tested. Statistical analysis included descriptive statistics, sensitivity and specificity, Passing & Bablok regression and Bland-Altman plot. RESULTS: The quantitative comparison between the HemosIL® (x) and Technofluor (y) methods showed a strong correlation (Pearson r = 0.98, n = 49). When considering an ADAMTS13 activity of <10% as a hallmark for the diagnosis of TTP, two fully automated assays were both able to identify all TTP- and non-TTP-samples correctly, resulting in sensitivities and specificities of 100%. CONCLUSION: Both fully automated ADAMTS13 activity assays showed a good diagnostic performance and quantitative correlation among themselves, discriminating reliably between TTP- and non-TTP-patients.

Humoral and Cellular Immune Response After a 3-Dose Heterologous SARS-CoV-2 Vaccination Using the mRNA-BNT162b2 and Viral Vector Ad26COVS1 Vaccine in Hemodialysis Patients.

Background: Due to the waning humoral response after a two-dose SARS-CoV-2 mRNA vaccination, a third booster was recommended in hemodialyis patients. Data on a heterologous mRNA-vector regimen, which might improve immunogenicity, are very limited. Methods: In this observational study 36 chronic hemodialysis patients (mean (SD) age 66.9 (15.9) years, 33.3% females) were followed up for 13 months. All patients were vaccinated twice using the mRNA-BNT162b2 vaccine, followed by a 3rd dose of the vector vaccine Ad26COVS1 eight months later. We assessed the humoral response by quantifying the anti-SARS-CoV-2 spike IgG antibody and neutralizing antibody concentrations. The cellular immune response was evaluated via SARS-CoV-2 spike protein-specific interferon-γ release assay. Results: The seroconversion rate was 47.2%, 100%, 69.4% and 100% one month after the 1st dose, one and six months after the 2nd dose and four months after the heterologous 3rd dose. The median (Q1, Q3) anti-SARS-CoV-2 spike IgG concentrations at the same time were 28.7 (13.2, 69.4) BAU/ml, 1130.0 (594.5, 1735.0) BAU/ml, 89.7 (26.4, 203.8) BAU/ml, and 2080.0 (1062.5, 2080.0) BAU/ml. The percentage of patients with neutralizing antibodies was 58.3% after the 2nd dose and improved to 100% after the 3rd dose (P <0.001). A positive T-cell response was found in 50% of patients after the 3rd dose. Conclusions: A third heterologous booster dose helped to sustain humoral immunity in almost all hemodialysis patients and induced a significant T-cellular response in half of them. Stimulating the immune response against SARS-CoV-2 by two different vaccine platforms seems to be a promising approach.

The Association of Excess Body Weight with Risk of ESKD Is Mediated Through Insulin Resistance, Hypertension, and Hyperuricemia.

BACKGROUND: Insulin resistance, hypertension, hyperuricemia, and hypercholesterolemia are hypothesized to be important intermediates in the relationship between excess body weight and CKD risk. However, the magnitude of the total effect of excess body weight on ESKD mediated through these four pathways remains to be quantified. METHODS: We applied a model for analysis of correlated mediators to population-based data from 100,269 Austrian individuals (mean age 46.4 years). Association of body mass index (BMI) was coalesced with ESKD risk into direct association. Indirect associations were mediated through the triglyceride-glucose (TyG) index (as an indicator of insulin resistance), mean arterial pressure (MAP), uric acid (UA), and total cholesterol (TC). RESULTS: Mean follow-up was 23.1 years with 463 (0.5%) incident ESKD cases. An unhealthy metabolic profile (prevalence 32.4%) was associated with a markedly increased ESKD risk (multivariably adjusted hazard ratio (aHR), 3.57; 95% CI, 2.89 to 4.40), independent of BMI. A 5-kg/m2 higher BMI was associated with a 57% increased ESKD risk (aHRtotal association, 1.57; 1.38 to 1.77). Of this association, 99% (76% to 140%) arose from all mediators jointly; 33% (22% to 49%) through TyG index; 34% (24% to 50%) through MAP; 30% (21% to 45%) through UA; and 2% (-1% to 4%) through TC. The remaining direct association was nonsignificant (aHRdirect association, 1.01; 0.88 to 1.14). CONCLUSIONS: TyG index, MAP, and UA, but not TC, mediate the association of BMI with ESKD in middle-aged adults. Our findings highlight that in addition to weight reduction, the control of metabolic risk factors might be essential in mitigating the adverse effects of BMI on kidney function.

