Background Homozygous familial hypercholesterolemia (HoFH), characterized by extremely elevated low‐density lipoprotein cholesterol (LDL‐C) due to severely impaired LDL‐C clearance from circulation, remains challenging to treat. Here, we investigated clinical benefits of monoclonal antibody, evinacumab, inhibiting angiopoietin‐like 3, recently approved in children with homozygous familial hypercholesterolemia. Methods This retrospective, observational study included 13 children with homozygous familial hypercholesterolemia on oral lipid‐lowering therapy and assessed their attainment of LDL‐C goal, need for lipoprotein apheresis (LA), and cardiac plaque formation at initiation of evinacumab and at follow‐up of 2.0 (1.3–3.0) years. Results Evinacumab, initiated at age 11 (8.5–13.5) years, increased number of patients reaching LDL‐C goal from none before initiation to 9 of 13 (69%; P =0.004) at follow‐up. Mean±SD LDL‐C at follow‐up was 111 (44) mg/dL, compared with 206 (61) mg/dL before evinacumab (mean difference, −95 mg/dL [95% CI, −142 to −47]; P <0.001). Before initiation of evinacumab, 11 of 13 children received LA with average interval of 7.8 days. At follow‐up, LA frequency decreased in 7 of 11 children with average interval of 18.9 days; increase between LA sessions was 11.0 days (3.5–18.5; P =0.008), 42% longer session interval. For 3 (15%) children, due to evinacumab initiation, LA remained dispensable over the course of treatment. Coronary computed tomography angiography showed plaque stabilization (n=5), regression (n=3), and no formation (n=2), in 10 of 13 (77%) children, and plaque progression in 3 (23%) children. Conclusions Add‐on evinacumab increased number of children with homozygous familial hypercholesterolemia reaching and maintaining LDL‐C goal, concomitant reduction in LA frequency, and in most patients, stabilization or improvement in coronary computed tomography angiography findings.

Infantile nephropathic cystinosis (INC) is characterized by progressive short stature and low body fat. Although birth size is typically normal, early growth data are limited. In this prospective multicenter observational study, 77 conservatively treated children with INC and 527 congenital and hereditary CKD controls, stages 1–5, were analyzed. We investigated birth characteristics and linear body growth (length/stature), weight, and head circumference from birth up to 18 years. Linear mixed-effects models were applied to identify pre- and postnatal predictors of statural growth. Newborns with INC exhibited normal birth morphology, whereas CKD controls showed significantly reduced, disproportionate characteristics (each p < 0.01). Despite preserved birth morphology, born small for gestational age prevalence in INC was nearly twofold higher than in the general population, and CKD peers had an approximately 1.7 times higher prevalence than INC (p < 0.05). In INC, a weight–length dissociation emerged at approximately 6 months of age, followed by marked impairments in both characteristics within the first 2 years, persisting into adulthood. CKD peers showed only mild further decline and more favorable long-term growth. Statural growth in INC was associated with biochemical features of Fanconi syndrome and with birth weight in adolescence, whereas in CKD, birth weight remained the only consistent predictor. In INC, growth deterioration begins around 6 months with weight–length dissociation and progresses to sustained deficits in stature and weight. This pattern resembles early postnatal disturbances that durably constrain somatic development and are driven more by disease-specific disturbances than by reduced glomerular filtration.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe hepatorenal fibrocystic disorder. Its rareness and the variability of disease courses have been major obstacles for the establishment of clinical trials on treatment of kidney disease in ARPKD. In this observational study we characterized kidney disease progression in a very large cohort of up to 658 patients with the clinical diagnosis of ARPKD and identified risk factors associated with rapid kidney disease progression. The estimated probability of kidney failure by the age of 20 years was 50.1% (95% confidence interval 42.2%‒57.0%), with earlier kidney failure in specific subgroups. Mean yearly estimated glomerular filtration rate decline after the first year of life was 1.3 ml/min per 1.73m2 during childhood and adolescence in the overall cohort, ranging from 0.5 to 2.2 ml/min per 1.73m2 in various subgroups. Furthermore, we developed prediction models for the relative risk of early kidney failure to be applied at the age of two months in daily clinical life. The finally chosen predictor set for a score based on a Cox model encompassed five factors: gestational age at oligo- or anhydramnios, gestational age at birth, functional genotype, serum creatinine (mg/dl) as well as documentation of arterial hypertension at the age of two months. The derived simple prognostic score showed good prediction performance, especially in the first three years of life. It reliably identified patients who are not at risk of early kidney failure and may be helpful to identify patients at risk of more rapid disease progression that could benefit from novel therapeutic interventions.

