Gitelman Syndrome Research Articles

Cardiovascular and arrhythmic manifestations of Bartter's and Gitelman's syndromes: do not forget the heart. A narrative literature review.

Bartter's and Gitelman's syndromes (BS/GS) are genetically determined kidney tubulopathies leading to electrolyte and neurohormonal abnormalities. Although considered benign entities, major adverse cardiovascular events may complicate both syndromes, in form of ventricular arrhythmias leading to palpitations, syncope or sudden cardiac death, microvascular cardiac dysfunction and exercise-induced myocardial contractile deficit. The mechanisms leading to cardiovascular complications are not only driven by chronic electrolyte abnormalities, i.e. chronic hypokalemia and hypomagnesemia, but also by neurohormonal alterations that can impair vascular tone and myocardial contractility. In presence of triggering factors, BS/GS patients may experience a spectrum of cardiac arrhythmias necessitating prompt diagnosis and treatment. The aim of this review is to explore the pathophysiological mechanisms of BS and GS, highlighting those responsible for cardiovascular involvement, and to analyze the spectrum of associated cardiovascular complications. This highlights the importance of an integrated shared management of GS/BS patients between Nephrologist and Cardiologist.

Gitelman Syndrome in a 37-Years Old Woman with Urinary Tract Syndrome and History of Caesarean Section: A Case Report

Gitelman Syndrome (GS) is a rare genetic disorder often underdiagnosed due to its non-specific symptoms that can appear from neonatal stages to adulthood. It is more frequently observed in Asians, with a prevalence of approximately 1 in 40,000 people. Accurate diagnosis requires a comprehensive clinical interview and laboratory examinations. This report presents the case of a 37-year-old woman with GS who also experienced a urinary tract infection and had a history of cesarean section. Upon admission, she reported feeling fatigued and weak in all extremities. She had undergone a cesarean section a month prior due to pre-eclampsia. Initial laboratory tests revealed hypokalaemia, hyponatremia, and hypochloraemia. Further evaluation during hospitalization detected a urinary tract infection, hypocalciuria, and hypomagnesemia. The patient also suffered from carpopedal spasms and muscle cramps. Treatment included magnesium sulfate, calcium gluconate, potassium chloride, and sodium chloride infusions to restore electrolyte balance. The patient was discharged after six days, with a diagnosis of Gitelman Syndrome, which was unusual given her late onset of symptoms, as most cases are identified in childhood. The clinical presentation was largely driven by the patient’s electrolyte imbalances, especially hypokalaemia and hypomagnesemia, with hypomagnesemia further contributing to hypocalcemia and vitamin D deficiency. The patient’s symptoms improved after appropriate electrolyte supplementation. This case emphasizes the importance of a detailed clinical history and laboratory assessments in diagnosing GS, along with timely correction of electrolyte disturbances to improve the patient’s condition and prevent complications.

Thyrotoxic periodic paralysis-A retrospective study from southern India.

Thyrotoxic periodic paralysis is a rare manifestation of thyrotoxicosis. Here, we describe the clinical and biochemical features and treatment outcomes of this disorder. This retrospective study was conducted at a tertiary care centre in southern India. The clinical and biochemical features, treatment received, and therapeutic outcomes of all patients with thyrotoxicosis and acute flaccid paralysis without any other identifiable causes (cases for the study) were compared with an equal number of consecutively selected patients who presented with thyrotoxicosis but without features paralysis (controls for the study) during the same period. A total of 41 cases and controls were included in this study. The proportion of males was 92.6 % and 43.9 % among the cases and controls, respectively. The mean age was 32.8 (±7.6) years [cases] and 39.7 (±11.3) years [controls]. Among cases, 20 % of patients presented without clinical thyrotoxic features. Graves' disease was the most common aetiology of thyrotoxicosis in both groups (92.6% of cases and 87.8% of controls). The prevalence of goitre was significantly higher among controls (90.2 %) than among cases (53.7 %). The mean serum potassium, free T4 and Total T3 levels were significantly lower in the cases, than in the controls. Among these cases, two patients had an additional aetiology for persistent hypokalaemia, likely Gitelman's syndrome. This is one of the largest series of thyrotoxic periodic paralysis cases in India. Among subjects with thyrotoxicosis, serum potassium, free T4, and total T3 levels were significantly lower in those with periodic paralysis than in those without.

