Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife.

A study of 269 children enrolled into a National Registry for children with persistent glomerular hematuria identified 131 individuals with genetically confirmed X-linked Alport Syndrome. A single variant c.1871G>A p.Gly624Asp (G624D) in COL4A5 was predominant and accounted for 39% of X-linked Alport Syndrome in unrelated Polish families (44 of 113). To evaluate its origins, the genetic variation in a 2.79 Mb segment encompassing the COL4A5 locus on chromosome X was assessed. All G624D alleles were found on the same rare haplotype background, indicating a founder effect dating back to the 12-13th century. The phenotypic data of 131 children with X-linked Alport Syndrome and their 195 affected adult relatives revealed that the G624D variant was associated with a significantly milder clinical course in comparison to other pathogenic COL4A5 variants. Furthermore the clinical course of this genetically uniform cohort was milder than that observed in individuals with other COL4A5 missense mutations. In spite of the benign clinical manifestation throughout childhood and early adulthood, the G624D variant confers significant risk for both kidney failure and deafness in males, albeit 20-30 years later than that observed in individuals with other COL4A5 pathogenic variants (50% cumulative risk of starting dialysis at 54 years (95% confidence interval: 50-62) v. 26 years (95% confidence interval: 22-30)). Thus, males with G624D are candidates for existing and emerging therapies for Alport Syndrome.

Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period.

End-stage renal disease requiring renal replacement therapy (RRT) during the neonatal period is a very rare condition, and little information is available regarding long-term RRT and outcomes. To gain more information, we performed a collaborative study on patient characteristics and treatment outcomes in children who started RRT as neonates during their first month of life between 2000 and 2011 who were prospectively registered in the ESPN/ERA-EDTA, the IPPN (since 2007), the Japanese registry, or the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry. During the first month of life, 264 patients from 32 countries started RRT and were followed for a median of 29 months (interquartile range 11-60 months). Most neonates (242) started on peritoneal dialysis, 21 started on hemodialysis, and 1 patient with a transplant. The most important causes of renal failure were congenital anomalies of the kidney and urinary tract in 141, cystic kidneys in 35, and cortical necrosis in 30. Within 2 years after the start of RRT, 69 children changed dialysis modality and 53 received a renal transplant. After a median of 7 months, 45 children had died, mainly because of infection, resulting in an estimated 2-year survival of 81%, and 5-year survival of 76%. Growth retardation (63%), anemia (55%), and hypertension (57%) were still major problems after 2 years. Thus, relatively good medium-term patient survival may be achieved with RRT started during the neonatal period, but specific therapeutic challenges continue to exist in this age group.

Clinical practice recommendations for the care of infants with stage 5 chronic kidney disease (CKD5).

BACKGROUND: To provide recommendations for the care of infants with stage 5 chronic kidney disease (CKD5). SETTING: European Paediatric Dialysis Working Group. DATA SOURCES: Literature on clinical studies involving infants with CKD5 (end stage renal failure) and consensus discussions within the group. RECOMMENDATIONS: There has been an important change in attitudes towards offering RRT (renal replacement therapy) to both newborns and infants as data have accumulated on their improved survival and long-term outcomes. The management of this challenging group of patients differs in a number of ways from that of older children. The authors have summarised the basic recommendations for treating infants with CKD5 in order to support the multidisciplinary teams who endeavour on this difficult task.

Comprehensive Metabolic Signature of Renal Dysplasia in Children. A Multiplatform Metabolomics Concept.

