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 m
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.
Background
Growth restriction and retarded bone age are common findings in children with chronic kidney disease (CKD). We compared the automated BoneXpert™ method with the manual assessment of an ...X-ray of the non-dominant hand.
Methods
In this retrospective multicenter study, 359 patients with CKD stages 2–5, aged 2–14.5 (girls) or 2.5–17 years (boys) were included. Bone age was determined manually by three experts (according to Greulich and Pyle). Automated determination of bone age was performed using the image analysis software BoneXpert™.
Results
There was a strong correlation between the automatic and the manual method (
r
= 0.983,
p
< 0.001). The automatic method tended to generate higher bone age values (0.64 ± 0.73 years) in the younger patients (4–5 years) and to underestimate retardation or acceleration of bone age. The so-called “bone health index” (BHI) was reduced in comparison to the reference population. Bone health index standard deviation score (BHI-SDS) was not related to the stage of CKD, but weakly negatively correlated with plasma PTH concentrations (
r
= 0.12,
p
= 0.019).
Conclusions
BoneXpert™ allows an objective, time-saving, and in general valid bone age assessment in children with CKD. Possible underestimation of retarded or accelerated bone age should be taken into account. Validation of the BHI needs further study.
Tuberous sclerosis complex (TSC) is a phakomatosis and is a tumor predisposition syndrome. As a genetic multisystem disease, patients present with a broad range of changes in the brain, heart, skin, ...kidneys, and lungs.
Which imaging modalities are required to monitor TSC patients according to current international recommendations?
Common findings in TSC are cortical tubers, subependymal nodules, and giant cell astrocytomas in the central nervous system (CNS), rhabdomyomas in the heart, and cysts and angiomyolipomas in the kidneys. Magnetic resonance imaging (MRI) of the brain and kidneys and abdominal ultrasound are the imaging modalities of choice, due to the very good soft tissue contrast and lack of X‑ray radiation.
Using standard and functional MRI sequences in a multimodal approach, the type, malignancy, size, and morphology of changes in TSC can be reliably determined. Abdominal ultrasound using high-resolution transducers can be used to rapidly and reliably detect even the smallest changes in the kidneys.
Regular follow-up of patients with TSC using MRI and ultrasound is necessary for early detection of complications, for planning individualized therapy, and for optimal lifelong care.
Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS ...are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10−11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10−15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
Acid-base balance and peritoneal membrane longevity are of utmost relevance for pediatric patients undergoing peritoneal dialysis (PD). PD fluids with neutral pH and reduced glucose degradation ...product contents are considered more biocompatible, because they preserve peritoneal cell functions in vitro. To investigate the clinical effects of a novel PD fluid buffered with 34 mM pure bicarbonate at neutral pH, a randomized, prospective, crossover comparison with conventional, acidic, 35 mM lactate PD fluid was performed for two consecutive 12-wk periods with 28 children (age, 6 mo to 15 yr) undergoing automated PD (APD). Blood bicarbonate levels and arterial pH were significantly higher after 3 mo of bicarbonate PD (24.6 +/- 2.3 mM and 7.43 +/- 0.06, respectively), compared with lactate PD (22.8 +/- 3.9 mM and 7.38 +/- 0.05, respectively; P < 0.05). This effect was reversible among patients who returned from bicarbonate to lactate fluid. Low initial pH and young patient age independently predicted increased blood pH during bicarbonate APD. Peritoneal equilibration tests revealed subtle changes in solute transport, with a less steep creatinine equilibration curve during bicarbonate dialysis, suggesting reduced peritoneal vasodilation. The peritoneal release of carcinogen antigen-125 increased twofold during bicarbonate APD (29 +/- 15 versus 15 +/- 8 U/ml per 4 h, P < 0.01), which is consistent with recovery of the mesothelial cell layer. This effect was fully reversed when the patients returned to lactate fluid. Effluent carcinogen antigen-125 levels were inversely correlated with peritoneal glucose exposure during lactate but not bicarbonate APD, indicating improved in vivo mesothelial cell tolerance of high-dose glucose with the neutral-pH PD fluid with reduced glucose degradation product content. Among children undergoing APD, neutral-pH, bicarbonate-buffered PD fluid provides more effective correction of metabolic acidosis and better preservation of peritoneal cell mass than do conventional, acidic, lactate-based fluids.