Ochrobactrum anthropi infection in dialysis patients: A case report and literature summary.

INTRODUCTION: Ochrobactrum anthropi, a ubiquitous Gram-negative bacterium of low virulence, is an increasingly recognized cause of infection in immunocompromised hosts such as patients with kidney failure treated by dialysis. CASE REPORT: We report the case of a male hemodialysis patient with a central venous catheter, who developed an asymptomatic blood stream infection caused by Ochrobactrum anthropi. The infection was cured, and the dialysis catheter salvaged with intravenous meropenem and an antibiotic lock solution with ciprofloxacin. CONCLUSION: We identified 13 further cases of Ochrobactrum infection in hemodialysis patients and 10 cases in peritoneal dialysis patients in the literature. Antibiotic treatment depends on the results of susceptibility testing. In many patients, however, removal of the central venous or peritoneal dialysis catheter is required to cure the infection.

Cholecalciferol supplementation to improve the hepatitis B vaccination response in hemodialysis patients: A first randomized open label pilot study (DeVitaHep).

BACKGROUND: Patients with advanced chronic kidney disease should be vaccinated against hepatitis B. In observational studies vitamin D insufficiency is associated with a reduced seroconversion rate. The effect of cholecalciferol supplementation on hepatitis B vaccination response in haemodialysis patients with vitamin D insufficiency is unknown. METHODS: In this randomized open label pilot study 40 unvaccinated haemodialysis patients with 25(OH)D insufficiency (<30 ng/mL) were enrolled. In the supplementation group, we administered cholecalciferol orally in a dose of 28,000 IU weekly for a maximum of 12 weeks. Hepatitis B vaccination (HBvaxPRO 40 µg i.m. months 0, 1, 6) was performed after achieving a 25(OH)D level >30 ng/mL or after completing three months of supplementation despite failure to achieve the target level. In the control group, patients were vaccinated immediately after randomization. Anti-hepatitis B-antibody titer (anti-HBs) was measured eight weeks after completing the vaccination course. RESULTS: Thirty-seven (26 male, 11 female) patients aged 65 (13.5) years underwent randomization with 17 patients allocated to the control group and 20 patients included in the supplementation group. After 12 weeks of cholecalciferol supplementation, mean (SD) 25(OH)D concentration increased from 15.0 (8.0) to 31.0 (7.1) ng/mL, but remained unchanged in the control group (14.0 (7.1) to 11.6 (7.5) mg/mL). Neither the number of patients with seroconversion (anti-HBs titer ≥ 10 IU/L; n = 6 (35.3%) vs n = 3 (27.3%), p = 0.704), nor the number of patients with seroprotection (anti-HBs titer >100 IU/L; n = 4 (23.5%) vs n = 2 (18.2%) differed between treatment groups. Cholecalciferol supplementation was safe without treatment-related adverse events. CONCLUSION: In this small pilot study, high-dose oral cholecalciferol supplementation did not improve the hepatitis B vaccination response in haemodialysis patients with vitamin D insufficiency. This clinical trial was registered within EudraCT (EudraCT number 2011-004621-26).

The Risk of Severe Infections Following Rituximab Administration in Patients With Autoimmune Kidney Diseases: Austrian ABCDE Registry Analysis.