The application of international recommendations for paediatric maintenance haemodialysis (HD) could be strengthened by national laws or written recommendations. Our aim was therefore to describe the national rules governing paediatric maintenance HD in European countries. A national representative, approved by the president of each paediatric nephrology society, was contacted in all 42 European countries to complete two online questionnaires. Answers were received from 36 countries. The population served by HD centres varies from 83,000 to 1,197,000 residents below 18 years of age and the estimated mean number of children on HD per centre from 0.2 to 13.5. The lowest age at which a child can be dialysed in an adult centre varies from 0 to 18 years. Laws or written national recommendations specifying: this age, the need for a paediatrician as part of medical team in mixed adult–paediatric centres, the minimum number of doctors per centre and the number of patients per nurse or nurse’s aide required during sessions exist in only 25, 22, 22, 44 and 8

BACKGROUND:Office blood pressure (BP) trajectories may help assess hypertension progression and the effects of antihypertensive treatment in children with chronic kidney disease. METHODS:Analysis of antihypertensive treatment and BP slopes in 320 patients from the 4C study (Cardiovascular Comorbidity in Children with Chronic Kidney Disease) cohort with chronic kidney disease before renal replacement therapy, based on a minimum of 3 individual observations and 2 years of follow-up. RESULTS:At enrollment, 70 (22%) patients had uncontrolled or untreated hypertension, 130 (41%) patients had controlled hypertension, and 120 (37%) patients had normotension without antihypertensive treatment. Antihypertensive treatment medication was prescribed for 53% of patients at baseline and initiated or added for 91 patients (AHT-I [group with intensification of antihypertensive treatment] group, 28%) during follow-up. Overall BP SD score remained stable over time in the cohort (β=-0.037±0.034, P=0.34 and -0.029±0.348, P=0.093 per year for systolic and diastolic BP SD score). In the AHT-I group, systolic and diastolic BP SD scores were higher at baseline and decreased significantly during follow-up (-0.22±0.07, P<0.003 and -0.12±0.05 SD score per year, P=0.01). Only 8 of 70 (11%) patients from the previously untreated/uncontrolled group remained untreated at the last observation, while 31 (44%) were controlled during follow-up. Of the 120 normotensive patients at baseline, 60% remained normotensive while 40% progressed to uncontrolled/untreated (n=23, 19%) or controlled (n=24, 20%) hypertension. CONCLUSIONS:Although the overall BP of the population remained stable over time, individual patterns of BP management showed considerable variability. BP control improved significantly with intensified antihypertensive therapy; however, a significant number of previously normotensive individuals developed new-onset hypertension during the observation period.

BACKGROUND AND AIMS:Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) from birth, leading to accelerated atherosclerotic cardiovascular disease and premature death if untreated. Evinacumab, a monoclonal antibody targeting angiopoietin-like 3 (ANGPTL3), offers an LDL receptor-independent pathway to lower LDL-C. This study aimed to evaluate the effect of evinacumab on lipid levels and its potential to reduce lipoprotein apheresis (LA) frequency in children and adolescents with HoFH. METHODS:This was a single-center, retrospective, observational study of six patients aged 10-19 years who had genetically confirmed HoFH and were treated with stable doses of lipid-lowering therapy (LLT) and evinacumab with or without LA at the Medical University of Vienna. Demographic characteristics, lipid levels, and treatment details were collected. RESULTS:At the first visit, LDL-C levels ranged from 521 to 870 mg/dL (13.5-22.5 mmol/L). With stable LLT plus LA, pre-LA LDL-C levels were reduced to 212-352 mg/dL (5.5-9.1 mmol/L) and, after evinacumab was added, further reductions to 90-201 mg/dL (2.3-5.2 mmol/L) were observed. However, during periods of reduced LA frequency, pre-LA LDL-C levels increased to 105-216 mg/dL (2.7-5.6 mmol/L), exceeding the target of 115 mg/dL (3.0 mmol/L) in three out of four patients. LA frequency reduction from weekly to three times per month was only possible in one patient, but no patients had termination of LA. CONCLUSIONS:Evinacumab effectively lowers LDL-C in children and adolescents with HoFH. However, its ability to facilitate long-term reduction in LA frequency was not shown and remains unclear.