Background:
A multicenter, randomized, open-label, crossover study was performed to compare the efficacy and safety of sevelamer, a calcium-free phosphate binder, with calcium acetate in pediatric ...patients with chronic kidney disease (CKD).
Methods:
Children (age, 0.9 to 18 years) with CKD undergoing hemodialysis or peritoneal dialysis or with a glomerular filtration rate of 20 or greater and less than 60 mL/min/1.73 m
2 (≥0.33 and <1.00 mL/s/1.73 m
2) were randomly assigned to the following treatment scheme: 2 weeks of washout followed by 8 weeks of treatment with either sevelamer or calcium acetate in a crossover fashion. Phosphorus, calcium, and intact parathyroid hormone in serum were measured every 2 weeks, and phosphate binder dosages were adjusted, if needed. Serum lipid and vitamin concentrations were measured at the beginning and end of each treatment period. The primary end point was the decrease in serum phosphorus levels after 8 weeks of treatment.
Results:
Forty-four patients were screened. Altogether, data for 18 patients (5 girls) aged 12.4 ± 4.1 years were used for the crossover analysis. There was no significant difference in serum phosphorus levels at 8 weeks after the start of treatment in both groups. Total cholesterol (−27%) and low-density lipoprotein cholesterol (−34%) levels decreased significantly with sevelamer treatment (
P < 0.02 and
P < 0.005). An increased incidence of hypercalcemia (
P < 0.0005) was observed with calcium acetate treatment, whereas metabolic acidosis was more frequent with sevelamer treatment (
P < 0.005).
Conclusion:
Treatment of children with CKD with sevelamer and calcium acetate provides similar phosphorus level control. The marked decrease in lipid levels and lower rate of hypercalcemia may augment the long-term benefit of sevelamer.
Background. Adult data suggest that urinary tract infections occur frequently after renal transplantation (RTx) and contribute to mortality and graft loss; data in children are limited. Therefore, we ...evaluated prevalence, short and long-term morbidity and confounding factors of febrile UTI (fUTI) after paediatric RTx. Methods. In a retrospective cross-sectional study of three centres, we analysed data on 110 children followed for 4.9 ± 3.4 years after successful transplantation. Results. 40/110 (36%) patients had at least one fUTI at a median time of 0.98 years (range 0.02–8.96) after RTx; 11 patients (28%) had recurrent fUTI. Serum creatinine (SCr) rose significantly from 1.15 ± 1.13 to 1.83 ± 1.69 mg/dl, (P < 0.001) during the fUTI, declining to baseline values after treatment. At the last followed-up calculated mean, GFR was comparable between fUTI and non-fUTI groups (75 ± 26 vs 71 ± 22 ml/min/1.73 m2). During fUTI mean, C-reactive protein (CRP) increased to 123 ± 75 mg/l. Febrile UTI were significantly more frequent in girls compared to boys (22/44 vs 18/66, P < 0.05) but occurred significantly earlier in boys than in girls median 0.63 (range 0.02–4.15) vs 1.07 (0.04–8.96) years after RTx; P < 0.02. Also, patients with urinary tract malformations (UTMs) and neurogenic bladder as underlying diagnosis and those with urological surgery prior to transplantation had an increased risk for fUTI. Conclusion. fUTI is a frequent complication with significant short-term morbidity especially in girls and children with UTMs, neurogenic bladder and those with urological surgery. Long-term follow-up and prospective studies confirming specific risk factors, preventive measures and impact on graft survival are necessary.
PDF
