Morphological changes and their associations with clinical parameters in children with nephropathic cystinosis and chronic kidney disease prior to kidney replacement therapy over 25 years.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated. METHODS: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016). RESULTS: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients. CONCLUSIONS: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear.

Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants.

BACKGROUND: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. METHODS: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. RESULTS: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years). CONCLUSION: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Heterozygous variants in the DVL2 interaction region of DACT1 cause CAKUT and features of Townes-Brocks syndrome 2.

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled binding antagonist of beta catenin 1) gene encoding a cytoplasmic WNT signaling mediator. Our patient's features overlapped Townes-Brocks syndrome 2 (TBS2) previously described in a family carrying a DACT1 nonsense variant as well as those of Dact1-deficient mice. Therefore, we assessed the role of DACT1 in CAKUT pathogenesis. Taken together, very rare (minor allele frequency ≤ 0.0005) non-silent DACT1 variants were detected in eight of 209 (3.8%) CAKUT families, significantly more frequently than in controls (1.7%). All seven different DACT1 missense variants, predominantly likely pathogenic and exclusively maternally inherited, were located in the interaction region with DVL2 (dishevelled segment polarity protein 2), and biochemical characterization revealed reduced binding of mutant DACT1 to DVL2. Patients carrying DACT1 variants presented with kidney agenesis, duplex or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features. During murine development, Dact1 was expressed in organs affected by anomalies in patients with DACT1 variants, including the kidney, anal canal, vertebrae, and brain. In a branching morphogenesis assay, tubule formation was impaired in CRISPR/Cas9-induced Dact1-/- murine inner medullary collecting duct cells. In summary, we provide evidence that heterozygous hypomorphic DACT1 variants cause CAKUT and other features of TBS2, including anomalies of the skeleton, brain, distal digestive and genital tract.

Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis.

Infantile nephropathic cystinosis, due to impaired transport of cystine out of lysosomes, occurs with an incidence of 1 in 100-200,000 live births. It is characterized by renal Fanconi syndrome in the first year of life and glomerular dysfunction progression to end-stage kidney disease by approximately 10 years of age. Treatment with oral cysteamine therapy helps preserve glomerular function, but affected individuals eventually require kidney replacement therapy. This is because glomerular damage had already occurred by the time a child is diagnosed with cystinosis, typically in the second year of life. We performed a retrospective multicenter study to investigate the impact of initiating cysteamine treatment within the first 2 months of life in some infants and comparing two different levels of adherence in patients diagnosed at the typical age. We collected 3983 data points from 55 patients born between 1997 and 2020; 52 patients with 1592 data points could be further evaluated. These data were first analyzed by dividing the patient cohort into three groups: (i) standard treatment start with good adherence, (ii) standard treatment start with less good adherence, and (iii) early treatment start. At every age, mean estimated glomerular filtration rate (eGFR) was higher in early-treated patients than in later-treated patients. Second, a generalized additive mixed model (GAMM) was applied showing that patients with initiation of treatment before 2 months of age are expected to have a 34 ml/min/1.73 m2 higher eGFR than patients with later treatment start while controlling for adherence and patients' age. These data strongly suggest that oral cysteamine treatment initiated within 2 months of birth preserves kidney function in infantile nephropathic cystinosis and provide evidence of the utility of newborn screening for this disease.

Body growth, upper arm fat area, and clinical parameters in children with nephropathic cystinosis compared with other pediatric chronic kidney disease entities.

Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investigated linear growth, body proportion, body mass index (BMI), upper arm fat area (UFA) and biochemical parameters in 43 pediatric INC patients with CKD stages 1 to 5 and 49 age-matched CKD controls, with 193 annual measurements. INC patients showed more impaired height than CKD controls (-1.8 vs -0.7 z-score; P < .001), despite adequate cysteamine therapy, treatment for Fanconi syndrome and more frequent use of growth hormone. Only the youngest INC patients shared the same body pattern with CKD controls characterized by preferential impairment of leg length and rather preserved trunk length. In late-prepuberty, body pattern changed only in INC patients due to improved leg growth and more impaired trunk length. Mean UFA z-score in INC patients was slightly reduced in early childhood and progressively decreased thereafter reaching -0.8 z-score in adolescence, while CKD controls showed a steady increase in standardized BMI and UFA especially during adolescent age. Menarche in female INC patients was significantly delayed compared to CKD controls. Our data indicate that with age and progression of disease, pediatric INC patients undergo unique changes of body growth and fat stores that are distinct from those with CKD stemming from other causes, suggesting other factors apart from CKD to contribute to this development. Pediatric patients with infantile nephropathic cystinosis display more severe impaired linear growth than other peer CKD patients, despite of cysteamine treatment, supplementation for Fanconi syndrome, and more frequent use of growth hormone, with a distinct change of body proportions and overall lower body fat.

