Prevalence of kidney failure in adults diagnosed with hereditary tubulopathies.

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 m2. 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.

Low exposition to lithium prevents nephrogenic diabetes insipidus but not microcystic dilations of the collecting ducts in long-term rat model.

Lithium induces nephrogenic diabetes insipidus (NDI) and microcystic chronic kidney disease (CKD). As previous clinical studies suggest that NDI is dose-dependent and CKD is time-dependent, we investigated the effect of low exposition to lithium in a long-term experimental rat model. Rats were fed with a normal diet (control group), with the addition of lithium (Li+ group), or with lithium and amiloride (Li+/Ami group) for 6 months, allowing obtaining low plasma lithium concentrations (0.25 ± 0.06 and 0.43 ± 0.16 mmol/L, respectively). Exposition to low concentrations of plasma lithium levels prevented NDI but not microcystic dilations of kidney tubules, which were identified as collecting ducts (CDs) on immunofluorescent staining. Both hypertrophy, characterized by an increase in the ratio of nuclei per tubular area, and microcystic dilations were observed. The ratio between principal cells and intercalated cells was higher in microcystic than in hypertrophied tubules. There was no correlation between AQP2 messenger RNA levels and cellular remodeling of the CD. Additional amiloride treatment in the Li+/Ami group did not allow consistent morphometric and cellular composition changes compared to the Li+ group. Low exposition to lithium prevented overt NDI but not microcystic dilations of the CD, with differential cellular composition in hypertrophied and microcystic CDs, suggesting different underlying cellular mechanisms.

Claudin-10 Expression and the Gene Expression Pattern of Thick Ascending Limb Cells.

Many genomic, anatomical and functional differences exist between the medullary (MTAL) and the cortical thick ascending limb of the loop of Henle (CTAL), including a higher expression of claudin-10 (CLDN10) in the MTAL than in the CTAL. Therefore, we assessed to what extent the Cldn10 gene expression is a determinant of differential gene expression between MTAL and CTAL. RNAs extracted from CTAL and MTAL microdissected from wild type (WT) and Cldn10 knock out mice (cKO) were analyzed by RNAseq. Differential and enrichment analyses (GSEA) were performed with interactive R Shiny software. Between WT and cKO MTAL, 637 genes were differentially expressed, whereas only 76 were differentially expressed between WT and cKO CTAL. Gene expression patterns and GSEA analyses in all replicates showed that WT MTAL did not cluster with the other replicates; no hierarchical clustering could be found between WT CTAL, cKO CTAL and cKO MTAL. Compared to WT replicates, cKO replicates were enriched in Cldn16, Cldn19, Pth1r, (parathyroid hormone receptor type 1), Casr (calcium sensing receptor) and Vdr (Vitamin D Receptor) mRNA in both the cortex and medulla. Cldn10 is associated with gene expression patterns, including genes specifically involved in divalent cations reabsorption in the TAL.

State of knowledge on ammonia handling by the kidney.

The disposal of ammonia, the main proton buffer in the urine, is important for acid-base homeostasis. Renal ammonia excretion is the predominant contributor to renal net acid excretion, both under basal condition and in response to acidosis. New insights into the mechanisms of renal ammonia production and transport have been gained in the past decades. Ammonia is the only urinary solute known to be produced in the kidney and selectively transported through the different parts of the nephron. Both molecular forms of total ammonia, NH3 and NH4+, are transported by specific proteins. Proximal tubular ammoniagenesis and the activity of these transport processes determine the eventual fate of total ammonia produced and excreted by the kidney. In this review, we summarized the state of the art of ammonia handling by the kidney and highlighted the newest processes described in the last decade.

Vasorin as an actor of bone turnover?

Bone diseases are increasing with aging populations and it is important to identify clues to develop innovative treatments. Vasn, which encodes vasorin (Vasn), a transmembrane protein involved in the pathophysiology of several organs, is expressed during the development in intramembranous and endochondral ossification zones. Here, we studied the impact of Vasn deletion on the osteoblast and osteoclast dialog through a cell Coculture model. In addition, we explored the bone phenotype of Vasn KO mice, either constitutive or tamoxifen-inducible, or with an osteoclast-specific deletion. First, we show that both osteoblasts and osteoclasts express Vasn. Second, we report that, in both KO mouse models but not in osteoclast-targeted KO mice, Vasn deficiency was associated with an osteopenic bone phenotype, due to an imbalance in favor of osteoclastic resorption. Finally, through the Coculture experiments, we identify a dysregulation of the Wnt/ß-catenin pathway together with an increase in RANKL release by osteoblasts, which led to an enhanced osteoclast activity. This study unravels a direct role of Vasn in bone turnover, introducing a new biomarker or potential therapeutic target for bone pathologies.