CONTEXT:The pathophysiology of cystinosis-associated metabolic bone disease is complex. OBJECTIVE:We hypothesized a disturbed interaction between osteoblasts and osteoclasts. METHODS:This binational cross-sectional multicenter study included 103 patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1 to 5D/T at hospital clinics. Ten key bone markers were evaluated. RESULTS:Skeletal complications occurred in two-thirds of the patients, with adults having a 5-fold increased risk compared with children. Patients with CKD stages 1 to 3 showed reduced z-scores for serum phosphate and calcium and suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels, in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. CONCLUSION:Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counter-regulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia, may promote progressive bone loss.

Complement mediated thrombotic microangiopathy (C-TMA) is a rare disease resulting in kidney failure and other organ manifestations. Current treatments include the complement C5 blockers eculizumab and ravulizumab as well as plasma therapy. We report on a young adult man with a long-standing history of genetic C-TMA (GC-TMA) because of a likely pathogenic missense variant in CFH. After several years without clinical signs of TMA and normal kidney function (CKD G1A2), without recent specific therapies, he presented with acute kidney injury, microangiopathic hemolysis, and nephrotic range proteinuria. Plasma therapy and ravulizumab failed to stop hemolysis, and he commenced kidney replacement therapy 11 days after admission. Laboratory analyses disclosed suboptimal complement inhibition and low free ravulizumab serum concentrations. Four weeks after admission, we started treatment with crovalimab, a novel humanized anti-C5 antibody. Hemolysis improved immediately and kidney function recovered after 3 months of dialysis treatment and improved continuously during 1 year of therapy with crovalimab. The excellent and rapid response to crovalimab potentially suggests that the engineering of crovalimab, facilitating also subcutaneous administration, may result in a different pharmacokinetic and pharmacodynamic profile of crovalimab as compared with standard C5 inhibitors in patient with nephrotic range proteinuria.

Abstract Background and Aims Cystinosis-associated metabolic bone disease (CMBD) is a major challenge in the treatment of patients with infantile nephropathic cystinosis (NC). Study data are limited due to small case numbers, lack of adults or patients on renal replacement therapy and/or inadequate assessment of bone health. Method We investigated markers for CMBD in all age groups (1-44 years; 61% children) and CKD stages 1-5D/T in the largest NC cohort to date with 103 German and Austrian NC patients. Skeletal comorbidity and concentrations of fibroblast growth factor 23 (FGF23), the osteoblast marker bone-specific alkaline phosphatase (BAP), the bone remodeling inhibitor sclerostin, the osteoclast marker tartrate-resistant acid phosphatase 5b (TRAP5b), the soluble receptor activator of nuclear factor kappa B ligand (sRANKL), osteoprotegerin (OPG) and the sRANKL/OPG ratio as surrogates for the regulation of osteoclastogenesis by osteoblasts were determined by ELISA, converted into age- and sex-specific z-scores and compared as a function of eGFR. Multivariable regression analyses were used to identify specific influencing factors associated with biochemical and clinical findings in pre-transplant NC patients. Results Skeletal complications occurred in two-thirds of patients, with the risk being five times higher in adults than in children. Pediatric and adult NC patients with CKD stages 1-4 showed hypophosphatemia and hypocalcemia associated with suppressed FGF23 and PTH levels and elevated BAP concentrations. This was associated with age, eGFR and treatment with phosphate and active vitamin D, suggesting more vigorous treatment of Fanconi syndrome in pre-transplant patients. As indicated by the increased TRAP5b and decreased sRANKL/OPG ratio, osteoclast activity was increased despite counterregulation by osteoblasts, which in conjunction with increased sclerostin activity may have contributed to the progressive bone loss and skeletal comorbidity in our patient cohort. Conclusion Bone health in NC progressively deteriorates with age, largely due to persistent rickets/osteomalacia associated with inadequate treatment of Fanconi syndrome and increased osteoclast activity despite osteoblast counterregulation via OPG/RANKL. Our data suggest that a primary osteoclast defect in NC promotes increased bone resorption, limiting maximal bone mass and leading to progressive bone loss and increased skeletal comorbidity.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Objective Children with medical complexity (CMC) are among the most vulnerable patient groups. This study aimed to evaluate their prevalence and risk factors for medication misunderstanding and potential harm (PH) at discharge. Design and setting Cross-sectional study at a tertiary care centre. Study population CMC admitted at Medical University of Vienna between May 2018 and January 2019. Intervention CMC and caregivers underwent a structured interview at discharge; medication understanding and PH for adverse events were assessed by a hybrid approach. Main outcome measures Medication misunderstanding rate; PH. Results For 106 included children (median age 9.6 years), a median number of 5.0 (IQR 3.0–8.0) different medications were prescribed. 83 CMC (78.3%) demonstrated at least one misunderstanding, in 33 CMC (31.1%), potential harm was detected, 5 of them severe. Misunderstandings were associated with more medications (r=0.24, p=0.013), new prescriptions (r=0.23, p=0.019), quality of medication-related communication (r=−0.21, p=0.032), low level of education (p=0.013), low language skills (p=0.002) and migratory background (p=0.001). Relative risk of PH was 2.27 times increased (95% CI 1.23 to 4.22) with new medications, 2.14 times increased (95% CI 1.10 to 4.17) with migratory background. Conclusion Despite continuous care at a tertiary care centre and high level of subjective satisfaction, high prevalence of medication misunderstanding with relevant risk for PH was discovered in CMC and their caregivers. This demonstrates the need of interventions to improve patient safety, with stratification of medication-related communication for high-risk groups and a restructured discharge process focusing on detection of misunderstandings (‘unknown unknowns’).