A Clinical Roadmap to Managing a Patient with Gitelman Syndrome

A Clinical Roadmap to Managing a Patient with Gitelman Syndrome

A Young Woman with Autosomal Dominant Polycystic Kidney Disease and Recurrent Kidney Stones Coexisting with Gitelman Syndrome

A Young Woman with Autosomal Dominant Polycystic Kidney Disease and Recurrent Kidney Stones Coexisting with Gitelman Syndrome

Clinical Overlap and Diagnostic Challenges: Differentiating HNF1B Mutation Disease from Gitelman Syndrome

Clinical Overlap and Diagnostic Challenges: Differentiating HNF1B Mutation Disease from Gitelman Syndrome

A Rare Case of Sjogren Syndrome Associated with Acquired Gitelman Syndrome

A Rare Case of Sjogren Syndrome Associated with Acquired Gitelman Syndrome

Effective Management of Gitelman Syndrome with Amiloride during Pregnancy and Breastfeeding: A Case Report

Effective Management of Gitelman Syndrome with Amiloride during Pregnancy and Breastfeeding: A Case Report

Prevalence of kidney failure in adults diagnosed with hereditary tubulopathies.

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. 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 < 60ml/min/1.73m2. 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. 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.

Paradoxes in magnesium transport in type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis.

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca2+ excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg2+ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca2+ and Mg2+ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg2+ preservation over Ca2+ in Bartter's syndrome and Ca2+ preservation over Mg2+ in Gitelman's syndrome and are stronger in females than in males.

Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

Genotype-phenotype correlations in children with Gitelman syndrome.

This study aimed to analyze genotype-phenotype correlations in children with Gitelman syndrome (GS). This multicenter retrospective study included 50 Korean children diagnosed with SLC12A3 variants in one or both alleles and the typical laboratory findings of GS. Genetic testing was performed using the Sanger sequencing except for one patient. The median age at the diagnosis was 10.5years (interquartile range, 6.8;14.1), and 41 patients were followed up for a median duration of 5.4years (interquartile range, 4.1;9.6). A total of 30 different SLC12A3 variants were identified. Of the patients, 34 (68%) had biallelic variants, and 16 (32%) had monoallelic variants on examination. Among the patients with biallelic variants, those (n=12) with the truncating variants in one or both alleles had lower serum chloride levels (92.2±3.2 vs. 96.5±3.8mMol/L, P=0.002) at onset, as well as lower serum potassium levels (3.0±0.4 vs. 3.4±0.3mMol/L, P=0.016), and lower serum chloride levels (96.1±1.9 vs. 98.3±3.0mMol/L, P=0.049) during follow-up than those without truncating variants (n=22). Patients with monoallelic variants on examination showed similar phenotypes and treatment responsiveness to those with biallelic variants. Patients with GS who had truncating variants in one or both alleles had more severe electrolyte abnormalities than those without truncating variants. Patients with GS who had monoallelic SLC12A3 variants on examination had almost the same phenotypes, response to treatment, and long-term prognosis as those with biallelic variants.

Management of potassium-wasting syndrome in the antepartum, intrapartum and postpartum period.

Potassium-wasting syndromes, including Gitelman or Bartter syndrome, require close medical and biochemical review during pregnancy to reduce potentially severe complications, morbidity and mortality. We report a case of severe potassium-wasting syndrome managed successfully in pregnancy with extremely high oral potassium intake.

Pathophysiological role of Na-Cl cotransporter in kidneys, blood pressure, and metabolism.

The Na-Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na+ reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na+ reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC's novel role in immune and metabolic regulation.

Gitelman Syndrome: Three Cases of a Rare Genetic Disorder in a Tertiary Care Hospital

Gitelman Syndrome: Three Cases of a Rare Genetic Disorder in a Tertiary Care Hospital

#2814 Characterization of cardiological manifestations in patients with sodium-wasting tubulopathies

