Screening for intracranial aneurysms in autosomal dominant polycystic kidney disease is cost-effective.

Intracranial aneurysm rupture is a dramatic complication of autosomal dominant polycystic kidney disease (ADPKD). It remains uncertain whether screening should be widespread or only target patients with risk factors (personal or familial history of intracranial aneurysm), with an at-risk profession, or those who request screening. We evaluated this in a single-center cohort of 495 consecutive patients with ADPKD submitted to targeted intracranial aneurysm screening. Cerebral magnetic resonance angiography was proposed to 110 patients with a familial history of intracranial aneurysm (group 1), whereas it was not our intention to propose it to 385 patients without familial risk (group 2). Magnetic resonance angiography results, intracranial aneurysm prophylactic repair, rupture events, and cost-effectiveness of intracranial aneurysm screening strategies were retrospectively analyzed. During a median follow up of 5.9 years, five non-fatal intracranial aneurysm ruptures occurred (incidence rate 2.0 (0.87-4.6)/1000 patients-year). In group 1, 90% of patients were screened and an intracranial aneurysm was detected in 14, treated preventively in five, and ruptured in one patient despite surveillance. In group 2, 21% of patients were screened and an intracranial aneurysm was detected in five, and treated preventively in one. Intracranial aneurysm rupture occurred in four patients in group 2. Systematic screening was deemed cost-effective and provides a gain of 0.68 quality-adjusted life years compared to targeted screening. Thus, the intracranial aneurysm rupture rate is high in ADPKD despite targeted screening, and involves mostly patients without familial risk factors. Hence, cost-utility analysis suggests that intracranial aneurysm screening could be proposed to all ADPKD patients.

Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome.

BACKGROUND: Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. METHODS: Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. RESULTS: Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing. CONCLUSIONS: Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

Rare inherited disorders with renal involvement-approach to the patient.

The list of rare inherited disorders with renal involvement is rapidly growing. Many are single gene diseases affecting children, but cases are not restricted to pediatrics and diagnosis is often difficult and delayed. The expanding use of next-generation sequencing techniques is expected to discover new diseases, to challenge the definition of rarity, to accelerate and shake up our diagnostic paradigms, to promote 'deep phenotyping', and ultimately improve disease ontology. Rare renal diseases are exemplary of a transition from pediatric to adult-type care and pluridisciplinary approach, necessitating cooperation between geneticists, nephropediatricians, adult nephrologists, other physicians, nurses, social workers, and dietitians. They have raised new ethical issues, not only in genetic counseling, but also in public health, regarding equity, and distribution of care. Patient's organizations have grown and have been very active to promote information and research. Efforts are underway to create interoperable patient's registries and ultimately worldwide networks gathering patients, researchers, clinicians, pharmaceutical industry, and health authorities. Progress in genetics and pathophysiological mechanisms will hopefully increase the number of efficient orphan medicinal products. Finally, new frontiers set by rare nephropathies may improve the understanding, treatments, and outcomes of more frequent renal diseases.

3-Nitrotyrosine as a biomarker for vascular involvement in Fabry disease.

Enzyme replacement therapy in Fabry disease was initiated in 2001. In a significant proportion of patients, the apparent removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease. Shu et al. show a link between accumulation of globotriaosylceramide in the endothelial cells and 3-nitrotyrosine formation, indicating endothelial nitric oxide synthase uncoupling. 3-Nitrotyrosine will be useful to better understand Fabry vasculopathy, and to evaluate additional therapeutic interventions targeting oxidative stress.

Increased risk of solid renal tumors in lithium-treated patients.