Fibroblast growth factor 23 but not copeptin is independently associated with kidney failure and mortality in patients with chronic kidney disease.

Background: Copeptin and intact fibroblast growth factor 23 (iFGF23) increase early during chronic kidney disease (CKD) and may be predictive of unfavourable outcomes. The aim of this study was to evaluate their respective associations with renal and vital outcomes in CKD patients. Methods: We included CKD patients from the NephroTest cohort with concomitant measurements of plasma copeptin and iFGF23 concentrations and isotopic glomerular filtration rate measurement (mGFR). The primary endpoint was a composite outcome including kidney failure (KF) (dialysis initiation, pre-emptive transplantation or a 57% decrease of mGFR, corresponding to doubling of serum creatinine) or death before KF. Hazard ratios (HRs) of the primary endpoint associated with log-transformed copeptin and iFGF23 concentrations were estimated by Cox models. The slope of mGFR over time was analysed using a linear mixed model. Results: A total of 329 CKD patients (243 men, mean age 60.3 ± 14.6 years) were included. Among them, 301 with an mGFR >15 ml/min/1.73 m2 were included in survival and mGFR slope analyses. During a median follow-up of 4.61 years (quartile 1-quartile 3: 3.72-6.07), 61 KFs and 32 deaths occurred. Baseline iFGF23 concentrations were associated with the composite outcome after multiple adjustments {HR 2.72 [95% confidence interval (CI) 1.85-3.99]}, whereas copeptin concentrations were not [HR 1.01 (95% CI 0.74-1.39)]. Neither copeptin nor iFGF23 were associated with mGFR slope over time. Conclusion: Our study shows for the first time in population of CKD patients an independent association between iFGF23 and unfavourable renal and vital outcomes and shows no such association regarding copeptin, encouraging the integration of iFGF23 measurement into the follow-up of CKD.

Claudin-19 localizes to the thick ascending limb where its expression is required for junctional claudin-16 localization.

The kidney is critical for mineral homeostasis. Calcium and magnesium reabsorption in the renal thick ascending limb (TAL) involves claudin-16 (CLDN16) and claudin-19 (CLDN19) and pathogenic variants in either gene lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) with severe calcium and magnesium wasting. While both CLDN16 and CLDN19 localize to the TAL, varying expression patterns in the renal tubule have been reported using different antibodies. We, therefore, studied the localization of CLDN19 in the kidneys of wild-type and Cldn19-deleted mice using three anti-CLDN19 antibodies and examined the role of Cldn19 deletion on CLDN16 and CLDN10 localization. We find that CLDN19 localizes to basolateral membrane domains of the medullary and cortical TAL but only to the tight junction of TALs in the outer stripe of outer medulla and cortex, where it colocalizes with CLDN16. Furthermore, in TALs from Cldn19-deleted mice, CLDN16 is expressed in basolateral membrane domains but not at the tight junction. In contrast, Cldn19 ablation does not change CLDN10 localization. These findings directly implicate CLDN19 in regulating permeability in the TAL by allowing junctional insertion of CLDN16 and may explain the shared renal phenotypic characteristics in FHHNC patients.

Comparison of 99mTc-DTPA and 51Cr-EDTA for glomerular filtration rate measurement with the continuous infusion method.