Background Despite significant cardiovascular (CV) morbidity in children on dialysis and after kidney transplantation, data on the evolution of CV damage in children with chronic kidney disease (CKD) approaching kidney replacement therapy (KRT) is unknown. Methods The burden, progression, and predictors of CV damage before KRT onset were explored in two prospective multicenter cohorts from Europe and Canada: Cardiovascular Comorbidity in Children with CKD (4C) and Haemodiafiltration, Heart and Height (3H) studies, conducted from 2009-19 and 2013-16, respectively. CV damage and risk factors were evaluated (i) cross sectionally at KRT-start (n = 248), and (ii) longitudinally over the 2-years preceding KRT start (n = 157; 331 patient-visits). Longitudinal analyses with mixed-effects models estimated associations of modifiable CV risk factors with change in carotid intima-media thickness (cIMT) standard deviation score (SDS), pulse wave velocity (PWV-SDS), left ventricular (LV) mass and systolic dysfunction. Findings 248 patients, age 14.3 (12.2, 16.2) years were evaluated at median 35 (28-114) days before KRT start. Elevated cIMT-SDS and PWV-SDS were present in 43% and 25%, and LV hypertrophy and systolic dysfunction in 49% and 33%. Aortic stiffness and LV hypertrophy significantly increased, especially in the year before KRT start (adjusted odds ratio, OR 0.33, P = 0.002 and OR 0.54, P = 0.01, respectively). 79% of children had >3 modifiable CV risk factors at KRT onset. Diastolic BP and BMI were strongly associated with a linear increase in all CV measures. After controlling for CV risk factors, the time to KRT onset no longer predicted the burden of CV damage. Interpretation This comprehensive CV evaluation shows the progressive accrual of modifiable risk factors and a high burden of CV damage in the years preceding KRT onset. CV damage in the pre-KRT period is preventable.

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. 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). 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. 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.

