Mitochondrial disorders are genetic defects of oxidative phosphorylation. Oxidative phosphorylation takes place in the mitochondrial inner membrane and consists of the oxidation of fuel molecules by ...oxygen and the concomitant energy transduction into ATP. The mitochondrial respiratory chain is a complex metabolic pathway. It is made of approximately 100 polypeptides, most of which are encoded in the nucleus whereas 13 are encoded in the mitochondria. Mitochondrial DNA is maternally inherited and its mutations are transmitted by the mother. During cell division, mitochondria are randomly partitioned in daughter cells. Therefore, in case normal and mutant DNA are present in the mother's cells, some lineage may have only mutant mitochondrial DNA or normal mitochondrial DNA while others may have both mutant and normal DNA, a condition named heteroplasmy. Renal involvement in mitochondrial cytopathies is rare. Patients most often present with a more or less complete de Toni-Debré-Fanconi syndrome. A few patients present with a nephrotic syndrome or with chronic tubulointerstitial nephritis. The investigation of patients with mitochondrial disorders include metabolic screening for abnormal oxidoreduction status in plasma, investigation of the mitochondrial respiratory chain, including polarographic and spectrophotometric studies, histopathologic studies and genetic studies.
Abstract Background and Aims Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosin, a lysosome membrane transporter, ...causing cystine accumulation. Specific treatment by cysteamine decreases renal and extrarenal complications frequency in cystinosis patients but data on long-term manifestations of the disease are lacking. The aim of the ECYSCO cohort is to describe the natural history of the disease and the effect of treatments. Methods We set up a European, multi-centre, longitudinal, non-interventional cohort, ECYSCO, that uses observational study methods to collect uniform data. 243 patients with a confirmed diagnosis of cystinosis and followed in 25 French and 5 European centers (Belgium, Italy, Spain and Germany) were included. Data are collected on the secure RaDiCo platform, via an e-CRF (REDCap). Results Data from 177 patients (50.8% male) were analyzed. Median age at diagnosis was 1.3 years IQ 0.9; 1.8, with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 158 patients: 46 (31.9%) presented with homozygous 57kb deletion in the CTNS gene, 57 (39.6%) with heterozygous 57kb deletion associated with another variant and 46 (26.4%) with other variants. The type of variant had no impact on the age at diagnosis. Median age at cysteamine start was 1.6 years (IQ 1.0-3.0). An improvement on age at treatment start was observed after the 1990s. All but 7 patients were treated with cysteamine. Sixty-seven patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was 1.2 nmol ½ cystine/mg protein (IQ 0.6; 2.2). The median duration of treatment was 21.5 years IQ 11.7; 31.1. 165 (93,2%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 18.4 years (IQ 10.4; 30.6). At that time, 104 patients (57.8%) had reached kidney failure (KF). There was no impact of genotype on age at KF. Median age at KF was 12.9 years IQ 9.9; 18.0. A 5-year gain in renal survival was observed after the 1990s. 102 patients (56.7%) received a kidney transplant. Among these transplanted patients: 76 (74.5%) received 1 transplant, 23 (22.5%) received 2 consecutive transplants, and 3 (2.9%) received 3. Median eGFR in the remaining patients was 58.9 ml/min IQ 40.4; 82.2. Extrarenal manifestations included hypothyroidism in 29 (16.4%) patients, diabetes mellitus in 15 (8.4%), skeletal manifestations in 89 (53.6%), myopathy in 28 (17.9%), and neurological disorders in 21 (13.5%). Skeletal manifestations involved patients before dialysis/transplantation in 46% of cases. The main complications in these patients were genu valgum (62.9%), genu varum (11.1%), kyphosis (21.2%), fractures (20.4%), and 12.6% required surgery. Patients with myopathy were dialysed or transplanted in 58.8% of cases. Conclusion Cystinosis is a good example of a pediatric disease with multiorgan involvement extending into adult care. More than half of patients are adults and have reached kidney failure even if age at renal replacement therapy start has increased. The high frequency of extra-renal manifestations demonstrates the importance of a multidisciplinary follow up of these patients.
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.
Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome ...in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.
This study assessed the long-term renoprotective effect of intensified blood-pressure control among children receiving a fixed high dose of an angiotensin-converting–enzyme inhibitor. Intensified ...blood-pressure control, achieved with additional medication, to reach a targeted 24-hour blood pressure in the low range of normal appeared to confer a substantial benefit with respect to a delay in the progression of renal disease among children with chronic kidney disease. However, reappearance of proteinuria after initial successful pharmacologic control was common.