Endurance-oriented training program with children and adolescents on maintenance hemodialysis to enhance dialysis efficacy-DiaSport.

OBJECTIVE: Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT). METHODS: Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter. RESULTS: We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14-13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 [0.33] vs. 1.79 [0.55]) at V0 and (1.70 [0.36] vs. 1.71 [0.51]) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions. CONCLUSIONS: Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.Gov ( Clinicaltrials.gov identifier: NCT01561118) on March 22, 2012.

Seasonal variation of blood pressure in children.

Seasonal blood pressure (BP) variation is mostly found between the summer and winter months. Guidelines for diagnosis and treatment of hypertension in children have not considered this variation until recently. This review aims to present an overview of seasonal BP variation in childhood along with potential underlying pathophysiological mechanisms and long-term implications as well as conclusions for future studies. In pediatric cohorts, seven studies investigated seasonal changes in BP. These changes amount to 3.4-5.9 mmHg (or 0.5-1.5 mmHg per - 1 °C difference in environmental temperature) in systolic BP with a peak in fall or winter. Potential mechanisms and mediators of seasonal BP variation include sympathetic activation of the nervous system with an increase of urinary and plasma norepinephrine levels in the winter season. Additionally, the physical activity among children and adolescents was inversely correlated with BP levels. Temperature sensitivity of BP and pediatric BP levels predict future systolic BP and target-organ damage. Therefore, cardiovascular events may even be long-term complications of seasonal BP variation in pediatric hypertensive patients. Overall, these data strongly suggest an important effect of ambient temperature on BP in children. Additional studies in pediatric cohorts are needed to define how best to incorporate such variation into clinical practice.

Different approaches to long-term treatment of aHUS due to MCP mutations: a multicenter analysis.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought to influence the severity of initial and recurring episodes, with milder courses in patients with mutations in membrane cofactor protein (MCP). METHODS: Twenty pediatric cases of aHUS due to isolated heterozygous MCP mutations were reported from 12 German pediatric nephrology centers to describe initial presentation, timing of relapses, treatment, and kidney outcome. RESULTS: The median age of onset was 4.6 years, with a female to male ratio of 1:3. Without eculizumab maintenance therapy, 50% (9/18) of the patients experienced a first relapse after a median period of 3.8 years. Kaplan-Meier analysis showed a relapse-free survival of 93% at 1 year. Four patients received eculizumab long-term treatment, while 3 patients received short courses. We could not show a benefit from complement blockade therapy on long term kidney function, independent of short-term or long-term treatment. To prevent 1 relapse with eculizumab, the theoretical number-needed-to-treat (NNT) was 15 for the first year and 3 for the first 5 years after initial presentation. CONCLUSION: Our study shows that heterozygous MCP mutations cause aHUS with a risk of first relapse of about 10% per year, resulting in large NNTs for prevention of relapses with eculizumab. More studies are needed to define an optimal treatment schedule for patients with MCP mutations to minimize the risks of the disease and treatment.

Bone and Mineral Metabolism in Children with Nephropathic Cystinosis Compared with other CKD Entities.

CONTEXT: Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD); however, systematic analyses are lacking. OBJECTIVE: To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across all stages of CKD. DESIGN: Cross-sectional multicenter study. SETTING: Hospital clinics. PATIENTS: Forty-nine children with NC, 80 CKD controls of the same age and CKD stage. MAIN OUTCOME MEASURES: Fibroblast growth factor 23 (FGF23), soluble Klotho, bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin, osteoprotegerin (OPG), biochemical parameters related to mineral metabolism, and skeletal comorbidity. RESULTS: Despite Fanconi syndrome medication, NC patients showed an 11-fold increased risk of short stature, bone deformities, and/or requirement for skeletal surgery compared with CKD controls. This was associated with a higher frequency of risk factors such as hypophosphatemia, hypocalcemia, low parathyroid hormone (PTH), metabolic acidosis, and a specific CKD stage-dependent pattern of bone marker alterations. Pretransplant NC patients in mild to moderate CKD showed a delayed increase or lacked an increase in FGF23 and sclerostin, and increased BAP, TRAP5b, and OPG concentrations compared with CKD controls. Post-transplant, BAP and OPG returned to normal, TRAP5b further increased, whereas FGF23 and PTH were less elevated compared with CKD controls and associated with higher serum phosphate. CONCLUSIONS: Patients with NC show more severe skeletal comorbidity associated with distinct CKD stage-dependent alterations of bone metabolism than CKD controls, suggesting impaired mineralization and increased bone resorption, which is only partially normalized after renal transplantation.

