Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome

ObjectiveTo report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.MethodsIn 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up.ResultsDeath (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker.ConclusionsThe long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome.Trial registration numberNCT00204022.

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The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: Clinical manifestations and long-term follow-up

Seminars in Arthritis and Rheumatism ◽

10.1016/j.semarthrit.2013.12.002 ◽

2014 ◽

Vol 43 (6) ◽

pp. 818-823 ◽

Cited By ~ 46

Author(s):

Luca Cantarini ◽

Donato Rigante ◽

Giampaolo Merlini ◽

Antonio Vitale ◽

Francesco Caso ◽

...

Keyword(s):

Clinical Manifestations ◽

Gene Variants ◽

Tnfrsf1a Gene ◽

Long Term Follow Up

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Looking Beyond the Allograft Survival: Long-Term, 5-Year Renal Outcome in Lung Transplant Recipients

Transplantation Proceedings ◽

10.1016/j.transproceed.2021.09.037 ◽

2021 ◽

Author(s):

Mohankumar Doraiswamy ◽

Eshetu Obole ◽

Mena Botros ◽

Brian C. Keller ◽

Todd Pesavento ◽

...

Keyword(s):

Lung Transplant ◽

Renal Outcome ◽

Transplant Recipients ◽

Allograft Survival ◽

Lung Transplant Recipients

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Long-term renal function and continence status in patients with

Canadian Urological Association Journal ◽

10.5489/cuaj.442 ◽

2013 ◽

Vol 1 (4) ◽

pp. 371 ◽

Cited By ~ 16

Author(s):

Luis H.P. Braga ◽

Armando J. Lorenzo ◽

Sumit Dave ◽

Maria H. Del-Valle ◽

Antoine E. Khoury ◽

...

Keyword(s):

Renal Function ◽

Glomerular Filtration Rate ◽

Glomerular Filtration ◽

Filtration Rate ◽

Urogenital Sinus ◽

Renal Outcome ◽

Urinary Continence ◽

Renal Ultrasound ◽

Common Channel

Introduction: Urinary continence after cloacal repair is difficult to achieveand renal outcome in patients with cloacal malformations has been scarcelyreported. As a result, we reviewed our experience with cloacal malformationsto determine the status of continence and the long-term renal function in thesechildren.Methods: A retrospective chart review from 1990 to 2003 identified 12 patientswith cloacal malformation (1 posterior, 4 complex and 7 classical) who underwentsurgical reconstruction. The confluence was defined as high (commonchannel ≥ 3 cm) and low (< 3 cm) by cystovaginoscopy. Renal ultrasound,voiding cystouretrogram, renal scan and sacral radiograph were performedin all children. Most patients underwent 1-stage abdominoperineal pull-through,applying the principle of total urogenital sinus mobilization. We collected dataregarding hydronephrosis, vesicoureteral reflux and split differential renal function.Renal outcome was evaluated based on glomerular filtration rate and ageadjustedserum creatinine values (μmol/L). Urinary continence was definedas a dry interval > 4 hours.Results: Patients’ mean age at surgery was 20 months (range 7–29 mo). Ofthe 12 children who underwent cloacal repair, 7 (58.3%) had a common channel≥ 3cm. Renal anomalies were identified in 3 of 12 (25%) girls: there were 2 solitary kidneys and 1 pelvic kidney. Lumbar–sacral radiography demonstrated bony abnormalities in 11 of the 12 (91.6%) cases: hemivertebra in 3 cases, sacral agenesis in 4 cases, hypoplastic sacrum in 3 cases and bifid sacrum in 1 case. Total urogenital sinus mobilization through an abdominoperineal approach in a single stage was performed in 8 girls. Follow-up ranged from 4 to 14 years (mean 8.5 yr). Eight (66.6%) children had dry intervals > 4 hours, 5 (62.5%) of them were on clean intermittent catheterization through aMitrofanoff channel and 1 (12.5%) was through the urethra. The remaining 2 (25%) patients were voiding spontaneously. Three (33.3%) patients were totally incontinent, and 1 (8.3%) patient was awaiting reconstruction. The mean measured glomerular filtration rate was 93.5 mL/min/1.73m2 (range 34–152 mL/min/1.73m2). Four (57.1%) of 7 patients who had a common channel ≥ 3 cm ended up needing augmentation cystoplasty, compared with none of the patients with a common channel < 3 cm (57.1% v. 0%, p = 0.038).Conclusion: Urinary continence can be achieved in most patients with cloacalmalformation at the expense of major reconstructive surgery and despite thepresence of associated urological abnormalities. However, these childrenharbour an important risk for renal impairment later in life and should be closelymonitored.

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Large-Scale Whole-Genome Sequencing Reveals the Genetic Architecture of Primary Membranoproliferative GN and C3 Glomerulopathy

Journal of the American Society of Nephrology ◽

10.1681/asn.2019040433 ◽

2020 ◽

Vol 31 (2) ◽

pp. 365-373 ◽

Cited By ~ 7

Author(s):

Adam P. Levine ◽

Melanie M.Y. Chan ◽

Omid Sadeghi-Alavijeh ◽

Edwin K.S. Wong ◽

H. Terence Cook ◽

...

Keyword(s):

Large Scale ◽

Rare Variants ◽

Alternative Pathway ◽

Atypical Hemolytic Uremic Syndrome ◽

Gene Mutations ◽

Whole Genome Sequence ◽

European Ancestry ◽

Whole Genome ◽

C3 Glomerulopathy ◽

Complement Gene

BackgroundPrimary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN.MethodsWe analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource–Rare Diseases Study. We examined copy number, rare, and common variants.ResultsOur analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10−8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10−8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure.ConclusionsWe found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

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