Intensified blood-pressure control to reach a targeted 24-hour blood pressure in the low range of normal appeared to confer a substantial benefit with respect to a delay in the progression of renal disease among children with chronic kidney disease. However, reappearance of proteinuria was common.
Among both adults and children, chronic kidney disease tends to progress to end-stage renal failure, which is a major clinical problem. Systemic hypertension and glomerular hyperfiltration lead to progressive nephron damage.
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Effective blood-pressure control delays the progression of renal disease in adults with chronic kidney disease, and antihypertensive agents that inhibit the renin–angiotensin system provide superior renoprotection, owing to their additional antiproteinuric, antiinflammatory, and antifibrotic properties.
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Children comprise less than 1% of the total population with chronic kidney disease and often have congenital kidney malformations, urinary tract disorders, or genetic disorders that affect nephron formation or function. Hypertension . . .
Abstract
BACKGROUND AND AIMS
Little is known about the long-term outcome during adulthood of childhood onset idiopathic nephrotic syndrome (INS). We aimed to determine which patients require ...long-term follow up after transition, to identify risk factors of relapse and to analyze treatment strategies.
METHOD
In this monocentric retrospective study, we included all patients admitted in our adult nephrology department with INS diagnosed during childhood. Patients who reached kidney failure during childhood were excluded. Data regarding the outcome at adult age were obtained through clinical database and medical charts.
RESULTS
Eighty-two patients (male/female = 2/1) were included, with a median age at diagnosis of 3.9 years (1.2–16.5). Sixty-eight patients had steroid-sensitive INS, including 52 with steroid-dependent nephrotic syndrome or frequently relapsing nephrotic syndrome. Fourteen patients had steroid-resistant nephrotic syndrome. A total of 89% of patients received corticosteroid sparing treatment during childhood. Median follow-up during adulthood was 6.2 (0.3–25) years. A total of 71% of patients experienced at least one relapse during adulthood. The total number of relapses during childhood and the number of relapses per year during childhood, reflecting disease activity, were significantly higher in patients who experienced relapses during adulthood than in patients who did not (Figure 1). The risk of relapse during adulthood was also significantly associated with the need for immunosuppressive regimen at the time of the transition visit (P = 0.002). To promote the successful transition of young people, we propose to organize a transition visit where the adolescent/young adult is seen jointly by pediatric and adult nephrologists, as it was done for 68% of patients in this study. The relapse rate was significantly lower (50%) in the subgroup of patients who had such a transition visit. We also found that relapse during the first two-years of adulthood follow-up was significantly associated with the risk of further relapse, highlighting the need for a close follow-up during the transition period. A total of 45% of patients received corticosteroid sparing treatment during adulthood, mainly mycophenolate mofetil (N = 23), calcineurin inhibitors (N = 21) and rituximab (N = 12). The main complications were high blood pressure (20/82, 26%) and osteopenia (19/26, 73% when bone densitometry was performed). Only one thrombo-embolic event and three severe infections were reported. At last follow-up, median eGFR was 87.1 (23.4–150.8) mL/min/1.73 m².
CONCLUSION
The incidence of relapses in adulthood is high in patients with active disease during childhood. A long-term follow-up is mandatory in these patients. Whereas renal function remained normal in most patients, high blood pressure and osteopenia were frequent and should be carefully monitored during adulthood. Transition visit should be carefully coordinated to prevent the risk of nonadherence.
Abstract
Background and Aims
Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosine, a lysosome membrane transporter ...causing cystine accumulation with a reported incidence of 1:180,000 live births. Specific treatment by cysteamine decreases renal and extrarenal complications frequency and increases life expectancy. Recently, new treatments for cystinosis entered into the European market with an extended-release formulation of cysteamine and a new formulation of eye drops. The aim of this project is to describe the natural history of the disease and long-term clinical manifestations.
Method
We set up a European, multi-centre, longitudinal, non-interventional cohort, ECYSCO, that uses observational study methods to collect uniform data. 243 patients with a confirmed diagnosis of cystinosis and followed in 25 French and 5 European centers (Belgium, Italy, Spain and Germany) were included. Data are collected on the secure RaDiCo platform, via an e-CRF (REDCap).
