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Background: Inherited tubulopathies are rare kidney diseases with few data available in the literature regarding their long-term renal prognosis. This study aimed to evaluate the prevalence of kidney failure in adults with confirmed genetic tubulopathy and to describe the corresponding clinical and genetic findings., Methods: In this observational cohort study, we focused on genetic tubulopathies assumed to impact kidney function. In all adult patients genetically diagnosed in our laboratory between 2001 and 2019, we estimated Glomerular Filtration Rate (eGFR) at diagnosis using the Modification of diet in renal disease (MDRD) formula. Kidney failure was defined as an eGFR < 60 ml/min/1.73 m 2 ., Results: A total of 2145 patients underwent genetic testing, confirming a genetic tubulopathy in 1031 cases (48%). We identified 116 patients out of 885 with available data with kidney failure, mostly diagnosed with Dent disease and distal renal tubular acidosis (respectively, 31% and 20%), followed by familial hypomagnesemia with hypercalciuria and nephrocalcinosis and renal hypophosphatemia/infantile hypercalcemia. Renal prognosis appeared particularly impacted in familial hypomagnesemia with hypercalciuria and nephrocalcinosis and Dent disease, while preserved in Gitelman syndrome., Conclusion: In this cohort, 13% of adults with genetic tubulopathy had kidney failure at diagnosis, with this rate varying greatly according to tubulopathies and suggesting a significant impact on renal prognosis. Even in adults, genetic analyses yield a good diagnostic rate in selected patients, and should be performed as soon as possible, in order to improve the renal management of patients and their relatives., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Aim: Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients., Methods: GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed., Results: A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe., Conclusion: Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester., (© 2020 Asian Pacific Society of Nephrology.)

Background: In the last two decades, progress in cytogenetic and genome research has enabled investigators to unravel the underlying molecular mechanisms of inherited tubulopathies such as Bartter's and Gitelman's syndromes and helped physicians to better understand not only these two pathologic entities but also renal pathophysiology and salt sensitive hypertension., Data Sources: Articles collected from PubMed and open access journals included original articles, research articles, and comprehensive reviews. They were evaluated by the authors with an special emphasis on originality and up to date information about molecular pathophysiology., Results: Bartter's and Gitelman's syndromes are two different inherited salt loosing tubulopathies. They are characterized by various inability of distal nephron to reabsorb sodium chloride with resultant extarcellular volume contraction and increased activity of the renin angiotensin aldosterone system. Hypokalemic metabolic alkalosis is a common feature of these two forms of tubulopathies. Hypercalciuria characterizes the majority of Bartter's syndrome, and hypomagnesemia with hypocalciuria characterizes Gitelman's syndrome. Low blood pressure is a common feature among patients who suffered from these tubulopathies. Bartter's syndromes encompass a heterogeneous group of ion channels defects localized at the thick ascending limp of Henle's loop with resultant loss of function of sodium-potassium-2 chloride cotransporter. These defects result in the impairment of the countercurrent multiplication system of the kidney as well as calcium, potassium and acid base disturbances which in the majority of cases are proved lethal especially in the antenatal and/or immediate postnatal life period. The underlying pathology in Gitelman's syndrome is defined to the distal convoluted tubule and is related to loss of function of the sodium-chloride cotransporter. The results of this defect encompass the inability of extracellular volume homeostasis, magnesium and potassium conservation, and acid base disturbances which are generally mild and in the majority of cases are not life-threatening., Conclusions: Recent advances in molecular pathophysiology of Bartter's and Gitelman's syndromes have helped physicians to better understand the underlying mechanisms of these pathologic entities which remain obscure. Data collected from experiments among genetically manipulated animals enable us to better understand the pathophysiology of mammalian kidney and the underlying mechanisms of salt sensitive hypertension and to lay a foundation for the future development of new drugs, especially diuretics and antihypertensive drugs.

In the last twenty years the knowledge of biochemical, hormonal and molecular abnormalities of Gitelman's syndrome, the most common phenotype of inherited hypokalemic salt losing renal tubular disorders, is increased in the medical community. In parallel with the increasing number of adult population affected by the syndrome and the remarkable improvement of its management, pregnancy have become an important issue for patients affected and their physicians. There are, however, few reports of pregnancies in Gitelman's patients. We review here the cases of pregnancies in Gitelman's patients reported in literature and report three more cases from our cohort of Gitelman's patients, giving particular attention to the materno-fetal outcome and therapeutic approach. The possible influences on pregnancy of Gitelman's patient of other main hemodynamic, hormonal and molecular features of Gitelman's syndrome such as cardiovascular hyporesponsiveness, abnormal vascular tone regulation, upregulation of nitric oxide and Angiotensin 1-7 systems with their possible influence on the reported alteration of cardiac rhythm and function, are also considered.

