Gitelman syndrome is an inherited renal disorder characterized by impaired NaCl reabsorption in the distal convoluted tubule and secondary hypokalemic alkalosis. In clinical practice, it is distinguished from other hypokalemic tubulopathies by the presence of both hypomagnesemia and normocalcemic hypocalciuria. To date, only mutations in a single gene encoding the thiazide-sensitive NaCl cotransporter have been found as the molecular basis of GS. We describe three unrelated patients presenting with the typical laboratory findings of GS. Mutational analysis in these patients revealed no abnormality in the SLC12A3 gene. Instead, all patients were found to carry previously described mutations in the CLCNKB gene, which encodes the kidney-specific chloride channel ClC-Kb, raising the possibility of genetic heterogeneity. Review of the medical histories revealed manifestation of the disease within the first year of life in all cases. Clinical presentation included episodes of dehydration, weakness, and failure to thrive, much more suggestive of classic Bartter syndrome than of GS. The coexistence of hypomagnesemia and hypocalciuria was not present from the beginning. In the follow-up, however, a drop of both parameters below normal range was a consistent finding reflecting a transition from cBS to GS phenotype. The phenotypic overlap may indicate a physiologic cooperation of the apical thiazide-sensitive NaCl cotransporter and the basolateral chloride channel for salt reabsorption in the distal convoluted tubule. Abbreviations GS, Gitelman syndrome cBS, classic Bartter syndrome DCT, distal convoluted tubule NCCT, thiazide-sensitive NaCl cotransporter ClC-Kb, kidney-specific basolateral chloride channel TAL, thick ascending limb of Henle's loop HPS/aBS, hyperprostaglandin E/antenatal Bartter syndrome GS (MIM 263800) is an inherited renal tubular disorder characterized by impaired conservation of potassium and magnesium (1). The mode of inheritance is autosomal-recessive. The first clinical presentation is usually observed during childhood or adolescence and may include transient episodes of weakness, paresthesia, and tetany. The course of disease is generally mild and some patients even remain asymptomatic (2, 3, 4). GS patients share several biochemical findings with the more severe cBS, such as hypokalemia, metabolic alkalosis, and elevated plasma aldosterone levels (5). However, the coexistence of hypomagnesemia and hypocalciuria is considered a pathognomonic laboratory finding in GS that allows the differentiation from cBS (6).Both the observation that the electrolyte disturbances in GS resemble the effect of chronic thiazide administration (7, 8) and the results of clearance studies have pointed to a defect in the distal thiazide-sensitive sodium chloride transport (9). This hypothesis has been substantiated by the demonstration that GS is caused by mutations in the SLC12A3 gene, which encodes the NCCT of the DCT (10). Meanwhile, more than 100 mutations throughout the NCCT have been described in GS patients, sugge...

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC, MIM 248250) is a complex renal tubular disorder characterised by hypomagnesaemia, hypercalciuria, advanced nephrocalcinosis, hyposthenuria and progressive renal failure. The mode of inheritance is autosomal recessive. A primary defect in the reabsorption of magnesium in the medullary thick ascending limb of the loop of Henle (mTAL) has been proposed to be essential in FHHNC pathophysiology. To identify the underlying genetic defect we performed linkage analysis in eight families, including three with consanguineous marriages. We found linkage to microsatellite markers on chromosome 3q27 with a maximum two-point lod score (Z max ) of 5.208 for D3S3530 without evidence for genetic heterogeneity. Haplotype analysis revealed crucial recombination events reducing the critical interval to 6.6 cM. Recently, mutations in the gene PCLN-1, mapping to 3q27 and coding for paracellin-1, were identified by Simon et al (1999) as the underlying genetic defect in FHHNC. Paracellin-1 represents a renal tight junction protein predominantly expressed in the TAL. Mutational analysis in our patient cohort revealed eight different mutations in the PCLN-1 gene, within six novel mutations. In seven of 13 mutant alleles we detected a Leu151 substitution without evidence for a founder effect. Leu151 is a residue of the first extracellular loop of paracellin-1, the part of the protein expected to bridge the intercellular space and to be important for paracellular conductance. This study confirms the implication of paracellin-1 defects in FHHNC and points to a predominant role of this protein in the paracellular reabsorption of divalent cations in the TAL.

GDP are rapidly absorbed from the peritoneal cavity. Administration of PD solutions with low-GDP content reduces plasma AGE levels and may thus improve the cardiovascular risk profile of dialysed children.

Background and objectives: The International Pediatric Peritonitis Registry (IPPR) was established to collect prospective data regarding peritoneal dialysis (PD)-associated peritonitis in children. In this report, we present the IPPR results that pertain to relapsing peritonitis (RP).Design, setting, participants, & measurements: This was an online, prospective entry into the IPPR of data that pertain to peritonitis cases by participating centers.Results: Of 490 episodes of nonfungal peritonitis, 52 (11%) were followed by a relapse. There was no significant difference between RP and non-RP in distribution of causative organisms and antibiotic sensitivities. Initial empiric therapy-ceftazidime with either first-generation cephalosporin or glycopeptide (vancomycin or teicoplanin)-was not associated with relapse. Switching to monotherapy with a first-generation cephalosporin on the basis of culture results was associated with higher relapse rate (23%) than other final antibiotic therapies (0 to 9%). Culture-negative RP was less likely to have a satisfactory early treatment response than non-RP (82 versus 98%). Young age, single-cuff catheter, downward-pointing exit site, and chronic systemic antibiotic prophylaxis were additional independent risk factors for RP in the multivariate analysis. Compared with non-RP, RP was associated with a lower rate of full functional recovery (73 versus 91%), higher ultrafiltration problems (14 versus 2%), and higher rate of permanent PD discontinuation (17 versus 7%).Conclusions: This is the largest multicenter, prospective study to date to examine RP in children. In addition, this is the first report in the literature to examine specifically the relationship of postempiric antibiotic treatment regimens to the subsequent risk for relapse.

In our prospective study, substantial extraction of albumin-bound and water-soluble candidate substances was detected with variable effect on respective blood levels. Notably, essential factors inducing liver regeneration were simultaneously removed. These data provide a basis for evaluation of liver restoration and efficacy of liver support in children with liver failure to devise a collaborative, multicentre trial.