Objective: To characterize the incidence, type, and risk factors of severe infections (SI) in patients with autoimmune kidney diseases treated with rituximab (RTX). Methods: We conducted a multicenter retrospective cohort study of adult patients with immune-related kidney diseases treated with at least one course of RTX between 2015 and 2019. As a part of the ABCDE Registry, detailed data on RTX application and SI were collected. SI were defined by Common Terminology Criteria for Adverse Events v5.0 as infectious complications grade 3 and above. Patients were dichotomized between "nephrotic" and "nephritic" indications. The primary outcome was the incidence of SI within 12 months after the first RTX application. Results: A total of 144 patients were included. Twenty-five patients (17.4%) presented with SI, mostly within the first 3 months after RTX administration. Most patients in the nephritic group had ANCA-associated vasculitis, while membranous nephropathy was the leading entity in the nephrotic group. Respiratory infections were the leading SI (n= 10, 40%), followed by urinary tract (n=3, 12%) and gastrointestinal infections (n=2, 8%). On multivariable analysis, body mass index (BMI, 24.6 kg/m2versus 26.9 kg/m2, HR: 0.88; 95%CI: 0.79-0.99; p=0.039) and baseline creatinine (HR: 1.25; 95%CI: 1.04-1.49; p=0.017) were significantly associated with SI. All patients in the nephritic group (n=19; 100%) who experienced a SI received oral glucocorticoid (GC) treatment at the time of infection. Hypogammaglobulinemia was frequent (58.5%) but not associated with SI. Conclusions: After RTX administration, impaired kidney function and lower BMI are independent risk factors for SI. Patients with nephritic glomerular diseases having concomitant GC treatment might be at higher risk of developing SI.

The Safety and Immunogenicity of the mRNA-BNT162b2 SARS-CoV-2 Vaccine in Hemodialysis Patients.

BACKGROUND: Hemodialysis patients are at high risk for severe COVID-19. SARS-CoV-2 vaccination related safety and immunogenicity data in these patients are rare. METHODS: In this observational study SARS-CoV-2-seronegative hemodialysis patients were vaccinated with two doses of the Pfizer/BioNTech mRNA-BNT162b2 vaccine (COMIRNATY® 30 µg) and followed for 90 days. Local and systemic side effects were assessed at every dialysis session during the first post-vaccination week after the first and second vaccine dose. Immunogenicity was determined four weeks after vaccination by quantifying anti-SARS-CoV-2 spike protein IgG antibodies (LIAISON® SARS-CoV-2-TrimericS IgG chemiluminescent immunoassay) expressed in binding activity units per milliliter (BAU/mL) adapted to the WHO International standard. RESULTS: Fifty patients (32% women, 68% men) with a mean (SD) age of 67.6 (14.8) years were included. Mild local reactions occurred in 38% after the first injection, and in 29.2% with mild, in 2.1% with moderate and in 2.1% with severe degree after the second injection. Systemic reactive events occurred less often, with diarrhea (4% mild, 4% moderate) and fatigue (8% mild) being the most frequent ones. After the first injection 42% of the patients developed a positive response using the assay specific cut-off value of 33.8 binding activity units per milliliter (BAU/mL) with a median (Q1, Q3) anti-SARS-CoV-2 spike IgG concentration of 20.0 (11.7, 51.0) BAU/mL. After the second injection the percentage of seropositive patients increased to 97.9% with an anti-SARS-CoV-2 spike IgG concentration of 1075 (290.8, 1735) BAU/mL. Higher age and immunosuppression were associated with lower, calcitriol treatment and prior seroconversion to hepatitis B vaccination with significantly higher antibody concentration. CONCLUSIONS: The mRNA-BNT162b2 SARS-CoV-2 vaccine appears to be safe and well-tolerated and shows a high immunogenicity in hemodialysis patients.

The Triglyceride-Glucose Index and Obesity-Related Risk of End-Stage Kidney Disease in Austrian Adults.