Primary osteoarthritis (OA) of peripheral joints is a common disease mainly occurring after the age of 50. It is important to distinguish primary from secondary OA. Younger age at disease onset, rapid progression, unusual disease manifestations and co-morbidities are signs of secondary OA. This review outlines an important group of secondary OA. Hereditary metabolic diseases can exhibit joint involvement. For some of these diseases, correct diagnosis is critical, since appropriate therapy influences not only joint function and quality of life, but can also prevent relevant end-organ damage.

Background: Gitelman's syndrome (GS), which is caused by homozygous or compound heterozygous mutations of the thiazide-sensitive sodium chloride cotransporter (NCC), usually manifests in children and is associated with low blood pressure. However, the prevalence of heterozygous NCC mutations and their association with blood pressure in children have not yet been studied., Methods: Five hundred unrelated children from the Taipei Children Heart Study were enrolled. Genomic DNA was isolated from peripheral blood and the SLC12A3 gene was amplified by polymerase chain reaction (PCR). The 15 NCC mutations previously identified in Chinese patients with GS were evaluated using restriction fragment length polymorphism (RFLP) analysis. Blood pressure, biochemistry and urine pH were measured. The allelic frequency of heterozygous NCC mutations and their association with low blood pressure were also investigated., Results: RFLP analysis for the 15 NCC mutations revealed heterozygous T60M in 1 child, T163M in 1, S283Y in 4, R642C in 2, W844X in 2, R928C in 9 and R959frameshift in 10 children. The overall incidence of positive heterozygous NCC mutations was approximately 2.9%. There were no significant differences in systolic or diastolic blood pressure, biochemical profiles or urine pH between children with heterozygous NCC mutations (n = 29) and non-affected controls (n = 471), except for slightly higher fasting plasma glucose concentrations in NCC-heterozygous children (91 +/- 2.3 versus 88 +/- 0.4 mg/dL, P < 0.05). Examination among the different NCC mutations showed that these children also had comparable blood pressures., Conclusions: We found a relatively high prevalence of heterozygous NCC mutations in Chinese children, suggesting that GS may not be rare in this population. Heterozygous NCC mutations were not associated with lower blood pressure in these Chinese children.

Mutations in the thiazide-sensitive Na-Cl cotransporter (SLC12A3) are considered to cause Gitelman's syndrome (GS), an autosomal recessive inherited renal tubular disorder. In the present study, to assess the prevalence of 3 SLC12A3 missense mutations(T180K, L849H, and R919C), involving community-based subjects with hypokalemia, mutation analysis was performed in 1567 subjects in Aomori Prefecture, a northern part of Japan. All subjects were participants in the Iwaki Health Promotion Project. Genotypes of the SLC12A3 mutations were determined by the TaqMan PCR method. Among these 1567 subjects, we detected missense mutations of T180K, L849H, and R919C in 40, 49, and 57 subjects, respectively. One subject had a homozygous (L849H) and heterozygous (R919C) mutation. Two subjects had homozygous mutations (R919C). Five subjects had compound heterozygous mutations: 2 subjects with T180K and R919C, one subject with T180K and R919C, and 2 subjects with L849H and R919C. One hundred and thirty-two subjects had a heterozygous mutation, and 1427 subjects had no mutations. The overall frequency of GS mutations was 8.9%. The mutant allele frequency of T180K, L849H, and R919C was 1.3, 1.6, and 1.9%, respectively. The GS mutant allele frequency of the 1,567 Japanese was more than 4.8%. The present study revealed that the allele frequency of these GS mutations was 4.8% in a Japanese population. In addition, these findings suggest that the allele frequency of GS mutations may be higher than expected, although GS is considered to be a rare disorder.

Background: Inactivating mutations of the SLC12A3 gene are the most common cause of Gitelman's syndrome (GS), a disorder inherited as an autosomal recessive trait. In a minority of cases, GS-like phenotypes are caused by mutations in the CLCNKB gene., Methods: We searched for SLC12A3 and CLCNKB gene mutations in 13 Chinese patients (9 males and 4 females, age 35 +/- 14 years) from 8 unrelated families with the clinical and biochemical features of GS. All coding regions, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis., Results: We identified 10 mutations distributed throughout the SLC12A3 gene. Seven are novel variants, including 4 missense mutations (Gly196Val, Cys430Gly, Gly439Val and Leu571Pro), 2 deletions (1384delG and 346-353delACTGATGG) and 1 in-frame insertion (997insCys). Three mutations were recurrent, including 2 missense mutations (Thr60Met and Asp486Asn) and 1 deletion (2883-2884delAG). The homozygous or heterozygous mutation Thr60Met was found in 8 of 13 patients. There were no mutations detected in the CLCNKB gene., Conclusions: Thr60Met may be the most common mutation in Chinese patients with GS. Possible specific genotype-phenotype correlations were difficult to identify., (Copyright 2008 S. Karger AG, Basel.)