Bartter's Syndrome Research Articles

Bartter Syndrome in A Nigerian Child with Recurrent Vomiting

Bartter syndrome is a rare renal tubular disease characterized by hypokalemic metabolic alkalosis and renal salt wasting. There is paucity of report of this condition from Africa. We report a case of a four–year–old Nigerian boy who presented with growth failure, recurrent episodes of vomiting, features of severe dehydration and normal blood pressure warranting in–hospital care on several occasions over a period of 16 months. This patient had hypokalemia, hypochloremia, hyponatraemia and hypercalciuria. He also had abdominal x-ray findings of a triangular-shaped calcific density in the right renal bed suggestive of right medullary nephrocalcinosis. Diagnosis of Bartter syndrome was confirmed by elevated plasma renin of 8.1ng/ml/hr (normal 0.5 – 5.9). The patient was managed with intravenous normal saline, potassium chloride infusion, calcium gluconate, and then oral potassium, calcium and magnesium supplements. Follow up at the clinic revealed significant weight gain and stable clinical state. A high index of suspicion is needed for early diagnosis of this rare syndrome, particularly in children presenting with persistent vomiting, failure to thrive and dyselectrolytemia. This, invariably, will improve survival and health-related quality of life of such children, hence the need for this report.

Bartter syndrome type I: a rare cause of polyuria-polydipsia syndrome with failure to thrive in a child

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MO041: Impaired ACE2 glycosylation and protease activity lowers susceptibility to SARS-COV-2 infection in Gitelman/Bartter syndromes

BACKGROUND AND AIMSACE2, part of the counter-regulatory arm of the renin–angiotensin system, serves both as protective toward oxidative stress and cardiovascular remodeling and as a key entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 has two isoforms, non-glycosylated and glycosylated, the latter being accountable for the binding with SARS-CoV-2. After the binding, viruses use proteases as cathepsin-L (Cat-L) to entry the cells. Both ACE2 glycosylation and Cat-L activity are pH-dependent. Gitelman and Bartter syndromes (GS/BS), rare genetic tubulopathies, are characterized by electrolytic alterations, activation of the renin–angiotensin system, yet normo-hypotension, increased levels of ACE2 and metabolic alkalosis with likely increased intracellular pH. We reported that during the first wave of COVID-19 in early 2020 none of our cohort of 128 GS/BS patients from the major hotspots in Northern Italy had been infected or suffered any major COVID-19 symptoms and in a second survey on the same cohort in 2021, we reported only eight positives, four asymptomatic and four with very light symptoms This study aims to investigate potential mechanisms as ACE2 glycosylation and Cat-L activity related to patients’ metabolic alkalosis and viral entry/infection.METHODMononuclear cells ACE2 glycosylation (Western blot) and blood Cat-L activity (ELISA) from 20 GS/BS patients have been compared with those from 15 healthy subjects.RESULTSNon-glycosylated ACE2 was higher in GS/BS (0.82 ± 0.19 d.u. versus 0.67 ± 0.13, P = 0.01); glycosylated ACE2 was not different (0.85 ± 0.28 in GS/BS versus 0.73 ± 0.23, P = 0.19). Cat-L activity was lower in GS/BS (3.90 ± 1.13 r.f.u. versus 5.31 ± 0.8, P <0 0.001) and inversely correlated with blood bicarbonate (HCO3−), while a negative correlation between glycosylated ACE2 and HCO3− approaches statistical significance (P = 0.08).CONCLUSIONGS/BS's metabolic alkalosis, likely by increasing intracellular pH, influences the glycosylation of ACE2 and the activity of Cat-L, providing a mechanistic explanation for the near-complete absence of COVID-19 or its symptoms reported in our cohort. These findings provide a rationale for pursuing the identification and/or synthesis of new drugs that specifically target ACE2 glycosylation and/or proteases involved in SARS-CoV-2 infection.