Renal dysplasia is a severe congenital abnormality of the kidney parenchyma, which is an important cause of end-stage renal failure in childhood and early adulthood. The diagnosis of renal dysplasia relies on prenatal or postnatal ultrasounds as children show no specific clinical symptoms before chronic kidney disease develops. Prompt diagnosis is important in terms of early introduction of nephroprotection therapy and improved long-term prognosis. Metabolomics was applied to study children with renal dysplasia to provide insight into the changes in biochemical pathways underlying its pathology and in search of early indicators for facilitated diagnosis. The studied cohort consisted of 72 children, 39 with dysplastic kidneys and 33 healthy controls. All subjects underwent comprehensive urine metabolic profiling with the use of gas chromatography and liquid chromatography coupled to mass spectrometry, with two complementary separation modes of the latter. Univariate and multivariate statistical calculations identified a total of nineteen metabolites, differentiating the compared cohorts, independent of their estimated glomerular filtration rate. Seven acylcarnitines, xanthine, and glutamine were downregulated in the urine of renal dysplasia patients. Conversely, renal dysplasia was associated with higher urinary levels of dimethylguanosine, threonic acid or glyceric acid. This is the first metabolomic study of subjects with renal dysplasia. The authors define a characteristic urine metabolic signature in children with dysplastic kidneys, irrespective of renal function, linking the condition with altered fatty acid oxidation, amino acid and purine metabolisms.

SIX2 and BMP4 mutations associate with anomalous kidney development.

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.

[Biofeedback treatment of giggle incontinence in a teenager]. / Zastosowanie metody biofeedback w leczeniu moczenia wywolanego smiechem.

UNLABELLED: Giggle incontinence is a rare syndrome in which apparently complete voiding occurs specifically during laughing. It needs to be differentiated from stress incontinence and detrusor instability. Reports on the treatment outcome of this disorder are rare. THE AIM OF THE STUDY: To present the effect of biofeedback treatment for giggle incontinence in a 15-year-old girl. A 15-year-old girl is presented with isolated symptoms of giggle incontinence from early childhood with 1-2 episodes per week of complete bladder emptying during laughter. She demonstrated no symptoms of detrusor hyperactivity or stress incontinence. Her urodynamic studies were normal. The child started pelvic floor muscle exercises using biofeedback according to the pediatric protocol of an UROSTYM device. Five hourly sessions were performed to teach the child control of her external urinary sphincter muscles. This was followed by daily home exercises and weekly biofeedback sessions. Improvement was immediate and during 2 months follow-up no incidents of giggle incontinence were observed. CONCLUSIONS: (1) Biofeedback can be used in children with giggle incontinence to strengthen their pelvic floor muscles and allow them to remain continent during an uncontrolled detrusor contraction provoked by laughing. (2) Biofeedback enables children to visualize the pelvic floor muscles during exercises helping them to attain better control of their function. (3) Pelvic muscle exercises with biofeedback technique are a promising additional mode of treatment for children with voiding disorders.

Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study.

Renal hypodysplasia (RHD) is characterized by a reduced nephron number, small kidney size, and disorganized renal tissue. A hereditary basis has been established for a subset of affected patients, suggesting a major role of developmental genes that are involved in early kidney organogenesis. Gene mutations that have dominant inheritance and cause RHD, urinary tract anomalies, and defined extrarenal symptoms have been identified in TCF2 (renal cysts and diabetes syndrome), PAX2 (renal-coloboma syndrome), EYA1 and SIX1 (branchio-oto-renal syndrome), and SALL1 (Townes-Brocks syndrome). For estimation of the prevalence of these events, an unselected cohort of 99 unrelated patients with RHD that was associated with chronic renal insufficiency were screened for mutations in TCF2, PAX2, EYA1, SIX1, and SALL1. Mutations or variants in the genes of interest were detected in 17 (17%) unrelated families: One mutation, two variants, and four deletions of TCF2 in eight unrelated patients; four different PAX2 mutations in six families; one EYA1 mutation and one deletion in two patients with branchio-oto-renal syndrome; and one SALL1 mutation in a patient with isolated RHD. Of a total of 27 patients with renal cysts, six (22%) carried a mutation in TCF2. It is interesting that a SIX1 sequence variant was identified in two siblings with renal-coloboma syndrome as a result of a PAX2 mutation, suggesting an oligogenic inheritance. Careful clinical reevaluation that focused on discrete extrarenal symptoms and thorough family analysis revealed syndrome-specific features in nine of the 17 patients. In conclusion, 15% of patients with RHD show mutations in TCF2 or PAX2, whereas abnormalities in EYA1, SALL1, and SIX1 are less frequent.