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.

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.

[Screening and management of intracranial aneurisms in patients with autosomal dominant polycystic kidney disease]. / Dépistage et prise en charge des anévrismes intracrâniens chez les patients atteints de polykystose rénale autosomique dominante.

Autosomal dominant polycystic kidney disease is the most frequent hereditary kidney disease. Intracranial aneurysm prevalence in this population is four to five times higher than the prevalence in the general population. The most frequent complication of intracranial aneurysms is rupture with subarachnoidal hemorrhage, which is associated with a high morbidity and mortality. The only identified risk factor for unruptured intracranial aneurysm is a family history of intracranial aneurysm. However, most cases of aneurysm rupture occur without any family history of intracranial aneurysm. Magnetic resonance angiography without contrast medium injection facilitates screening, and progress have been made in preventive (endovascular or neurosurgical) treatment of intracranial aneurysm. Recommendations have recently been published concerning intracranial aneurysm screening, and suggest screening patients with autosomal dominant polycystic kidney disease and a family history of intracranial aneurysm, those who have an at-risk activity and those who request screening despite adequate information. Conflicting opinions exist, however, in the literature. Furthermore, a study of practice was conducted among French-speaking nephrologists in Europe and showed that approximately a third of the participants were in favor of systematic screening for intracranial aneurysm in all patients with autosomal dominant polycystic kidney disease. Beyond intracranial aneurysm prevalence, it is necessary to better define rupture rates in the autosomal dominant polycystic kidney disease population, with and without familial history of intracranial aneurysm. This would allow optimizing intracranial aneurysm screening practices in autosomal dominant polycystic kidney disease.

Paraganglioma of the bladder in a kidney transplant recipient: A case report.

Renal transplantation has been associated with a significantly increased risk of developing cancer, including bladder neoplasia, with urothelial carcinoma being the most frequent type of bladder cancer. Bladder paraganglioma, also referred to as extra-adrenal pheochromocytoma, is a rare but severe condition that may cause a severe hypertensive crisis during handling and mobilization of the tumor. We herein present the case of a 67-year-old kidney transplant recipient with a bladder polyp consistent with paraganglioma of the bladder. During bladder polyp resection, the patient developed severe hypertension, which resolved with appropriate treatment. The histological analysis of the resected bladder polyp was consistent with extra-adrenal pheochromocytoma, or paraganglioma, and the patient finally underwent partial cystectomy, with no reported postoperative recurrence. To the best of our knowledge, this is the first report of a case of paraganglioma of the bladder in a kidney tranplant recipient. Total or partial bladder cystectomy is considered to be an effective treatment for this type of bladder tumor. Screening for mutations of the succinate dehydrogenase subunit B gene may also be recommended.

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.

Heterogeneous histologic and clinical evolution in 3 cases of dense deposit disease with long-term follow-up.

Dense deposit disease is characterized by dense deposits in the glomerular and tubular basement membranes. We report 3 cases with long-term follow-up differing in histologic pattern and clinical evolution. Clinical and histologic data were collected between 1976 and 2012. Age at the first manifestations was 6, 11, and 23 years, respectively. They included proteinuria (patient 1) and nephrotic syndrome (patients 2 and 3); renal function was normal in all cases. Two patients (1 and 3) had low complement component 3 (C3) levels. All patients had C3 nephritic factor. Genetic analysis revealed a rare variant of the factor I gene (patient 1) and a heterozygous mutation in complement factor H-related 5 gene (patient 2). Patient 1 underwent 3 biopsies during her 38 years of follow-up. Thickening of the capillary walls of the glomerular and tubular basement membranes was observed, with mild mesangial proliferation and progressive C3 and complement membrane attack complex mesangial deposits. However, renal function remained normal. Patient 2 also underwent 3 biopsies (22 years of follow-up), revealing a gradual decrease in C3 deposition and mesangial cell proliferation. He presented mild renal insufficiency. Patient 3 underwent 2 biopsies, which displayed unusual bulky membranous deposits, confirmed by electron microscopy, with no mesangial cell proliferation and little C3 and complement membrane attack complex deposits. Kidney function remained normal. These 3 cases of dense deposit disease differed in histologic pattern evolution: accumulation of C3 deposits, decrease in C3 deposits and proliferation, and isolated dense deposits. The histologic factors involved in clinical progression remain to be identified.

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.

[Renal biopsies in Fabry disease: a multicenter French study]. / La biopsie rénale dans la maladie de Fabry : étude multicentrique française.

This study has been initiated to test the scoring form developed to evaluate renal lesions in Fabry disease. This has been established by 10 international experts. Thus, we have collected data on 34 Fabry patients from 19 French centers ; only 28 renal biopsies were adequate for study. Males (23) and females (five) were of similar age (mean 50 years old). Specific glycolipid storage changes were found in all cases. Fibrous changes, involving glomeruli (in about 25% of the cases), interstitium (35% of the cases) and vascular (50 to 60%), were frequently detected. Renal function was significantly and negatively correlated with this fibrous changes, even though three patients with stages 1 and 2 chronic kidney disease had chronic interstitial fibrosis extending over more than 30% of the renal parenchyma. The extend of fibrous changes was not tightly correlated with age of the patients. The results of this study suggest that renal biopsy is of value before initiating enzyme replacement therapy, in patients older than 30 to 40 years.

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.

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.

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.

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.