FC034: Genomic Approach of the Undetermined Kidney Disease

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) is considered as a public health problem. Almost 20%–25% of patients with end-stage kidney disease have been reported with an undetermined kidney disease (UKD) in large national registry. Recent data have shown that the number of monogenic disease-causing variants among patients with CKD is about 20%–30%. Monogenic disease-causing variants are underdiagnosed. We performed whole exome sequencing on patients in our centre with UKD. METHOD All patients gave their written informed consent for genetic testing. Whole exome sequencing by next-generation sequencing was proposed in routine care practice to patient with UKD between January 2019 and December 2021. High and reproducible coverage achieved by our sequencing approach enabled copy-number variation (CNV) analysis. All patients with inconclusive biopsy results were included. Only one patient from the same pedigree was included. We excluded patients with a typical presentation of ADPKD, familial IgA nephropathy, patients with typical presentation of Gitelman or Bartter syndrome or established genetic diagnosis in the family. RESULTS A total of 211 adult patients were included (120 males) with a median age of 48 years (range 37–62 years). Of these, 50 patients were treated with haemodialysis, 34 patients had a kidney transplantation. A total of 156 had self-declared Caucasian. Consanguinity was reported by 12 patients and suspected in 11 patients. Family history of kidney disease was present in 108 patients with both first and second degree affected in 38 patients. Kidney biopsy were inconclusive in 62 patients. Kidney biopsy was impossible in 57 incidents patients with CKD during the study period. A WES was performed first to avoid kidney biopsy in nine patients. A negative genetic testing prior to the WES with gene panel has been performed in 31 patients. We detected 27 monogenic renal disorders in 73 patients with either pathogenic or likely pathogenic variants and 5 copy number variants among 211 patients (37%). The glomerular disease represent the first yielded diagnostic subgroup in which Alport diseases (COL4A3/4/5) represent the dominant diagnostic (COL4A4 n = 18; COL4A3 n = 12; COL4A5 n = 7; TTC21B n = 3; APOL1 = 2; INF2 n = 2; PAX2 n = 2; TRPC6 n = 2; TREX1 n = 1; COQ8B n = 1; NPHS1 n = 1). Tubulointerstitial diseases is the second yielded diagnostic subgroup (UMOD n = 7; NPHP1 n = 2; NPHP3 n = 1; CCL5 n = 1; HNF1B n = 1; CNM4 n = 1; KCNJ1 n = 1). Cystic disease and CAKUT is the third yielded diagnostic subgroup (PKHD1 n = 3; DNAJB11 n = 2; VHL n = 1; PKD1 n = 1; GREB1L n = 1; PBX1 n = 1). In addition, we find two patients with pathogenic complement variation (CFH et C3), one patient with TTR amyloidosis and one patient with familial renal glucosuria (SLC5A2). Six of the nine patients with WES first to avoid renal biopsy, have positive diagnostic (five Alport disease and one APOL1 nephropathy). Interestingly, one of these nine patients had a WES for nephrotic syndrome during type-I diabetes and a dialysis sister with undetermined glomerular disease and consanguineous parents, which detected a known variation in TTC21B gene (P209L) at a heterozygote state that did not explain the nephrotic syndrome. We performed Sanger sequencing for her sister and revealed the same variation at a homozygous state and explain her renal phenotype. Among 57 patients with impossible kidney biopsy, the WES was positive for 18 patients. The diagnostic yield of WES was higher in consanguineous patients (P = 0.04) and familial history of kidney disease (P &amp;lt; 0.0001). The diagnostic yielded reach 60.5% when the patient had family history of renal disease in both first and second degree of the pedigree. CONCLUSION WES identified a molecular diagnosis in almost 40% of patients with UKD in our centre. An exome first may have a high diagnostic yielded and avoid an invasive procedure like kidney biopsy or when it is impossible. WES must be included as a standard of care for patients with UKD.

Thick ascending limb specific inactivation of Myh9and Myh10 results in progressive kidney disease with sexually dimorphic sodium transport regulation