BACKGROUND: In late 2018, the production of 51Chromium-labelled ethylenediamine tetra-acetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for measuring glomerular filtration rate, was halted. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) has been validated for GFR measurement with a single bolus injection, a procedure not suitable in patients with extracellular compartment hyperhydration. In such cases, a bolus followed by continuous infusion of the tracer is required. The aim of this study was to evaluate whether 99mTc-DTPA with the infusion protocol can replace 51Cr-EDTA for GFR measurement. METHODS: We conducted a prospective single centre study during February and March 2019. All patients referred for GFR measurement received both radiotracers simultaneously: 51Cr-EDTA and 99mTc-DTPA bolus and continuous infusion were administered concomitantly through the same intravenous route. Over four and a half hours, plasma and urine samples were collected to calculate urinary and plasma clearance. RESULTS: Twenty-two patients were included (mean age 63.4 ± 17.5 years; 68% men). Mean urinary clearance of 51Cr-EDTA and 99mTc-DTPA was 52.4 ± 22.5 mL/min and 52.8 ± 22.6 mL/min, respectively (p = 0.47), with a mean bias of 0.39 ± 2.50 mL/min, an accuracy within 10% of 100% (95% CI 100; 100) and a Pearson correlation coefficient of 0.994. Mean plasma clearance of 51Cr-EDTA and 99mTc-DTPA was 54.8 ± 20.9 mL/min and 54.4 ± 20.9 mL/min, respectively (p = 0.61), with a mean bias of - 0.43 ± 3.89 mL/min, an accuracy within 10% of 77% (95% CI 59; 91) and a Pearson correlation coefficient of 0.983. CONCLUSIONS: Urinary and plasma clearance of 99mTc-DTPA can be used with the infusion protocol to measure GFR.

Mechanisms of paracellular transport of magnesium in intestinal and renal epithelia.

Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.

Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

Possible role for rare TRPM7 variants in patients with hypomagnesaemia with secondary hypocalcaemia.

BACKGROUND: Hypomagnesaemia with secondary hypocal-caemia (HSH) is a rare autosomal recessive disorder caused by pathogenic variants in TRPM6, encoding the channel-kinase transient receptor potential melastatin type 6. Patients have very low serum magnesium (Mg2+) levels and suffer from muscle cramps and seizures. Despite genetic testing, a subgroup of HSH patients remains without a diagnosis. METHODS: In this study, two families with an HSH phenotype but negative for TRPM6 pathogenic variants were subjected to whole exome sequencing. Using a complementary combination of biochemical and functional analyses in overexpression systems and patient-derived fibroblasts, the effect of the TRPM7-identified variants on Mg2+ transport was examined. RESULTS: For the first time, variants in TRPM7 were identified in two families as a potential cause for hereditary HSH. Patients suffer from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcaemia. In the first family, a splice site variant caused the incorporation of intron 1 sequences into the TRPM7 messenger RNA and generated a premature stop codon. As a consequence, patient-derived fibroblasts exhibit decreased cell growth. In the second family, a heterozygous missense variant in the pore domain resulted in decreased TRPM7 channel activity. CONCLUSIONS: We establish TRPM7 as a prime candidate gene for autosomal dominant hypomagnesaemia and secondary hypocalcaemia. Screening of unresolved patients with hypocalcaemia and secondary hypocalcaemia may further establish TRPM7 pathogenic variants as a novel Mendelian disorder.

Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review.

The approach utilized a systematic review of the medical literature executed with specifically designed criteria that focused on the etiologies and pathogenesis of hypoparathyroidism. Enhanced attention by endocrine surgeons to new knowledge about parathyroid gland viability are reviewed along with the role of intraoperative parathyroid hormone (ioPTH) monitoring during and after neck surgery. Nonsurgical etiologies account for a significant proportion of cases of hypoparathyroidism (~25%), and among them, genetic etiologies are key. Given the pervasive nature of PTH deficiency across multiple organ systems, a detailed review of the skeletal, renal, neuromuscular, and ocular complications is provided. The burden of illness on affected patients and their caregivers contributes to reduced quality of life and social costs for this chronic endocrinopathy. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Impact of claudin-10 deficiency on amelogenesis: Lesson from a HELIX tooth.

In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations.

The importance of kidney calcium handling in the homeostasis of extracellular fluid calcium.

Extracellular fluid calcium concentration must be maintained within a narrow range in order to sustain many biological functions, encompassing muscle contraction, blood coagulation, and bone and tooth mineralization. Blood calcium value is critically dependent on the ability of the renal tubule to reabsorb the adequate amount of filtered calcium. Tubular calcium reabsorption is carried out by various and complex mechanisms in 3 distinct segments: the proximal tubule, the cortical thick ascending limb of the loop of Henle, and the late distal convoluted/connecting tubule. In addition, calcium reabsorption is tightly controlled by many endocrine, paracrine, and autocrine factors, as well as by non-hormonal factors, in order to adapt the tubular handling of calcium to the metabolic requirements. The present review summarizes the current knowledge of the mechanisms and factors involved in calcium handling by the kidney and, ultimately, in extracellular calcium homeostasis. The review also highlights some of our gaps in understanding that need to be addressed in the future.