Abstract Background and Aims Bartter (BS) and Gitelman (GS) syndromes are rare tubulopathies caused by mutations affecting renal NaCl transporters, resulting in similar symptoms like muscle weakness, cramps, and electrolyte imbalances, with GS also presenting with hypomagnesemia. Treatment focuses on electrolyte and fluid balance, using supplements and drugs to inhibit prostaglandin production and RAAS activation. Electrolyte deficits in these conditions can extend the QT interval and increase the risk of potentially fatal cardiac arrhythmias. This study aims to profile BS and GS patients followed at our hospital, focusing on cardiological phenotyping. We assessed diagnostic, clinical, and lab data, particularly examining the link between electrolyte imbalances (like hypokalemia or hypomagnesemia) and electrocardiographic changes or cardiac symptoms during follow-up. Method We screened all BS and GS patients for study inclusion, requiring a genetic diagnosis with disease-causing mutations and comprehensive clinical and electrocardiographic data. We excluded cases lacking sufficient data. We gathered demographic and health information retrospectively, categorizing patients based on electrocardiographic results into groups: 1) persistent long QT interval, 2) transient long QT interval, and 3) no long QT interval. Data were summarized with medians, interquartile ranges, and frequencies. Results A total of 27 patients were enrolled in the study, 16 with Bartter Syndrome (BS) and 11 with Gitelman Syndrome (GS); median length of follow-up was 6 years (range 3-19). Only one patient was classified in group 1, with a constant QTc prolongation (446.3 ms); 8 patients (34.8%) fell into group 2 with median QTc values of 420 ms, all exhibiting hypokalemia and hypomagnesemia. The majority (14/23, 61%) were in group 3, with a median QTc of 399.2 ms and 79% displaying hypokalemia and hypomagnesemia. All 9 patients who experienced cardiac-related symptoms were adults, with 8 presenting these symptoms during intercurrent episodes. The study also compared clinical differences between BS and GS patients, noting a higher frequency of hypokalemia and hypomagnesemia in GS, whereas BS patients had more electrocardiographic alterations, although not statistically significant. No echocardiographic abnormalities were detected from the available data, and there were no recorded incidents of malignant arrhythmias or sudden death. Conclusion Electrocardiographic abnormalities in BS and GS patients fluctuate, often related to episodic events, with QT prolongation in one-third of cases but no severe cardiac complications, indicating a generally positive prognosis.

#2640 Hyperuricemia in Gitelman syndrome 132 patients

Abstract Background and Aims Thiazide diuretics, the most common prescription for hypertension, were partly restricted by the hyperuricemia induced by the impairment of uric acid clearance serum uric acid. Gitelman syndrome (GS, OMIM263800), caused by mutations of the SLC12A3 gene encodes the thiazide-sensitive human Na–Cl co-transporter (hNCC), might shed light on the precision mechanism of hyperuricemia induced by Thiazide diuretics. Method We retrospectively reviewed 132 GS patients and pertinent articles and analyzed their clinical and genetic characteristics with or without hyperuricemia. Our study also employed Illumina Human Asian Screening Array-24 + v1.0 (ASA) gene chips to screen available samples from 87 patients with Gitelman Syndrome, which included a subgroup of 17 individuals exhibiting elevated uric acid levels characteristic of GS. Results The average uric acid level of 132 genetic-confirmed GS patients was 351.4 ± 95.1 µmol/l, with 21.2% hyperuricemia (mean 482.1 µmol/l) and 2 cases of gout. The GS patients with hyperuricemia had higher BMI (24.3 ± 3.9 vs. 21.6 ± 3.5 kg/m2, P = 0.001), lower FEUA (4.6 ± 1.0 vs. 7.0 ± 2.7%, P &amp;lt; 0.001), urinary calcium/creatinine (0.05 vs. 0.11 mmol/mmol, P = 0.01), and△FECl (0.6 ± 0.4% vs 1.2 ± 1.1%, P = 0.02) of the HCT test, indicating more severe NCC function injury. Fisher's exact test yielded non-significant associations of the ten uric acid-predicting SNPs between the patients with or without hyperuricemia at the conventional P-value cut-off of 0.05. Conclusion The prevalence of hyperuricemia in GS patients exceeds that observed in the general population. GS patients with hyperuricemia might be because of a high body mass index (BMI) and more severe impairment of NCC function, which suggested the crosstalk between NCC and Uric acid transporter.