Mutations in MYH9 gene that encodes for actin associated molecular motor nonmuscle myosin II (NM2) result in kidney disease in some patients. Based on our previous work that demonstrated a novel role for NM2 motors, we hypothesized that NM2 genes might play a critical role in renal epithelial transport. To test our hypothesis, we generated pan renal tubular conditional knockout (cKO) of Myh9&amp;10 in adult mice that resulted in progressive kidney disease of TAL origin with aberrant transport of TAL cargoes UMOD and NKCC2 (Otterpohl et al; 2020). To confirm the cell‐autonomous role for NM2 proteins in adult TAL epithelium, we generated a TAL‐specific cKO mouse model of Myh9&amp;10using a TAL specific cre transgenic mice, UMOD‐&gt;CreERT2. Cre transgene was induced at 5 weeks of age with tamoxifen injections, age matched control and cKO littermates were part of every cohort. The mice underwent metabolic, histologic, immunohistochemical, and biochemical analysis at varying time points until moribund. The TAL‐specific Myh9&amp;10 cKO mice develop progressive kidney disease indicated by increase in BUN and serum creatinine as well as increasing levels of the tubular injury marker, NGAL. Our results show that Myh9&amp;10 TAL‐ cKO females had significant loss of weight at 12 weeks, the female cKO animals became moribund between 13 – 14 weeks, while the male cohorts survive up to 25 weeks. Histology confirmed the tubulointerstitial disease in Myh9&amp;10 TAL‐cKO with dilated tubules and cellular infiltration. Urine pH declined starting at 9‐weeks of age in females and 12‐week in males. Interestingly, female cKO mice have hypernatremia at 12‐weeks of age compared to male mice which maintain normal sodium levels. Since the pan renal tubular Myh9&amp;10 cKO exhibited loss of NKCC2 leading to salt wasting, this result was unexpected. We analyzed NKCC2 protein levels in kidney lysates, loss of NKCC2 was evident in both female and male Myh9&amp;10 TAL‐cKO. We also observe significant decline in serum potassium levels in 7.5‐week females. We speculated that the hypernatremia in TAL‐Myh9&amp;10 cKO females is due to tubular adaptation in the distal nephron and the collecting duct. Characterization of sodium cotransporters and channels in distal nephron and collecting duct segment revealed an increase in NCC/pNCC levels in males and a decrease in females. Immunostaining experiments showed increase in ENaC gamma expression in the cortical collecting ducts of the females. This could potentially explain the hypernatremia and early morbidity observed in Myh9&amp;10 TAL‐cKO females. We speculate that females upregulate ENaC gamma to compensate for loss of NKCC2, instead males upregulate NCC/pNCC that prevents their early lethality. These experiments confirm the critical role for Myh9&amp;10 proteins in TAL tubule and identify a novel, sex specific tubular adaptation mechanisms. NM2 motor regulating the unique, TAL‐specific sodium cotransporter is intriguing and warrants further analysis. Our model also provides a good resource for understanding the sex‐specific differences of sodium handling and potentially clarify mechanisms underlying Type I Bartter Syndrome.

Characterization of Hyperactive Mutant forms of the Renal Potassium Channel, ROMK, a Protein Linked to Hypertension

Hypertension affects one billion people worldwide and is the most common risk factor for cardiovascular disease. Despite the high heritability of hypertension, the relative contributions of known and as yet undiscovered genetic factors are not fully defined. However, amongst the regulators of hypertension are salt‐handling transporters in the kidney, one of which is the renal outer medullary K+ (ROMK) channel. Recent data from our labs indicate that unstable mutant forms of ROMK are prone to premature degradation, which give rise to Bartter syndrome Type II, a renal salt‐wasting disease. Intriguingly, heterozygous carriers of these same mutations are protected from hypertension. Therefore, we hypothesized that hyperactive, gain‐of‐function (GOF) mutations in ROMK that increase potassium flux will predispose individuals to hypertension. To test this hypothesis, we expressed ROMK mutants in yeast lacking its endogenous potassium transporters and then screened for potential GOF mutations that improve yeast growth on low K+. By utilizing both an unbiased genetic screen and a candidate‐based approach, we identified six GOF mutations, including one that exists in the NIH TOPMed human database. To assess how these mutations affect protein function and channel activity, we next performed cellular, biochemical, and electrophysiological assays in yeast, Xenopusoocytes, and human HEK293 cells. Data from these assays categorize the mutations into two main groups. In the first group, two mutations promote biosynthesis by stabilizing the proteins in the endoplasmic reticulum, thus promoting tetrameric channel assembly and increasing cell‐surface expression. In contrast, the second group reside in the PIP2‐binding pocket and significantly increase channel currents, yet protein synthesis is unaffected. Ongoing studies will elucidate how mutations in the PIP2 binding site allosterically affect channel function via patch‐clamp studies, and future efforts will be dedicated to developing murine models in which blood pressure regulation can be directly assessed. Ultimately, our findings will bring us one step closer to uncovering the complex genetics of hypertension as well as enhancing our understanding of how ROMK functions at the molecular level. Both efforts will aid in the development of new therapeutic strategies for hypertension.

Rare genetic tubulopathies Gitelman's and Bartter's syndromes and their naturally occurring protection from COVID-19.

