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Background: X-linked hypophosphatemia (XLH) is a rare disorder characterized by elevated levels of fibroblast growth factor 23 (FGF-23), leading to hypophosphatemia and complications in diagnosis due to its clinical heterogeneity. Metabolomic analysis, which examines metabolites as the final products of cellular processes, is a powerful tool for identifying in vivo biochemical changes, serving as biomarkers of pathological abnormalities, and revealing previously uncharted metabolic pathways. Methods: A multicenter cross-sectional case-control study of adult patients diagnosed with XLH was conducted. Serum metabolomic analysis was performed with an Ultra-Performance Liquid Chromatography equipment (UPLC) coupled to a high-resolution mass spectrometer (MS). An analysis of metabolic pathways using MetaboAnalyst version 5.0 and a quantitative enrichment analysis (QEA) was performed. We employed multivariate statistical models, including a principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) regression model. Results: A cohort of 20 XLH patients and 19 control subjects were recruited. A total of 104 metabolites were identified. The differential metabolites identified included glycine, taurine, hypotaurine, phosphoethanolamine, pyruvate, guanidoacetic acid, serine, succinate, 2-aminobutyric acid, glutamine, 2-hydroxyvaleric acid, methionine, ornithine, phosphorylcholine, hypoxanthine, lysine, and N-methylnicotinamide. Enrichment analysis identified disturbances in key metabolic pathways, including phosphatidylethanolamine biosynthesis, sphingolipid metabolism, and phosphatidylcholine biosynthesis. Additionally, pathways related to cysteine metabolism, glycolysis, and pyruvate metabolism. Conclusions: This study identified significant differences in the metabolic profiles of individuals with XLH compared to healthy controls. These findings enhance understanding of potential pathogenic mechanisms and offer a metabolic basis for further in-depth investigations into XLH. [ABSTRACT FROM AUTHOR]

Abstract Background The KCNJ16 gene has been associated with a novel kidney tubulopathy phenotype, viz. disturbed acid–base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistic links between Kir5.1 and tubulopathy, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advanced in vitro human kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the tubulopathy and potential therapeutic interventions. Methods We used CRISPR/Cas9 to generate KCNJ16 mutant (KCNJ16 +/− and KCNJ16 −/−) cell lines from healthy human induced pluripotent stem cells (iPSC) KCNJ16 control (KCNJ16 WT ). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air–liquid interface. Results KCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated that KCNJ16 −/− organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition in KCNJ16 −/− kidney organoids. Conclusions Mature kidney organoids represent a relevant in vitro model for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney.

Background: The KCNJ16 gene has been associated with a novel kidney tubulopathy phenotype, viz. disturbed acid–base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistic links between Kir5.1 and tubulopathy, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advanced in vitro human kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the tubulopathy and potential therapeutic interventions. Methods: We used CRISPR/Cas9 to generate KCNJ16 mutant (KCNJ16+/− and KCNJ16−/−) cell lines from healthy human induced pluripotent stem cells (iPSC) KCNJ16 control (KCNJ16WT). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air–liquid interface. Results: KCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated that KCNJ16−/− organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition in KCNJ16−/− kidney organoids. Conclusions: Mature kidney organoids represent a relevant in vitro model for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney. [ABSTRACT FROM AUTHOR]

Pathogenic variants in TARS2 are associated with combined oxidative phosphorylation deficiency 21 (COXPD21), an autosomal recessive disorder usually presenting as mitochondrial encephalomyopathy. Kidney impairment has been documented in a minority of COXPD21 patients, mostly with distal renal tubular acidosis.

