Clinical course and outcome after kidney transplantation in patients with C3 glomerulonephritis due to CFHR5 nephropathy.

BACKGROUND: Complement factor H-related protein 5 (CFHR5) nephropathy is an inherited renal disease characterized by microscopic and synpharyngitic macroscopic haematuria, C3 glomerulonephritis and renal failure. It is caused by an internal duplication of exons 2-3 within the CFHR5 gene resulting in dysregulation of the alternative complement pathway. The clinical characteristics and outcomes of transplanted patients with this rare familial nephropathy remain unknown. METHODS: This is a retrospective case series study of 17 kidney transplant patients with the established founder mutation, followed-up over a span of 30 years. RESULTS: The mean (±SD) age of patients at the time of the study and at transplantation was 58.6 ± 9.9 and 46.7 ± 8.8 years, respectively. The 10- and 15-year patient survival rates were 100 and 77.8%, respectively. Proteinuria was present in 33.3% and microscopic haematuria in 58.3% of patients with a functional graft. Serum complement levels were normal in all. 'Confirmed' and 'likely' recurrence of CFHR5 nephropathy were 16.6 and 52.9%, respectively; however, 76.5% of patients had a functional graft after a median of 120 months post-transplantation. Total recurrence was not associated with graft loss (P = 0.171), but was associated with the presence of microscopic haematuria (P = 0.001) and proteinuria (P = 0.018). Graft loss was associated with the presence of proteinuria (P = 0.025). CONCLUSIONS: We describe for the first time the clinical characteristics and outcome of patients with CFHR5 nephropathy post-transplantation. Despite the recurrence of CFHR5 nephropathy, we provide evidence for a long-term favourable outcome and support the continued provision of kidney transplantation as a renal replacement option in patients with CFHR5 nephropathy.

A functional variant in NEPH3 gene confers high risk of renal failure in primary hematuric glomerulopathies. Evidence for predisposition to microalbuminuria in the general population.

BACKGROUND: Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on long-term follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. METHODS: We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as "Severe" or "Mild", based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. RESULTS AND CONCLUSIONS: Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0x10-3, OR = 6.64 adjusting for gender/age; allelic association: p = 4.2x10-3 adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0x10-3). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohorts (11,258 individuals) was highly significant (p = 1.3x10-5, OR = 7.46). Functional studies showed that Neph3 homodimerization and Neph3-Nephrin heterodimerization are disturbed by variant 353M. Additionally, 353M was associated with differential activation of the unfolded protein response pathway, when overexpressed in stressed cultured undifferentiated podocyte cells, thus attesting to its functional significance. Genetics and functional studies support a "rare variant-strong effect" role for NEPH3-V353M, by exerting a negative modifier effect on primary glomerular hematuria. Additionally, genetics studies provide evidence for a role in predisposing homozygous subjects of the general population to micro-albuminuria.

Molecular and Clinical Investigation of Cystinuria in the Greek-Cypriot Population.

BACKGROUND AND AIMS: Cystinuria represents 3% of nephrolithiasis in humans. Two genes have been identified as the main genetic causes of cystinuria, SLC3A1 and SLC7A9, with an autosomal recessive mode of inheritance. In the present study, we studied for the first time, genetically and clinically, all the cystinuric families identified so far in the Greek-Cypriot population. METHODS: Discovery of mutations was performed through polymerase chain reaction (PCR)-single analysis and DNA resequencing. New families were investigated through PCR-RFLPs. Clinical data were collected through the hospital patients' records and analytical follow-up of the families. RESULTS AND DISCUSSION: We found a total of five mutations in 28 Greek-Cypriot cystinuric patients belonging in 12 families. The most frequent mutation among the 28 Greek-Cypriot patients is the SLC3A1-p.T216M, which is also the second most frequent mutation in Europe, representing a genetic founder effect. Sixteen of the 28 patients are homozygous for this mutation. Even though a consanguinity loop was obvious in only one family, other patients were from families in small villages where endogamy was practiced for many centuries. Timely clinical and genetic diagnosis, accompanied by early treatment, is significant for the good health of most of our patients. Only ∼14% of them developed chronic renal failure, and only one reached end-stage renal disease (ESRD). CONCLUSION: Five SLC3A1 and SLC7A9 mutations appear to be responsible for the genetic basis of cystinuria in the Greek-Cypriot patients; having such a limited number of causative mutations will simplify diagnostics for this population.

Postpartum thrombotic microangiopathy revealed as atypical hemolytic uremic syndrome successfully treated with eculizumab: a case report.

INTRODUCTION: Differential diagnosis of thrombotic microangiopathies can be difficult. Atypical hemolytic uremic syndrome is a rare, life-threatening disease caused by uncontrolled chronic activation of alternative complement pathway, resulting in microvascular thrombosis, organ ischemia and damage. Prognosis is poor: up to 65 percent of patients require dialysis or have kidney damage of varying severity or die despite plasma exchange/plasma infusion treatment. CASE PRESENTATION: We describe the case of a 23-year-old woman of Hellenic origin who, after a preeclampsia-induced premature delivery, developed thrombotic microangiopathy with renal failure, tonicoclonic seizures, anasarca edema and hypertension. Intensive plasma exchange was initiated twice daily, in parallel to dialysis for one month. Three months later, our patient was discharged with nondialysis-dependent renal failure and without signs of hemolysis. Three months after discharge our patient was readmitted with cardiomyopathy (left ventricular ejection fraction of 25 percent) and signs and symptoms of thrombotic microangiopathy. Our patient was diagnosed with atypical hemolytic uremic syndrome and was started on eculizumab (a complement inhibitor), which improved clinical and laboratory parameters. However, a transient pause in treatment resulted in thrombotic microangiopathy relapse, which was rapidly blocked with reintroduction of eculizumab treatment. During long-term eculizumab treatment, thrombotic microangiopathy manifestations were inhibited and renal and cardiac function restored, with no need for other invasive treatments. CONCLUSIONS: Establishing the diagnosis of atypical hemolytic uremic syndrome in patients presenting with thrombotic microangiopathy is challenging since common symptoms are shared with other conditions like Shiga toxin-producing Escherichia coli hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. The described case illustrates the complexity and importance of rapid diagnosis in a rare disease and the need for appropriate and specific treatment for best long-term outcomes.