Rare genetic tubulopathies Gitelman's and Bartter's syndromes and their naturally occurring protection from COVID-19.

Syndromes of Pseudo-Hyperaldosteronism.

Syndromes of Pseudo-Hyperaldosteronism.

Neonatal Bartter syndrome diagnosed by rapid genomics following low risk pre-conception carrier screening.

Advances in the speed and accessibility of genomic sequencing are broadening the application of this technology to rapid, acute care diagnostics and pre‐conception carrier screening. In both circumstances, genetic counselling plays a critical role in preparing couples for the strengths and limitations of the testing. For pre‐conception carrier screening in particular, it is important that parents and clinicians are aware that even in the absence of an identified risk for recessive disease, a baby with a genetic condition may still be conceived. As an example, we present the genomic journey of a couple who underwent pre‐conception carrier screening and following a low‐risk result, delivered a baby boy who was diagnosed with Type 1 Bartter syndrome. Ultra‐rapid, post‐natal, trio whole genome sequencing resolved both parents as carriers of pathogenic variants in SLC12A1, a gene not included in the original pre‐conception screening panel. This family's story highlights (i) the intricacy of gene selection for pre‐conception screening panels, (ii) the benefits of high‐quality pre‐test genetic counselling in supporting families through adverse genomic findings and (iii) the role rapid genomics can play in resolving uncertainty for families and clinicians in circumstances where suspicion of genetic disease exists. This article is accompanied by a Patient Voice perspective written by the child's parents, placing emphasis on the essential role genetic counselling played in their journey.

Novel SLC12A1 mutations cause Bartter syndrome in two patients with different prognoses

BackgroundBartter syndrome is an inherited renal tubular disorder that is characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Bartter syndrome type 1 is caused by SLC12A1 mutations. MethodsThe patients were from two unrelated non-consanguineous Chinese families. Both patients presented with intrauterine growth retardation, premature delivery, failure to thrive, polyuria and metabolic alkalosis. Whole-exome sequencing was used to identify the causative gene. ResultsExome sequencing identified three novel SLC12A1 mutations in our patients. And we found the two patients had significantly different outcomes when they were two years of age. Moreover, we identified four novel variants of SLC12A1 that were likely to be pathogenic, from our in-house database. A review of the whole-exome sequencing data of patient 1 lead to her brother being genetically diagnosed with pulmonary alveolar microlithiasis, which was caused by compound heterozygous SLC34A2 variations. ConclusionWe reported two children from one family who were affected by different rare conditions. This study expanded the mutation spectra of the SLC12A1 and SLC34A2 genes. We showed the important role of early genetic testing for disease diagnosis and emphasized the importance of standardized treatment and management.

A new missense mutation of calcium sensing receptor with isoleucine replaced by serine at codon 857 leading to type V Bartter syndrome

Several genetic defects on thick ascending limb (TAL) of Henle loop were reported to cause Bartter syndrome (BS) characterized by metabolic alkalosis, hypokalemia, and normal or low blood pressure. Among them, defective basolateral calcium sensing receptors (CaSR) on TAL could result in type V BS that not only presents typical characteristics of BS but also hypocalcemia. Herein we report a 54 years old female patient with a novel mutation of CaSR that leads to type V BS. A sequencing of CaSR gene in peripheral blood mononuclear cells and urine stem cells both disclosed a heterozygous substitution of thymine for guanine (NM_001178065.1:c.2570T > G) in exon 7 at codon 857 resulting in substitution of isoleucine for serine (p.I857S). We performed functional tests of the mutant CaSR gene in vitro using urine stem cells to determine whether this mutation is responsible for the clinical presentations. Urine stem cells expressing abundant CaSR on flow cytometry of this patient and a normal subject were obtained for in vitro functional studies, including intracellular calcium and inositol 1,4,5-trisphosphate concentrations in response to increasing concentrations of extracellular calcium. The results show all of their responses to extracellular calcium are extremely sensitive in urine stem cells of the case as compared to those of the normal subject, indicating a prominent gain-of-function mutation. A novel mutation I857S in transmembrane domain 7 of CaSR in our patient would be added to the list of mutations leading to type V BS.