Sex and age as determinants for high blood pressure in pediatric renal transplant recipients: a longitudinal analysis of the CERTAIN Registry.

BACKGROUND: High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated. METHODS: This retrospective analysis included 336 pediatric renal transplant recipients (62% males) from the Cooperative European Pediatric Renal Transplant Initiative Registry (CERTAIN) with complete BP measurement at discharge and 1, 2 and 3 years post-transplant. RESULTS: At discharge and 3 years post-transplant, arterial hypertension was highly prevalent (84% and 77%); antihypertensive drugs were used in 73% and 68% of the patients. 27% suffered from uncontrolled and 9% from untreated hypertension at 3 years post-transplant. Children transplanted at age < 5 years showed sustained high systolic BP z-score and received consistently less antihypertensive treatment over time. Younger age, shorter time since transplantation, male sex, higher body mass index (BMI), high cyclosporine A (CSA) trough levels, and a primary renal disease other than congenital anomalies of the kidney and urinary tract (CAKUT) were significantly associated with higher systolic BP z-score. Sex-stratified analysis revealed a significant association between high CSA and higher systolic BP in older girls that likely had started puberty already. An association between BP and estimated glomerular filtration rate was not detected. CONCLUSIONS: BP control during the first 3 years was poor in this large European cohort. The description of age- and sex-specific risk profiles identified certain recipient groups that may benefit from more frequent BP monitoring (i.e. young children) or different choices of immunosuppression (i.e. older girls).

Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.

Outcome of renal transplantation in small infants: a match-controlled analysis.

BACKGROUND: Infants with a body weight of less than 10 kg are often not considered to be suitable candidates for renal transplantation (RTx). The objective of this study was to evaluate this arbitrary weight threshold for pediatric RTx. METHODS: We conducted a multicenter, retrospective, match-controlled cohort study on infants weighing less than 10 kg at time of engrafting (low-weight group [LWG], n = 38) compared to a matched control group (n = 76) with a body weight of 10-15 kg, using data from the first 2 years post-transplant derived from the CERTAIN Registry. RESULTS: Patient survival was 97 and 100% in the LWG and control groups, respectively (P = 0.33), and death-censored graft survival was 100 and 95% in the LWG and control groups, respectively (P = 0.30). Estimated glomerular filtration rate at 2 years post-transplant was excellent and comparable between the groups (LWG 77.6 ± 34.9 mL/min/1.73 m2; control 74.8 ± 29.1 mL/min/1.73 m2; P = 0.68). The overall incidences of surgery-related complications (LWG 11%, control 23%; P = 0.12) and medical outcome measures (LWG 23%, control 36%, P = 0.17) were not significantly different between the groups. The medical outcome measures included transplant-related viral diseases (LWG 10%, control 21%; P = 0.20), acute rejection episodes (LWG 14%, control 29%; P = 0.092), malignancies (LWG 3%, control 0%; P = 0.33) and arterial hypertension (LWG 73%, control 67%; P = 0.57). CONCLUSIONS: These data suggest that RTx in low-weight children is a feasible option, at least in selected centers with appropriate surgical and medical expertise.

Vaccination titres pre- and post-transplant in paediatric renal transplant recipients and the impact of immunosuppressive therapy.

BACKGROUND: Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication. METHODS: In the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national study and analysed vaccination titres pre- and post-transplant in 155 patients with serial titre measurements in comparison with published data in healthy children. RESULTS: The percentage of patients with positive vaccination titres before renal transplantation (RTx) was low, especially for diphtheria (38.5%, control 75%) and pertussis (21.3%, control 96.3%). As few as 58.1% of patients had a hepatitis B antibody (HBsAb) titre >100 IU/L before RTx. 38.1% of patients showed a vaccination titre loss post-transplant. Patients with an HBsAb titre between 10 and 100 IU/L before RTx experienced a significantly (p < 0.05) more frequent hepatitis B vaccination titre loss post-transplant than patients with an HBsAb titre >100 IU/L. The revaccination rate post-transplant was low and revaccination failed to induce positive titres in a considerable number of patients (27.3 to 83.3%). Treatment with rituximab was associated with a significantly increased risk of a vaccination titre loss post-transplant (odds ratio 4.26, p = 0.033). CONCLUSIONS: These data show a low percentage of patients with positive vaccination titres pre-transplant, a low revaccination rate post-transplant with limited antibody response, and a high rate of vaccination titre losses.

Incomplete vaccination coverage in European children with end-stage kidney disease prior to renal transplantation.