Importance: It is unknown whether the triglyceride-glucose (TyG) index as a measure of insulin resistance is associated with the risk of developing end-stage kidney disease (ESKD). Because individuals who are overweight or obese often develop insulin resistance, mediation of the association between body mass index (BMI) and ESKD risk through the TyG index seems plausible but has not been investigated. Objective: To evaluate whether the TyG index is associated with ESKD risk and, if so, to what extent the TyG index mediates the association between BMI and ESKD. Design, Setting, and Participants: A total of 176 420 individuals were recruited during routine health examinations to participate in the Austrian Vorarlberg Health Monitoring and Promotion Program (VHM&PP), a prospective, population-based cohort study with participant enrollment between January 1, 1988, and June 30, 2005, and a mean follow-up of 22.7 years. Data analysis was conducted from March 1, 2020, to September 30, 2020. Exposures: Body mass index and the logarithmized product of fasting triglyceride and glucose concentrations (TyG index), as determined during the baseline health examination. Main Outcomes and Measures: End-stage kidney disease, as indicated by initiation of kidney replacement therapy, either dialysis or kidney transplantation. Results: Of the 176 420 participants, 94 885 were women (53.8%); mean (SD) age was 42.5 (15.4) years. During a mean (SD) follow-up of 22.7 (6.9) years, 454 (0.3%) participants developed ESKD and 35 234 (20.0%) died. In multivariable-adjusted Cox proportional hazards models, the TyG index was significantly associated with the risk of ESKD, both with (hazard ratio [HR] per 1-SD increase, 1.68; 95% CI, 1.56-1.82) and without (HR per 1-SD increase, 1.79; 95% CI, 1.66-1.93) the inclusion of BMI as a covariate. Mediation analysis using a newly proposed 2-stage regression method for survival data showed that a 5-point increase in BMI increased the risk of ESKD by 58% (HR [total association], 1.58; 95% CI, 1.43-1.75), and that 41.7% of the total association (95% CI, 31.6%-51.8%) was mediated through the TyG index (HR [indirect association], 1.21; 95% CI, 1.18-1.25). Conclusions and Relevance: This study found that the TyG index appeared to be associated with ESKD risk and mediates nearly half of the total association between BMI and ESKD in the general population. Public health efforts aiming at the reduction of body weight might decrease the kidney sequelae of insulin resistance and the burden of ESKD.

SARS-CoV-2 infection and recurrence of anti-glomerular basement disease: a case report.

BACKGROUND: Anti-glomerular basement membrane disease (GBM) disease is a rare autoimmune disease causing rapidly progressive glomerulonephritis and pulmonary haemorrhage. Recently, an association between COVID-19 and anti-glomerular basement membrane (anti-GBM) disease has been proposed. We report on a patient with recurrence of anti-GBM disease after SARS-CoV-2 infection. CASE PRESENTATION: The 31-year-old woman had a past medical history of anti-GBM disease, first diagnosed 11 years ago, and a first relapse 5 years ago. She was admitted with severe dyspnoea, haemoptysis, pulmonary infiltrates and acute on chronic kidney injury. A SARS-CoV-2 PCR was positive with a high cycle threshold. Anti-GBM autoantibodies were undetectable. A kidney biopsy revealed necrotising crescentic glomerulonephritis with linear deposits of IgG, IgM and C3 along the glomerular basement membrane, confirming a recurrence of anti-GBM disease. She was treated with steroids, plasma exchange and two doses of rituximab. Pulmonary disease resolved, but the patient remained dialysis-dependent. We propose that pulmonary involvement of COVID-19 caused exposure of alveolar basement membranes leading to the production of high avidity autoantibodies by long-lived plasma cells, resulting in severe pulmonary renal syndrome. CONCLUSION: Our case supports the assumption of a possible association between COVID-19 and anti-GBM disease.

Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to UMOD Mutations.

INTRODUCTION: Autosomal dominant tubulo-interstitial kidney disease due to UMOD mutations (ADTKD-UMOD) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the UMOD gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD-UMOD and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival. METHODS: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78, P < 0.001). RESULTS: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected (P < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An in vitro score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD. CONCLUSION: We report the clinical characteristics associated with 125 UMOD mutations. Male gender and a new in vitro score predict age of ESKD.