Epistatic role of the MYH9/APOL1 region on familial hematuria genes.

Familial hematuria (FH) is explained by at least four different genes (see below). About 50% of patients develop late proteinuria and chronic kidney disease (CKD). We hypothesized that MYH9/APOL1, two closely linked genes associated with CKD, may be associated with adverse progression in FH. Our study included 102 thin basement membrane nephropathy (TBMN) patients with three known COL4A3/COL4A4 mutations (cohort A), 83 CFHR5/C3 glomerulopathy patients (cohort B) with a single CFHR5 mutation and 15 Alport syndrome patients (cohort C) with two known COL4A5 mild mutations, who were categorized as "Mild" (controls) or "Severe" (cases), based on renal manifestations. E1 and S1 MYH9 haplotypes and variant rs11089788 were analyzed for association with disease phenotype. Evidence for association with "Severe" progression in CFHR5 nephropathy was found with MYH9 variant rs11089788 and was confirmed in an independent FH cohort, D (cumulative p value = 0.001, odds ratio = 3.06, recessive model). No association was found with APOL1 gene. Quantitative Real time PCR did not reveal any functional significance for the rs11089788 risk allele. Our results derive additional evidence supporting previous reports according to which MYH9 is an important gene per se, predisposing to CKD, suggesting its usefulness as a prognostic marker for young hematuric patients.

Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.

BACKGROUND AND OBJECTIVES: Complement factor H and related proteins (CFHR) are key regulators of the alternative complement pathway, where loss of function mutations lead to a glomerulopathy with isolated mesangial C3 deposits without immunoglobulins. Gale et al. (12) reported on 26 patients with the first familial, hematuric glomerulopathy caused by a founder mutation in the CFHR5 gene in patients of Cypriot descent living in the United Kingdom. CFHR5 nephropathy is clinically characterized by continuous microscopic hematuria whereas some patients present with additional episodes of synpharyngitic macrohematuria, associated with infection and pyrexia. A subgroup of patients, particularly men, develop additional proteinuria, hypertension, and chronic renal disease or ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We herewith expand significantly on the study by Gale et al., reporting on histologic, molecular, and clinical findings in 91 patients from 16 families with the same founder mutation. RESULTS: Eighty-two patients (90%) exhibited microscopic hematuria; 51 (62%), exhibited only microscopic hematuria, whereas the remaining 31 additionally had proteinuria (38%); 28 proteinuric patients developed chronic renal failure (CRF). Among carriers of CFHR5 mutation aged >50 years, 80% of the men and 21% of the women developed CRF; 18 developed ESRD (14 men [78%], 4 women [22%]). CONCLUSIONS: The diagnosis of CFHR5-related, isolated C3 glomerulopathy was established in 2009 using newly described mutation analysis after decades of follow-up with unclear diagnoses, occasionally confused with IgA nephropathy. This larger patient cohort establishes the clinical course, significant variable expressivity, and marked gender difference regarding the development of CRF and ESRD.

Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis.

BACKGROUND: Heterozygous mutations in the COL4A3/ COL4A4 genes are currently thought to be responsible for familial benign microscopic haematuria and maintenance of normal long-term kidney function. METHODS: We report on 11 large Cypriot pedigrees with three such mutations. A total of 236 at-risk family members were genetically studied, and 127 (53.8%) carried a heterozygous mutation. Clinico-pathological correlations were available in all of these patients. Renal biopsies in 21 of these patients all showed various stages of focal, segmental glomerulosclerosis (FSGS). Thirteen of these biopsies were also studied with EM and showed thinning of the glomerular basement membrane. RESULTS: Mutation G1334E (COL4A3) was found in six pedigrees, mutation G871C (COL4A3) in four and mutation 3854delG (COL4A4) in one pedigree. Clinical and laboratory correlations in all 127 mutation carriers (MC) showed that microscopic haematuria was the only urinary finding in patients under age 30. The prevalence of 'haematuria alone' fell to 66% between 31 and 50 years, to 30% between 51 and 70 and to 23% over age 71. Proteinuria with CRF developed on top of haematuria in 8% of all MC between 31 and 50 years, to 25% between 51 and 70 years and to 50% over 71 years. Altogether 18 of these 127 MC (14%) developed ESRD at a mean age of 60 years. Two members with different mutations married, and two of their children inherited both mutations and developed adolescent, autosomal recessive Alport syndrome (ATS), confirming that these mutations are pathogenic. CONCLUSIONS: Our data confirm for the first time a definite association of heterozygous COL4A3/COL4A4 mutations with familial microscopic haematuria, thin basement membrane nephropathy and the late development of familial proteinuria, CRF, and ESRD, due to FSGS, indicating that the term 'benign familial haematuria' is a misnomer, at least in this cohort. A strong hypothesis for a causal relationship between these mutations and FSGS is also made. Benign familial haematuria may not be so benign as commonly thought.