BACKGROUND: Because infections constitute a major cause of morbidity and mortality in paediatric renal allograft recipients, avoidance of preventable systemic infections by vaccination before transplantation is of utmost importance. However, data on the completeness of vaccinations and factors associated with incomplete vaccination coverage are scarce. METHODS: Within the framework of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN), we therefore performed a multi-centre, multi-national, retrospective study investigating the vaccination coverage before transplantation of 254 European children with end-stage renal disease (mean age 10.0 ± 5.6 years). RESULTS: Only 22 out of 254 patients (8.7%) presented complete vaccination coverage. In particular, the respective vaccination coverage against human papillomavirus (27.3%), pneumococci (42.0%), and meningococci (47.9%) was low. Patients with complete pneumococcal vaccination coverage had numerically less lower respiratory tract infections during the first 3 years post-transplant than children without vaccination or with an incomplete status (16.4% vs 27.7%, p = 0.081). Vaccine-preventable diseases post-transplant were 4.0 times more frequently in unvaccinated than in vaccinated patients. Factors associated with an incomplete vaccination coverage were non-Caucasian ethnicity (OR 9.21, p = 0.004), chronic dialysis treatment before transplantation (OR 6.18, p = 0.001), and older age at transplantation (OR 1.33, p < 0.001). CONCLUSIONS: The vaccination coverage in paediatric kidney transplant candidates is incomplete. Paediatric nephrologists, together with primary-care staff and patients' families, should therefore make every effort to improve vaccination rates before kidney transplantation.

High Incidence of Proteinuria in Children With Chronic Intestinal Failure Under Long-term Parenteral Nutrition.

Long-term home parenteral nutrition (LTPN) in children with chronic intestinal failure (CIF) is associated with renal complications such as fluid and electrolyte imbalances, nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD). The etiology of CIF-associated nephropathy is multifactorial. The aim of this study was to evaluate renal involvement under LTPN. In this study, 50 patients with CIF, median age 4.2 years (1.4-9.3; 23 girls) were included. Kidney involvement was a frequent finding in this study. CKD was present in 30% of patients without correlation with LTPN duration. Glomerular proteinuria was found in the majority of patients (76%), an important long-term risk factor for the progression of CKD. Increased urinary α-1 microglobulin was significantly associated with duration (years) of LTPN and was increased in patients with CKD.

Effects of growth hormone treatment on adult height in severely short children with X-linked hypophosphatemic rickets.

BACKGROUND: We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients. METHODS: We carried out a follow-up analysis of a randomized controlled open-label GH study in short prepubertal children with XLH on phosphate and active vitamin D treatment. The changes in SD scores (SDS) of height, sitting height, leg and arm length, and sitting height index (i.e., the ratio between sitting height and height) were analyzed in 11 out of 16 patients followed-up until adult height. RESULTS: At baseline, XLH patients showed disproportionately short stature with reduced standardized height (-3.2 ± 0.6), sitting height (-1.7 ± 0.6), leg (-3.7 ± 0.7) and arm (-2.5 ± 0.8) length, and markedly elevated sitting height index (3.3 ± 0.6; each p < 0.01 versus healthy children). In GH-treated patients, adult height, sitting height, leg length, and arm length exceeded baseline values by 0.7 SDS, 1.7 SDS, 0.7 SDS, and 1.2 SDS respectively, although this was only significant for sitting height. In controls, no significant changes in linear body dimensions were noted. Adult height did not statistically differ between groups (-2.4 ± 0.7 vs -3.3 ± 1.2, p = 0.082). GH did not exaggerate body disproportion. CONCLUSIONS: Growth hormone treatment did not significantly increase adult height in this group of short children with XLH, which may be at least partly due to the small number of patients included in our study.

Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies.

BACKGROUND AND OBJECTIVES: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS: In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS: Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

Hemodialysis in MNGIE transiently reduces serum and urine levels of thymidine and deoxyuridine, but not CSF levels and neurological function.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been suggested as a treatment to reduce accumulation of thymidine and deoxyuridine. However, all studies so far have failed to measure the toxic metabolites in cerebrospinal fluid (CSF), which is the crucial compartment for CNS damage.Our study is the first prospective, longitudinal investigation, exploiting detailed serial testing of predefined clinical and molecular outcome parameters (including serial CSF assessments) in a 29-year-old MNGIE patient undergoing 1 year of extensive HMD. We demonstrate that HMD only transiently restores increased serum and urine levels of thymidine and deoxyuridine, but fails to reduce CSF levels of the toxic metabolites and is ineffective to influence neurological function. These findings have direct important implications for clinical practice: They prevent a burdensome, long-term invasive, but ultimately probably ineffective procedure in future MNGIE patients.