Different roles of the RAAS affect bone metabolism in patients with primary aldosteronism, Gitelman syndrome and Bartter syndrome

BackgroundComponents of the RAAS may influence bone metabolism. Different roles of the RAAS are found in patients with primary aldosteronism (PA), Gitelman syndrome (GS) and Bartter syndrome (BS). We collected inpatient medical records including 20 patients with Gitelman syndrome (GS group),17 patients with Bartter syndrome (BS group) and 20 age-matched patients with primary aldosteronism (PA group). We found the following results. (1) PA patients had significantly higher serum magnesium, potassium, plasma aldosterone, serum parathyroid hormone, urinary calcium and BMI (p<0.05) while significantly lower serum calcium and phosphorus (P < 0.05) than GS and BS patients. (2) Total hip and femoral neck bone mineral density (BMD) in PA patients were significantly lower than those in GS and BS patients (P<0.05). (3) GS patients had lower serum magnesium and urinary calcium than BS patients (P < 0.05). (4) Compared with BS patients, the vertebral BMD in GS patients were significantly higher (P < 0.05). So we believe higher aldosterone and PTH levels may be the reason that PA patients have lower hip BMD. Lower urinary calcium and inactivation of the NCC gene (Na-Cl cotransporter) in GS patients may have protective effects on vertebral bone mineral density.ConclusionsWith persistence disordered RAAS, PA patients have lower BMD, especially hip BMD as compared with GS and BS patients. We presumed the lower renin and higher aldosterone level may be the reason. With the same level of renin and aldosterone, BS patients have lower vertebrate BMD than GS patients. Decreased urinary calcium excretion may be the reason.

The success of the Cystic Fibrosis Registry of Turkey for improvement of patient care.

Cystic fibrosis (CF) registries play an essential role in improving disease outcomes of people with CF. This study aimed to evaluate the association of newly established CF registry system in Turkey on follow-up, clinical, growth, treatment, and complications of people with this disease. Age at diagnosis, current age, sex, z-scores of weight, height and body mass index (BMI), neonatal screening results, pulmonary function tests, history of meconium ileus, medications, presence of microorganisms, and follow-up were evaluated and compared to data of people with CF represented in both 2017 and 2019 registry data. There were 1170 people with CF in 2017 and 1637 in 2019 CF registry. Eight hundred and fourteen people were registered in both 2017 and 2019 of whom z-scores of heights and BMI were significantly higher in 2019 (p = 0.002,p =0.039, respectively). Inhaled hypertonic saline, bronchodilator, and azithromycin usages were significantly higher in 2019 (p =0.001,p = 0.001,p = 0.003, respectively). The percent predicted of forced expiratory volume in 1 sec and forced vital capacity were similar in 2017 and 2019 (88% and 89.5%,p = 0.248and 84.5% and 87%,p =0.332, respectively). Liver diseases and osteoporosis were significantly higher, and pseudo-Bartter syndrome (PBS) was significantly lower in 2019 (p = 0.011,p = 0.001,p = 0.001,respectively). The z-scores of height and BMI were higher, the use of medications that protect and improve lung functions was higher and incidence of PBS was lower in 2019. It was predicted that registry system increased the care of people with CF regarding their follow-up. The widespread use of national CF registry system across the country may be beneficial for the follow-up of people with CF.

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

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. 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). 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 (7.5pmol/L) and 56% had hyperparathyroidism (PTH>7.0pmol/L).Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42versus 2.49mmol/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. 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.

Синдром Барттера в практиці нефролога (спостереження з практики)

У статті викладено питання патогенезу, клініки та лікування синдрому Барттера на прикладі клінічного випадку.

Gitelman Syndrome in a 32-Years-Old Female Patient

Introduction. Gitelman syndrome is an autosomal recessive disorder that is milder than Bartter syndrome and is often not diagnosed until late childhood or even adulthood. However, this syndrome is usually symptomatic and can result in serious clinical manifestations, such as muscle spasms that can be severe and involve the hands and feet. These symptoms are frequently observed in almost all patients, partly due to hypokalemia and hypomagnesemia.&#x0D; Case presentation. A 32-year-old female patient is being treated in the Internal Medicine ward of Dr. M. Djamil Padang General Hospital with the main complaint of cramping of the left hand, which has gotten worse since 1 day ago. The patient also complained that both legs were prone to cramping that went on and on since 1 month ago. The patient had been hospitalized with the same complaint and is currently taking slow release potassium (KSR) medication. Examination of the patient's limbs revealed a positive trousseau sign and carpopedal spasms. Laboratory examination of the patient showed potassium levels of 1.8 mmol/L, calcium levels of 5.7 mg/dl, Magnesium levels of 0.8 mg/dl, and electrolyte disturbances in the patient's urine. ECG results revealed a prolonged QT interval.&#x0D; Conclusion. Gitelman syndrome is an autosomal recessive disorder and often goes undiagnosed. However, this syndrome is usually symptomatic and can lead to serious clinical manifestations. Most patients require oral potassium and magnesium supplementation, as drug therapy is usually not fully effective.

