Hypophosphatemia is a genetically heterogeneous disease. Here, we mapped an autosomal recessive form (designated ARHP) to chromosome 4q21 and identified homozygous mutations in DMP1 (dentin matrix protein 1), which encodes a non-collagenous bone matrix protein expressed in osteoblasts and osteocytes. Intact plasma levels of the phosphaturic protein FGF23 were clearly elevated in two of four affected individuals, providing a possible explanation for the phosphaturia and inappropriately normal 1,25(OH)2D levels and suggesting that DMP1 may regulate FGF23 expression.
The health-related quality of life (HRQOL) of adolescents with end-stage renal disease (ESRD) is an important marker of disease burden. Our aims were to investigate HRQOL in a group of children and adolescents with ESRD and to compare them with the reference population norms. Ours was a cross-sectional study of 81 patients aged 10 years to 21 years with ESRD (68 with kidney transplants and 13 on dialysis) at five Spanish paediatric nephrology centres. HRQOL was investigated with the Spanish version of the child health and illness profile, adolescent edition (CHIP-AE). Clinical variables such as underlying diagnosis, number of rejection episodes, pre-emptive transplantation, anaemia and height were also analysed. No differences were found between patients with kidney transplants and their healthy peers in any domain or sub-domain of CHIP-AE. The group on dialysis scored lower than healthy controls and patients with transplants for satisfaction with health. Discomfort was higher in patients with transplants who had suffered one rejection episode. Physical discomfort was increased in anaemic patients with transplants. Short patients scored less in the satisfaction domain, with lower self-esteem and lower satisfaction with health. Adolescents with kidney transplants had better satisfaction with health than the group on dialysis, which matched the level of a healthy population. Further long-term prospective research is warranted.
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsortion in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.
Demonstration of a novel point mutation within the SLC12A3 gene in our cohort of Gypsy families with Gitelman syndrome is highly suggestive of a founder effect. This finding will facilitate the identification of the genetic defect in further cases of Gitelman syndrome among the Gypsy population. Our study represents the largest series ever published of patients with Gitelman syndrome having the same underlying mutation, and supports the lack of correlation between genotype and clinical phenotype in this disease.
The purpose of the study was to determine whether DNA polymorphisms at the renin-angiotensinaldosterone (RAS) genes were associated with evolution to renal scar formation and, consequently, with reflux nephropathy (RN) in patients with vesicoureteral reflux (VUR). Some authors have suggested that the DD genotype of the angiotensin-converting enzyme (ACE) gene would be an adverse renal prognosis factor. We recruited 246 patients (aged 3 months to 22 years) from four Spanish hospitals. These included 69 patients with VUR, 110 with RN (determined by absence/presence of renal scarring on dimercaptosuccinc acid scan), 27 with chronic renal failure due to RN, and 40 patients (control group) with urinary tract infection and normal findings on renal ultrasonography and voiding cystoureterogram.The ACE I/D, angiotensin II type 1 receptor AT1 A1166C, angiotensin II type 2 receptor A3123C AT2, and angiotensinogen AGT M235T polymorphisms were determined on the basis of polymerase chain reaction amplification. ACE serum levels were determined by spectrophotometric methods. We found no statistical differences in the distribution of RAS polymorphisms between the different groups. The ACE D allele was linked to higher ACE serum levels. We found no association between ACE I/D polymorphism and presence of hypertension, proteinuria, grade of VUR, or unilateral/bilateral VUR. Patients with the DD genotype had a lower incidence of febrile urinary tract infection as a first symptom of VUR/RN (P<0.05). We conclude that genetic polymorphisms of RAS components are not independent prognostic indicators of renal scarring in patients with VUR.
Our study is the first to characterize mutations in the CLCN5 gene in Spanish patients with Dent's disease and expands the spectrum of CLCN5 mutations associated with this disease.
Aim: Assessment of final adult height and its predictive factors in children transplanted (RTx) and followed up in a single center. Methods: A cohort of 32 patients (17 boys, 15 girls) who received RTx before the age of 15 years and had reached a final adult height was selected. Twenty patients received a single RTx, 9 patients received two RTx, and 3 patients received three RTx. Seven children were transplanted preemptively, while the remaining 25 children received peritoneal dialysis for relatively short periods of time. In 11 patients, recombinant human growth hormone (rhGH) was administered either before (n = 8) or after (n = 3) RTx. Results: In 13 patiens (41%), the final height standard deviation score for chronological age (hSDS) was –2.3±0.5, below the 95% confidence limits for target height (group A), while in 19 patients (59%), it was –0.7±0.8, within the 95% confidence limits for target height (group B). The hSDS values at the start of dialysis and at the time of first RTx were significantly lower in group A than in group B. A higher hSDS at the start of dialysis and at the time of first RTx had a significant positive influence on the final height (FH), whereas a longer duration of dialysis had a significant negative effect on the FH. Administration of rhGH after RTx played an important role in the achievement of a normal FH in 3 girls. No differences were observed between group A and B with respect to age at start of dialysis, chronological or bone age at first RTx, number of rejection episodes, duration of the study period from last RTx to FH, glomerular filtration rate during this study period, or percentage of time on prednisone therapy. Conclusions: The FH is almost exclusively predetermined by the height achieved at the start of dialysis and at the time of first RTx. Therefore, to reach target adult height after RTx, the best strategy is to shorten the time of dialysis and to start rhGH administration at a young age and as early as possible during the course of chronic renal failure. Administration of rhGH after RTx is also highly effective, but, given its potential danger, still remains a matter of investigation.
There are few data describing the current practices of treatment selection for children with endstage renal disease (ESRD). In an effort to establish a consensus among Spanish pediatric nephrologists for inclusion and exclusion criteria for renal replacement therapy in children with ESRD, in 1995 we surveyed members of the Spanish Pediatric Nephrology Association. Although only 43% of members responded, pediatric nephrologists and bioethicists studied the results and compiled a list of ten guidelines for treatment of children with ESRD. The proposed guidelines are meant to be a starting point for further discussion. An emphasis on flexibility, individual case assessment, and consideration of the best interests of the patient must remain central to any treatment plan. Decision making should ideally be shared by parents, professionals, the child, when appropriate, and ethics committees, as necessary.
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