Background: X-linked hypophosphatemia (XLH) is a rare disorder characterized by elevated levels of fibroblast growth factor 23 (FGF-23), leading to hypophosphatemia and complications in diagnosis due to its clinical heterogeneity. Metabolomic analysis, which examines metabolites as the final products of cellular processes, is a powerful tool for identifying in vivo biochemical changes, serving as biomarkers of pathological abnormalities, and revealing previously uncharted metabolic pathways. Methods: A multicenter cross-sectional case-control study of adult patients diagnosed with XLH was conducted. Serum metabolomic analysis was performed with an Ultra-Performance Liquid Chromatography equipment (UPLC) coupled to a high-resolution mass spectrometer (MS). An analysis of metabolic pathways using MetaboAnalyst version 5.0 and a quantitative enrichment analysis (QEA) was performed. We employed multivariate statistical models, including a principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) regression model. Results: A cohort of 20 XLH patients and 19 control subjects were recruited. A total of 104 metabolites were identified. The differential metabolites identified included glycine, taurine, hypotaurine, phosphoethanolamine, pyruvate, guanidoacetic acid, serine, succinate, 2-aminobutyric acid, glutamine, 2-hydroxyvaleric acid, methionine, ornithine, phosphorylcholine, hypoxanthine, lysine, and N-methylnicotinamide. Enrichment analysis identified disturbances in key metabolic pathways, including phosphatidylethanolamine biosynthesis, sphingolipid metabolism, and phosphatidylcholine biosynthesis. Additionally, pathways related to cysteine metabolism, glycolysis, and pyruvate metabolism. Conclusions: This study identified significant differences in the metabolic profiles of individuals with XLH compared to healthy controls. These findings enhance understanding of potential pathogenic mechanisms and offer a metabolic basis for further in-depth investigations into XLH.

X-linked hypophosphatemia (XLH) is a rare genetic disorder that increases fibroblast growth factor 23 (FGF23). XLH patients have an elevated risk of early-onset hypertension. The precise factors contributing to hypertension in XLH patients have yet to be identified. A multicenter cross-sectional study of adult patients diagnosed with XLH. Metabolomic analysis was performed using ultra-performance liquid chromatography (UPLC) coupled to a high-resolution mass spectrometer. Twenty subjects were included, of which nine (45%) had hypertension. The median age was 44 years. Out of the total, seven (35%) subjects had a family history of hypertension. No statistically significant differences were found between both groups for nephrocalcinosis or hyperparathyroidism. Those with hypertension exhibited significantly higher levels of creatinine (1.08 ± 0.31 mg/dL vs. 0.78 ± 0.19 mg/dL; p = 0.01) and LDL-C (133.33 ± 21.92 mg/dL vs. 107.27 ± 20.12 mg/dL, p = 0.01). A total of 106 metabolites were identified. Acetylcarnitine (p = 0.03), pyruvate p = (0.04), ethanolamine (p = 0.03), and butyric acid (p = 0.001) were significantly different between both groups. This study is the first to examine the metabolomics of hypertension in patients with XLH. We have identified significant changes in specific metabolites that shed new light on the potential mechanisms of hypertension in XLH patients. These findings could lead to new studies identifying associated biomarkers and developing new diagnostic approaches for XLH patients. [ABSTRACT FROM AUTHOR]

X-linked proximal tubulopathies are rare diseases that predominantly affect men. Women are generally carriers and clinical or biochemical manifestations are usually absent or mild. We present the case of a young woman who presented with a full phenotype of Dent disease type 1 due to a de novo mutation in the CLCN5 gene and a skewed X-chromosome inactivation. Although cases of overt Dent disease type 2 and Lowe syndrome in women have been described in the literature, to our knowledge this is the first case of overt Dent disease type 1. [ABSTRACT FROM AUTHOR]

Acquired tubulopathies are frequently underdiagnosed. They can be characterized by the renal loss of specific electrolytes or organic solutes, suggesting the location of dysfunction. These tubulopathies phenotypically can resemble Bartter or Gitelman syndrome). These syndromes are infrequent, they may present salt loss resembling the effect of thiazides (Gitelman) or loop diuretics (Bartter). They are characterized by potentially severe hypokalemia, associated with metabolic alkalosis, secondary hyperaldosteronism, and often hypomagnesemia. Tubular dysfunction has been described as nephrotoxic effects of platinum-based chemotherapy. We present 4 cases with biochemical signs of tubular dysfunction (Bartter-like/Gitelman-like phenotype) related to chemotherapy.