Results
Data from 180 patients (50.0% male) were analyzed. Median age at diagnosis was 1.3 years IQ 0.8; 1.9, with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 174 patients: 57 (32.8%) presented with homozygous 57kb deletion in the CTNS gene, 71 (40.8%) with heterozygous 57kb deletion associated with another variant and 46 (26.4%) with other variants. The type of variant had no impact on the age at diagnosis. Median age at cysteamine start was 1,6 years (IQ 1.0-3.0). An improvement on age at treatment start was observed after the 1990s. All but 6 patients were treated with cysteamine. 71 patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was correct at 1.2 nmol ½ cystine/mg protein (IQ 0.59; 2.20). The median duration of treatment was 21.5 years IQ 11.7; 31.1. 167 (95,9%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 19.08 years (IQ 10.43; 31.41). At that time, 104 patients (57.8%) had reached end-stage renal disease (ESRD). There was no impact of genotype on age at ESRD. Median age at ESRD was 12.9 years IQ 9.9; 18.0. A 5-year gain in renal survival was observed after the 1990s. 102 patients (56.7%) received a kidney transplant. Among these transplanted patients: 76 (74.5%) received 1 transplant, 23 (22.5%) received 2 consecutive transplants, and 3 (2.9%) received 3. Median eGFR in the remaining patients was 58.9 ml/min IQ 40.4; 82.2. Extrarenal manifestations included hypothyroidism in 61 (33.9%) patients, diabetes mellitus in 11 (6.1%), skeletal manifestations in 73 (40.5%), myopathy in 32 (17.8%), and neurological disorders in 22 (12.2%). At inclusion, 36 patients had no ESRD and no extra-renal complication.
Conclusion
Cystinosis is a good example of a pediatric disease with multiorgan involvement extending into adult care. More than half of patients are adults and have reached ESRD even if age at renal replacement therapy start has increased. The high frequency of extra-renal manifestations demonstrates the importance of a multidisciplinary follow up of these patients.
Les cytopathies mitochondriales sont des maladies génétiques affectant la phosphorylation oxydative consistant en la production d’adénosine triphosphate (ATP), source de l’énergie dans les tissus et ...les organes. La chaîne respiratoire mitochondriale comprend plus de 100 polypeptides dont la majorité est codée par des gènes nucléaires tandis que 13 sont codés par l’acide désoxyribonucléique (ADN) mitochondrial. L’ADN mitochondrial est transmis par la mère et les mutations sont donc de transmission maternelle. Durant la division cellulaire, les mitochondries sont réparties au hasard dans les cellules filles et le pourcentage de molécules d’ADN mutées et de molécules d’ADN normales dans les cellules filles peut varier au cours du temps. L’atteinte rénale au cours des cytopathies mitochondriales est rare. La manifestation la plus fréquente est une tubulopathie proximale, responsable d’une forme plus ou moins complète et sévère de syndrome de de Toni-Debré-Fanconi. Certains patients présentent un syndrome néphrotique et d’autres une néphropathie tubulo-interstitielle. Les investigations comportent des études métaboliques de l’état d’oxydoréduction dans le plasma, des études spectrophotométriques et spectroscopiques de la chaîne respiratoire mitochondriale, des études histologiques et des études génétiques.
Mitochondrial disorders are genetic defects of oxidative phosphorylation. Oxidative phosphorylation takes place in the mitochondrial inner membrane and consists of the oxidation of fuel molecules by oxygen and the concomitant energy transduction into ATP. The mitochondrial respiratory chain is a complex metabolic pathway. It is made of approximately 100 polypeptides, most of which are encoded in the nucleus whereas 13 are encoded in the mitochondria. Mitochondrial DNA is maternally inherited and its mutations are transmitted by the mother. During cell division, mitochondria are randomly partitioned in daughter cells. Therefore, in case normal and mutant DNA are present in the mother's cells, some lineage may have only mutant mitochondrial DNA or normal mitochondrial DNA while others may have both mutant and normal DNA, a condition named heteroplasmy. Renal involvement in mitochondrial cytopathies is rare. Patients most often present with a more or less complete de Toni-Debré-Fanconi syndrome. A few patients present with a nephrotic syndrome or with chronic tubulointerstitial nephritis. The investigation of patients with mitochondrial disorders include metabolic screening for abnormal oxidoreduction status in plasma, investigation of the mitochondrial respiratory chain, including polarographic and spectrophotometric studies, histopathologic studies and genetic studies.
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