AbstractRationaleTo investigate blood pressure (BP) trajectories, and the impact of pharmacological intervention in children with chronic kidney disease (CKD).MethodsAnalysis of antihypertensive treatment (AHT) and BP slopes in 320 patients of the 4C Study cohort with CKD prior to renal replacement therapy, based on a minimum of three individual observations and two years of follow-up.ResultsAt enrollment, 70 patients (22%) had uncontrolled or untreated hypertension, 130 patients (41%) had controlled hypertension, and 120 patients (37%) had normotension without antihypertensive treatment. AHT medication was prescribed in 53% of patients at baseline and initiated or added in 91 patients (AHT-I, 28%) during follow-up.Overall BP standard deviation score (SDS) remained stable over time in the cohort (ß= -0.037±0.034, p=0.34 and -0.029± 0.348, p=0.093 per year for systolic and diastolic BP SDS). In the AHT-I group, systolic and diastolic BP SDS was higher at baseline and decreased significantly during follow-up (−0.22±0.07, p<.003 and -0.12±0.05 SDS per year, p=0.01). Only 8/70 (11%) patients of the previously untreated/uncontrolled group remained untreated at the last observation, while 31 (44%) were controlled during follow-up. Of the 120 normotensive patients at baseline, 60% remained normotensive while 40% progressed to uncontrolled/untreated (n=23, 19%) or controlled (n=24, 20%) hypertension.ConclusionsThe study provides comprehensive real-world evidence on long-term management of blood pressure in children with CKD from the 4C Study. Although blood pressure control improved significantly with the intensification of antihypertensive therapy, a notable proportion of previously normotensive patients developed de novo hypertension over the observation period.

BACKGROUND:Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions. METHODS:In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. FINDINGS:659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5·6% [95% CI -8·6 to -2·7] vs 1·0% [-1·9 to 3·9], p<0·0001, in ESCAPE; -6·2% [-7·3 to -5·0] vs -1·5% [-2·9 to -0·1], p<0·0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0·27 [95% CI 0·14 to 0·55], p=0·0003, number needed to treat 4·0 [95% CI 3·7 to 4·4] vs 250·0 [66·9 to ∞]) and the need for kidney replacement therapy (HR 0·33 [0·13 to 0·85], p=0·021, number needed to treat 6·7 [6·1 to 7·2] vs 31·0 [27·4 to 35·9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0·0001). INTERPRETATION:Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering. FUNDING:None.

The guidelines for training of patients and caregivers to perform home peritoneal dialysis (PD) uniformly include recommendations pertaining to the prevention of peritonitis. The objective of this study conducted by the International Pediatric Peritoneal Dialysis Network (IPPN) was to investigate the training practices for pediatric PD and to evaluate the impact of these practices on the peritonitis and exit-site infection (ESI) rate. A questionnaire regarding details of the PD program and training practices was distributed to IPPN member centers, while peritonitis and ESI rates were either derived from the IPPN registry or obtained directly from the centers. Poisson univariate and multivariate regression was used to determine the training-related peritonitis and ESI risk factors. Sixty-two of 137 centers responded. Information on peritonitis and ESI rates were available from fifty centers. Training was conducted by a PD nurse in 93.5

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. 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. 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). 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.

Next to the skin, the peritoneum is the largest human organ, essentially involved in abdominal health and disease states, but information on peritoneal paracellular tight junctions and transcellular channels and transporters relative to peritoneal transmembrane transport is scant. We studied their peritoneal localization and quantity by immunohistochemistry and confocal microscopy in health, in chronic kidney disease (CKD) and on peritoneal dialysis (PD), with the latter allowing for functional characterizations, in a total of 93 individuals (0–75 years). Claudin-1 to -5, and -15, zonula occludens-1, occludin and tricellulin, SGLT1, PiT1/SLC20A1 and ENaC were consistently detected in mesothelial and arteriolar endothelial cells, with age dependent differences for mesothelial claudin-1 and arteriolar claudin-2/3. In CKD mesothelial claudin-1 and arteriolar claudin-2 and -3 were more abundant. Peritonea from PD patients exhibited increased mesothelial and arteriolar claudin-1 and mesothelial claudin-2 abundance and reduced mesothelial and arteriolar claudin-3 and arteriolar ENaC. Transperitoneal creatinine and glucose transport correlated with pore forming arteriolar claudin-2 and mesothelial claudin-4/-15, and creatinine transport with mesothelial sodium/phosphate cotransporter PiT1/SLC20A1. In multivariable analysis, claudin-2 independently predicted the peritoneal transport rates. In conclusion, tight junction, transcellular transporter and channel proteins are consistently expressed in peritoneal mesothelial and endothelial cells with minor variations across age groups, specific modifications by CKD and PD and distinct associations with transperitoneal creatinine and glucose transport rates. The latter deserve experimental studies to demonstrate mechanistic links. Clinical Trial registration: The study was performed according to the Declaration of Helsinki and is registered at www.clinicaltrials.gov (NCT01893710).