Hypomagnesemia, Hypocalcemia, and Tubulointerstitial Nephropathy Caused by Claudin-16 Autoantibodies.

BACKGROUND: Chronic hypomagnesemia is commonly due to diarrhea, alcoholism, and drugs. More rarely, it is caused by genetic defects in the effectors of renal magnesium reabsorption. METHODS: In an adult patient with acquired severe hypomagnesemia, hypocalcemia, tubulointerstitial nephropathy, and rapidly progressing kidney injury, similarities between the patient's presentation and features of genetic disorders of renal magnesium transport prompted us to investigate whether the patient had an acquired autoimmune cause of renal magnesium wasting. To determine if the patient's condition might be explained by autoantibodies directed against claudin-16 or claudin-19, transmembrane paracellular proteins involved in renal magnesium absorption, we conducted experiments with claudin knockout mice and transfected mouse kidney cells expressing human claudin-16 or claudin-19. We also examined effects on renal magnesium handling in rats given intravenous injections of IgG purified from sera from the patient or controls. RESULTS: Experiments with the knockout mice and in vitro transfected cells demonstrated that hypomagnesemia in the patient was causally linked to autoantibodies directed against claudin-16, which controls paracellular magnesium reabsorption in the thick ascending limb of Henle's loop. Intravenous injection of IgG purified from the patient's serum induced a marked urinary waste of magnesium in rats. Immunosuppressive treatment combining plasma exchange and rituximab was associated with improvement in the patient's GFR, but hypomagnesemia persisted. The patient was subsequently diagnosed with a renal carcinoma that expressed a high level of claudin-16 mRNA. CONCLUSIONS: Pathogenic claudin-16 autoantibodies represent a novel autoimmune cause of specific renal tubular transport disturbances and tubulointerstitial nephropathy. Screening for autoantibodies targeting claudin-16, and potentially other magnesium transporters or channels in the kidney, may be warranted in patients with acquired unexplained hypomagnesemia.

Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study.

BACKGROUND: Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. METHODS: Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). RESULTS: A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs -0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate-standard deviation score < -2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. CONCLUSIONS: Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

Practice patterns for chronic hypoparathyroidism: data from patients and physicians in France.

Context: Recent guidelines have provided recommendations for the care of patients with chronic hypoparathyroidism. Very little is known about actual physicians' practices or their adherence to such guidelines. Objective: To describe the physicians' practice patterns and their compliance with international guidelines. Design: The cohort studies included were Épi-Hypo (118 physicians and 107 patients, from September 2016 to December 2019) and ePatients (110 patients, November 2019). Methods: Internet-based cohorts involving all settings at a nationwide level (France). Participants were (i) physicians treating patients with chronic hypoparathyroidism and patients with chronic hypoparathyroidism either participating in the (ii) Épi-Hypo study (Épi-Hypo 2019 patients), or (iii) Hypoparathyroidism France, the national representative association (ePatients). Results: The physicians' specialties were mainly endocrinology (61%), nephrology (28%), family medicine (2.5%), pediatrics (2.5%), rheumatology (2%), or miscellaneous (4%) and 45% were practicing in public universities. The median number of pharmaceutical drug classes prescribed was three per patient. The combination of active vitamin D and calcium salt was given to 59 and 58% of ePatients and Épi-Hypo 2019 patients, respectively. Eighty-five percent of ePatients and 87% of physicians reported monitoring plasma calcium concentrations at a steady state at least twice a year. In 32 and 26% of cases, respectively, ePatients and physicians reported being fully in accordance with international guidelines that recommend targeting symptoms, plasma calcium and phosphate values, and urine calcium excretion. Conclusions: The care of patients with chronic hypoparathyroidism involves physicians with very different practices, so guidelines should include and target other specialists as well as endocrinologists. Full adherence to the guidelines is low in France.

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.