Comparison of Renal Stones and Nephrocalcinosis in Children: Findings From Two Tertiary Centers in Saudi Arabia.

Background: Renal stones (nephrolithiasis and urolithiasis) and nephrocalcinosis are uncommon in children; however, their incidences in pediatric populations have been increasing.Patients and Methods: This multicenter retrospective study compared the clinical presentation, etiology, and outcomes of childhood nephrolithiasis or urolithiasis with those of nephrocalcinosis.Results: The study included 144 children: 93 with renal stones and 51 with nephrocalcinosis. The mean age at presentation was 72 months and 54 months for children with renal stones and nephrocalcinosis, respectively. A history of consanguinity was found in 65% and 76% of the cases of renal stones and nephrocalcinosis, respectively. Congenital anomalies of the kidneys and urinary tract (CAKUT) were present in 28 and 9.8% of the patients with renal stones and nephrocalcinosis, respectively. The most common symptoms of renal stones were flank pain (29%), hematuria (15%), and dysuria (11%). Urinary tract infection was the primary presentation in the nephrocalcinosis group (18%), followed by failure to thrive (16%), polyuria (12%), and dehydration (12%). The majority of renal stone cases were caused by metabolic disorders, including hyperoxaluria (18%), cystinuria (18%), hypercalciuria (12%), and hyperuricosuria (2%). In contrast, the most common underlying disorders in cases of nephrocalcinosis were familial hypomagnesemia, hypercalciuria, nephrocalcinosis (35%), distal renal tubular acidosis (23%), and Bartter syndrome (6%). Clinical outcomes were significantly better in children with nephrolithiasis/urolithiasis than in those with nephrocalcinosis, who showed radiological evidence of worsening/persistent calcinosis and progressed more frequently to chronic kidney disease (stage II-IV) and end-stage kidney disease.Conclusion: The average age at presentation for children with renal stones was greater than that for those presenting with nephrocalcinosis. More than 25% of the children with renal stones were found to have CAKUT. Nephrocalcinosis was associated with worse clinical outcomes related to kidney function and disease resolution than nephrolithiasis.

Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study

Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College of Medical Genetics 2015 guidelines and pathogenic (P)/likely pathogenic (LP) variants were considered causative. There were 77 index cases (male =73%). Median age at diagnosis was 48 months (IQR 18.5 to 108 months). At recruitment, the number of children in each clinical group was as follows: distal renal tubular acidosis (dRTA) = 25; Bartter syndrome = 18; isolated hypophosphatemic rickets (HP) = 6; proximal tubular dysfunction (pTD) = 12; nephrogenic diabetes insipidus (NDI) = 6; kidney stone/nephrocalcinosis (NC) = 6; others = 4. We detected 55 (24 novel) P/LP variants, providing genetic diagnoses in 54 children (70%). The diagnostic yield of WES was highest for NDI (100%), followed by HP (83%; all X-linked HP), Bartter syndrome (78%), pTD (75%), dRTA (64%), and NC (33%). Molecular testing had a definite impact on clinical management in 24 (31%) children. This included revising clinical diagnosis among 14 children (26% of those with a confirmed genetic diagnosis and 18% of the overall cohort), detection of previously unrecognized co-morbidities among 8 children (sensorineural deafness n = 5, hemolytic anemia n = 2, and dental changes n = 1) and facilitating specific medical treatment for 7 children (primary hyperoxaluria n = 1, cystinosis n = 4, tyrosinemia n = 2). WES is a powerful tool in the diagnosis and management of children with inherited tubulopathies in the Indian population. A higher resolution version of the Graphical abstract is available as Supplementary information.

A Bartter syndrome patient presenting with severe growth retardation: Answers.

A Bartter syndrome patient presenting with severe growth retardation: Answers.

A Bartter syndrome patient presenting with severe growth retardation: Questions.

A Bartter syndrome patient presenting with severe growth retardation: Questions.