#1012 Lifetime risk of autosomal recessive kidney diseases calculated from genetic databases

Abstract Background and Aims Genetic kidney diseases represent an often rare and clinically diverse group. Their distinct clinical and genetic variations and biases in patient referrals and identification pose challenges in phenotype-based estimated prevalences. This study aimed to determine the calculated lifetime risk of autosomal recessive kidney diseases. Method We conducted a thorough literature review to compile a list of 149 genes linked to these diseases. Disease-causing variants were collected from ClinVar, HGMD, LOVD, and our database and reevaluated according to current guidelines. Minor allele frequencies were obtained from gnomAD and our database. We estimated the lifetime risk of autosomal recessive kidney diseases in a dataset of 12,800 disease-causing variants across 149 disease-associated genes (31 glomerulopathy, 16 tubulopathy, 87 ciliopathy, and 15 CAKUT genes). Results The combined estimated lifetime risk is 10.68 per 100,000 (95% confidence interval 6.29-18.40) based on our data and 22.77 per 100,000 (15.86-33.77) using the European gnomAD dataset. Notably, the three disorders with the highest lifetime risk (≥1.2 per 100,000), collectively accounting for 28% of the overall lifetime risk, were caused by PKHD1 (autosomal recessive polycystic kidney disease), SLC12A3 (Gitelman syndrome), and COL4A3 (Alport syndrome) variants (Fig. 1). Extrapolation to all modes of inheritance, the overall lifetime risk for monogenic kidney disease in adults ranged from 1 in 602 to 1 in 1,283 (Fig. 2). Conclusion This study provides a population-genetic estimate of lifetime risk for autosomal recessive kidney diseases across different populations, addressing underestimated prevalences and diagnostic probabilities. The data, therefore, informs resource allocation for therapy development, public health management, and biomedical research.

Association of X-linked adrenoleukodystrophy with Gitelman syndrome: a hypothesis to be confirmed by genetics

Association of X-linked adrenoleukodystrophy with Gitelman syndrome: a hypothesis to be confirmed by genetics

DCT Transcriptional and Structural Remodeling: Impacts on Magnesium Handling

Loss of activity of the NaCl Cotransporter (NCC) in Gitelman syndrome and with chronic thiazide treatment results in hypomagnesemia but the underlying mechanism remains unresolved. The prevailing hypothesis is that it results indirectly from distal convoluted tubule (DCT) atrophy lowering magnesium (Mg)-reabsorbing capacity by this segment. We tested the hypothesis that NCC inhibition directly disrupts a cellular mechanism related to Mg handling independent of DCT atrophy. We used the NCC-Cre+−/−- INTACT+/- mouse line to allow enrichment of DCT nuclei via Cre-dependent GFP expression in DCT nuclei. Eight- to 10-week-old male mice were given 50 mg/kg/day metolazone (MTZ) orally in food for 4 days; littermate controls receiving only vehicle. After nuclei isolation, GFP+ events (DCT nuclei) were sorted by fluorescence assisted nuclei sorting. Purified DCT nuclei were sequenced using 10X Chromium controller. Reads were then analyzed using a standard transcriptomic bioinformatics pipeline with Seurat. Tubule morphometrics using optical tissue clearing was performed on kidneys from animals receiving the same treatment. MTZ-treated mice had lower plasma Mg compared to controls recapitulating thiazide-induced hypomagnesemia. Our snRNAseq dataset containing 45,953 cells from 3 MTZ-treated and 3 control mice showed clear separation into early DCT (DCT1) and late DCT (DCT2) based on canonical segment markers. Gene expression analysis showed the DCT1 contained a magnesium cassette consisting of known magnesiotropic genes Trpm6, Trpm7, Egf, Umod, Prox1, Fxyd2, Cnnm2, and Slc41a3 so we focused subsequent analyses on DCT1. NCC inhibition caused DCT1 degeneration as indicated by lower mean DCT1 score of DCT1 cells and a greater proportion of DCT1 cells with low differentiation state in the MTZ group. Similarly, MTZ-treated samples had lower DCT1/DCT2 cell proportion in our snRNAseq dataset and morphometrics revelead significantly shorter DCT1 tubules implying that the degeneration process eventually leads to DCT1 atrophy. Using the aggregate expression of the magnesium cassette genes, we computationally defined a Mg score as a surrogate marker for Mg reabsorption capacity for each individual cells. The average Mg score was lower in the MTZ-treated group compared to the controls. Our data supports the long-standing hypothesis that hypomagnesemia is a secondary consequence of the loss of effective surface area for Mg reabsorption. Additionally, we uncovered that even at the single cell level, the Mg handling capacity of the cell decreases as a result of NCC inhibition implying that a disruption in sodium reabsorption disrupts expression of the Mg reabsorption machinery. NIH DK51496, NIH DK054983, NIDDK DK132066, VA 1I01BX002228, LeDucq Foundation, DOST-PCHRD-ASTHRDP. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.