Cystic kidney diseases and toxic interstitial nephritis may be complicated by renal tumors. Long-term lithium intake is associated with tubulointerstitial nephritis and renal cysts but to date such an association with tumors has not been determined. We evaluated this in a retrospective study to determine whether lithium-treated patients were at higher risk of renal tumors compared with lithium-free patients with chronic kidney disease (CKD), and to the general population. Over a 16-year period, 14 of 170 lithium-treated patients had renal tumors, including seven malignant and seven benign tumors. The mean duration of lithium exposure at diagnosis was 21.4 years. The renal cancers included three clear-cell and two papillary renal cell carcinomas, one hybrid tumor with chromophobe and oncocytoma characteristics, and one clear-cell carcinoma with leiomyomatous stroma. The benign tumors included four oncocytomas, one mixed epithelial and stromal tumor, and two angiomyolipomas. The percentage of renal tumors, particularly cancers and oncocytomas, was significantly higher in lithium-treated patients compared with 340 gender-, age-, and estimated glomerular filtration rate (eGFR)-matched lithium-free patients. Additionally, the Standardized Incidence Ratio of renal cancer was significantly higher in lithium-treated patients compared with the general population: 7.51 (95% confidence interval (CI) (1.51-21.95)) and 13.69 (95% CI (3.68-35.06)) in men and women, respectively. Thus, there is an increased risk of renal tumors in lithium-treated patients.

Kidney failure: aims for the next 10 years and barriers to success.

Although in some parts of the world acute and chronic kidney diseases are preventable or treatable disorders, in many other regions these diseases are left without any care. The nephrology community needs to commit itself to reduction of this divide between high-income and low-income regions. Moreover, new and exciting developments in fields such as pharmacology, genetic, or bioengineering, can give a boost, in the next decade, to a new era of diagnosis and treatment of kidney diseases, which should be made available to more patients.

Incidence of renal failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations.

We studied here the clinical course of heterozygous carriers of X-linked Alport syndrome and a subgroup of patients with thin basement membrane disease due to heterozygous autosomal recessive Alport mutations whose prognosis may be worse than formerly thought. We analyzed 234 Alport carriers, including 29 with autosomal recessive mutations. Using Kaplan-Meier estimates and log-rank tests, autosomal and X-linked carriers were found to have similar incidences of renal replacement therapy, proteinuria, and impaired creatinine clearance. Further, age at onset of renal replacement therapy did not differ between X-chromosomal and autosomal carriers. Both groups showed an impaired life expectancy when reaching renal replacement therapy. RAAS inhibition significantly delayed the onset of end-stage renal failure. Not only carriers of X-linked Alport mutations but also heterozygous carriers of autosomal recessive mutations were found to have an increased risk for worse renal function. The risk of end-stage renal disease in both groups affected life expectancy, and this should cause a greater alertness toward patients presenting with what has been wrongly termed 'familial benign hematuria.' Timely therapy can help to delay onset of end-stage renal failure. Thus, yearly follow-up by a nephrologist is advised for X-linked Alport carriers and patients with thin basement membrane nephropathy, microalbuminuria, proteinuria, or hypertension.

Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis.

The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCε1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS.

Progress in nephron sparing therapy for renal cell carcinoma and von Hippel-Lindau disease.

PURPOSE: Patients with von Hippel-Lindau disease frequently have early, multiple and recurrent renal cell carcinoma. Renal cell carcinoma treatment, which must prevent metastatic disease and spare nephrons, has changed in the last 2 decades. We evaluated renal cell carcinoma treatments in the long term in a large series of patients with von Hippel-Lindau disease. MATERIALS AND METHODS: We retrospectively evaluated the use and results of surgery and radio frequency ablation in patients with von Hippel-Lindau followed at our institution between 1988 and 2009. Renal anatomical survival was analyzed according to 3 periods, including 1) 1988 to 1994--the learning phase of nephron sparing surgery, 2) 1995 to 2003--routine nephron sparing surgery and 3) 2004 to 2009--the emergence of radio frequency ablation. RESULTS: A first renal cell carcinoma was treated at a mean age of 38 years (range 15 to 67) in 113 patients with von Hippel-Lindau disease. During a median followup of 7.2 years 251 therapeutic procedures were performed in a total of 176 kidneys. We observed a shift of first line renal cell carcinoma treatment with time, that is nephrectomy in 52% of cases in period 1, tumorectomy in 75% in period 2 and radio frequency ablation in 43% in period 3. The shift paralleled improved renal survival. While nephron sparing surgery was primarily done for lesions greater than 30 mm, radio frequency ablation was used to treat less numerous and smaller ipsilateral lesions but they required more frequent intervention. Radio frequency ablation became the most widely used second or third line procedure and allowed renal salvage in 8 patients. CONCLUSIONS: Nephron sparing surgery and more recently radio frequency ablation enable earlier treatment of smaller tumors and are associated with a significant improved renal prognosis in patients with von Hippel-Lindau disease.

Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome.

The HELLP syndrome, defined by the existence of hemolysis, elevated liver enzymes, and low platelet count, is a serious complication of pregnancy-related hypertensive disorders and shares several clinical and biologic features with thrombotic microangiopathy (TMA). Several recent studies have clearly shown that an abnormal control of the complement alternative pathway is a major risk for the occurrence of a peculiar type of TMA involving mainly the kidney. The aim of this study was to screen for complement abnormalities in 11 patients with HELLP syndrome and renal involvement. We identified 4 patients with a mutation in one of the genes coding for proteins involved in the regulation of the alternative pathway of complement. Our results suggest that an abnormal control of the complement alternative pathway is a risk factor for the occurrence of HELLP syndrome.

Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN).

BACKGROUND: In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. METHODS: An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. RESULTS: We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 micromol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m(2) and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1-2 chronic kidney disease with minimal proteinuria. CONCLUSIONS: The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for longitudinal assessment of prognosis and responses to therapy for Fabry nephropathy.

Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.

Mutations of NPHS2, encoding podocin, are the main cause of autosomal recessive steroid-resistant nephrotic syndrome (NS) presenting in childhood. Adult-onset steroid-resistant NS has been described in patients heterozygous for a pathogenic NPHS2 mutation together with the p.R229Q variant. To determine the frequency and the phenotype of patients carrying the p.R229Q variant, we sequenced the complete coding region of NPHS2 in 455 families (546 patients) non-responsive to immunosuppressive therapy or without relapse after transplantation. Among affected Europeans, the p.R229Q allele was significantly more frequent compared to control individuals. Thirty-six patients from 27 families (11 families from Europe and 14 from South America) were compound heterozygotes for the p.R229Q variant and one pathogenic mutation. These patients had significantly later onset of NS and end stage renal disease than patients with two pathogenic mutations. Among 119 patients diagnosed with NS presenting after 18 years of age, 18 patients were found to have one pathogenic mutation and p.R229Q, but none had two pathogenic mutations. Our study shows that compound heterozygosity for p.R229Q is associated with adult-onset steroid-resistant NS, mostly among patients of European and South American origin. Screening for the p.R229Q variant is recommended in these patients along with further NPHS2 mutation analysis in those carrying the variant.

Monitoring of glomerular filtration rate in lithium-treated outpatients--an ambulatory laboratory database surveillance.

BACKGROUND: The long-term risk of chronic kidney disease (CKD) in lithium (Li)-treated patients has been well established in the recent years. METHODS: We have evaluated GFR and serum calcium monitoring in 1179 Li-treated outpatients from an ambulatory laboratory database study. This has been performed in a single private laboratory in Paris from February 1997 to December 2004. Estimated GFR (eGFR) has been calculated using the abbreviated MDRD equation. RESULTS: During an 8-year period, 695 patients (59%) had at least one serum creatinine measurement, whereas 484 had no creatinine measurement. The former group had also more frequent serum Li measurements. Mean serum lithium levels, were similar in both groups, 0.65 mmol/l vs 0.62 mmol/l. The percentage of patients with CKD stage 3 (eGFR 30-59 ml/min/1.73 m(2)) were 36%, 53%, 73% and 77%, and with CKD stage 4, 3%, 5%, 5%, 8% in patients aged 20-39, 40-59, 60-69, and > or = 70 years respectively. There was no significant rise in creatinine measurements (from 35% of the patients with at least one serum creatinine in 2003 to 39% in 2004; P = 0.66) despite intervention to intensify GFR monitoring by physicians. Serum calcium was tested at least once in 212 patients (18%) of whom 15 (7%) were found with hypercalcaemia. CONCLUSION: A very high percentage of Li-treated outpatients have low eGFR. GFR monitoring is neglected in these patients, the majority of whom are no longer attending specialized clinics. Hypercalcaemia is less common but serum calcium monitoring is even more neglected. Ambulatory laboratory database surveillance provides a powerful means to contribute to CKD screening and monitoring.

Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.

INTRODUCTION: Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic uraemic syndrome (HUS). In some instances, HUS may be associated with an unusual glomerulonephritis with isolated C3 deposits (glomerulonephritis C3). We determined whether HUS and glomerulonephritis C3 share common genetic susceptibility factors. METHODS: We identified 19 patients with glomerulonephritis C3. We measured levels of circulating complement components, performed assays for the detection of C3 nephritic factor (C3NeF) and screened factor H, factor I and MCP coding genes for the presence of mutations. RESULTS: Patients were divided in two groups based on renal pathology findings: group I (n = 13) had typical features of type I membranoproliferative glomerulonephritis (glomerulonephritis C3 with membranoproliferative glomerulonephritis (MPGN)) and group II (n = 6) was characterised by mesangial and epimembranous C3 deposits in the absence of mesangial proliferation (glomerulonephritis C3 without MPGN). Mutations in complement regulatory genes were detected in 4/6 patients with glomerulonephritis C3 without MPGN (heterozygous mutations in factor H gene (two patients) with low factor H antigenic level in one case, heterozygous mutations in factor I gene (two patients)) and in only 2/13 patients with glomerulonephritis C3 with MPGN (heterozygous mutations in factor H gene (one patient) and double heterozygous mutation in CD 46 gene (one patient)). In contrast, C3NeF was present in 5/13 patients with glomerulonephritis C3 with MPGN and in 2/6 patients with glomerulonephritis C3 without MPGN, one of whom had a factor H mutation. CONCLUSION: HUS and glomerulonephritis C3 without MPGN share common genetic risk factors. Constitutional or acquired dysregulation of the CAP is probably associated with a wide spectrum of diseases, ranging from HUS to glomerulonephritis C3 with MPGN.

Exonic duplication of the hepatocyte nuclear factor-1beta gene (transcription factor 2, hepatic) as a cause of maturity onset diabetes of the young type 5.

CONTEXT: Maturity onset diabetes of the young (MODY) type 5 has been described as the association of early-onset diabetes and renal disease. Actually, MODY5 encompasses multiple phenotypes, including nondiabetic progressive renal failure, kidney and genital tract malformations, atypical familial hyperuricemic nephropathy, pancreas atrophy, and liver test abnormalities. The occurrence of MODY5 has been associated with various molecular abnormalities of TCF2, including missense, nonsense, small insertion/deletions, and splice site mutations, as well as large genomic deletions or single exonic deletion of TCF2. DESIGN: Using quantitative multiplex PCR amplification of short fluorescent fragments, we have analyzed the TCF2 gene in a French family of which three relatives presented a MODY5 phenotype. The proband had an extended clinical phenotype, including hyperuricemic nephropathy and early gout, chronic renal failure, renal morphological abnormalities, abnormal liver tests, and diabetes. His son had almost no clinical expression of the disease, whereas his grandson had a restricted but severe renal phenotype present from birth. RESULTS: We show that a duplication of the exon 5 of TCF2 is responsible for the MODY5 phenotypes in this family. CONCLUSIONS: Thus, we describe a novel molecular mechanism that may be responsible for MODY5, and we emphasize the wide intrafamilial variability of MODY5 expressivity. These observations suggest that the diagnosis of MODY5 may be raised even in subjects with partial phenotypes. They also confirm that quantitative multiplex PCR amplification of short fluorescent fragments analysis should be the first step of genetic screening in patients with a MODY5 phenotype.