Pathogenic variants in TARS2 are associated with combined oxidative phosphorylation deficiency 21 (COXPD21), an autosomal recessive disorder usually presenting as mitochondrial encephalomyopathy. Kidney impairment has been documented in a minority of COXPD21 patients, mostly with distal renal tubular acidosis. We report on the first COXPD21 patient with generalized tubular dysfunction and early childhood progression to chronic kidney disease (CKD). Thorough diagnostic evaluation was initiated at six months of age due to failure to thrive, muscular hypotonia, motor delay and recurrent bronchiolitis. The boy was lost to follow-up until the age of two years, when he was readmitted with elevated creatinine level, reduced estimated glomerular filtrate rate, normochromic anaemia, metabolic acidosis and hyperkalaemia. Urine abnormalities pointed to generalized tubular dysfunction. Two novel heterozygous missense variants in TARS2 gene were detected by the means of whole exome sequencing: c.1298T>G (p.Phe438Cys) of maternal origin and c.1931A>T (p.Asp644Val) of paternal origin. Currently, at 4.5 years of age, the boy has failure to thrive, severe motor and verbal delay and end stage of CKD. We referred the patient to paediatric centre that provides renal replacement therapy. The overall clinical course in the patient we report on corresponds well to the previously reported cases of TARS2 related COXPD21, especially in regard to neurological and developmental aspects of the disease. However, we point out the generalized tubulopathy and early occurrence of CKD in our patient as atypical renal involvement in COXPD21. Additionally, this is the first report of hypothyroidism and hypoparathyroidism in a COXPD21 patient. [ABSTRACT FROM AUTHOR]

Hereditary tyrosinemia type 1 or hepatorenal tyrosinemia is a severe orphan autosomal-recessive disorder of tyrosine metabolism caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH). The disease is diagnosed in approximately 1:100 000-1:120 000 cases of live births, and in certain regions (such as the Chechen Republic in Russian Federation) the estimated frequency of diagnosis can be significantly higher. In hereditary tyrosinemia type 1, blood levels of tyrosine, succinylacetone and other toxic metabolites are increased, which results in the accumulation of the toxic metabolites in target organs causingliver damage with progressive development of liver failure and liver cirrhosis, damage to the renal tubules resulting in Fanconi syndrome and hypophosphatemic rickets, and central nervous system. In some patients, myocardium could be involved in the pathological process, resulting in the development of hypertrophic cardiomyopathy. The disease presents a great challenge for differential diagnosis due to its polyorganic nature and frequent combination with other hereditary disorders. The modern treatment of hereditary tyrosinemia type 1 includes an elimination-based diet and pathogenetic drug therapy. The potential of genetic engineering methods in target therapy of hereditary tyrosinemia type 1 is being actively researched. Within the article if presented a case of early onset hereditary tyrosinemia type 1 in an infant with multiple congenital defects of central nervous system, including Dandy – Walker syndrome, and congenital defects of maxillofacial area, with signs of an immunodeficiency state and a severe generalized recurring infectious process involving poly-resistant mixed flora. The dynamic changes of neurologic signs are provided for the first year of life of the patient receiving the pathogenetic therapy for the main disease. Laboratory findings are provided, showing the dynamic changes in liver function of the patient.

The prevalence of cystinuria as an inborn error of metabolism in dogs is unknown. The purpose of this study was to evaluate the prevalence of cystinuria in dogs of various breeds in the Czech Republic. In total, 326 voided urine samples from client owned dogs were obtained. Samples were divided into four groups according to the breed - Irish Terriers (n = 58), Dachshunds (n = 67), French Bulldogs (n = 64) and a group of various breeds (n = 137). Urinary cystine concentration was measured using liquid chromatography/mass spectrometry, urinary creatinine concentration was determined by Jaffe method. Samples with urinary cystine concentrations above 178 µmol/g creatinine were considered as cystinuric. Urinary cystine concentration above the upper limit was found in 71 dogs (21.8%) with significantly higher incidence in intact males of Irish Terriers. In general, cystinuria was more common in intact males. In Irish Terriers, Dachshunds, French Bulldogs, German Shorthaired Pointer, Pomeranian, and Fox Terrier, cystinuria was identified in females. Cystinuria appears to be a relatively common finding in dogs in the Czech Republic, with some breeds being more affected. The finding of cystinuria in two female Irish Terriers calls into question the classification of cystinuria in this breed as androgen dependent only. The detection of cystinuria in related dogs suggests that other individuals in the same family should be examined as part of the management of a cystinuric patient. [ABSTRACT FROM AUTHOR]

Background Leptospirosis is one of the most important public-health zoonotic diseases in the tropics that can cause severe organ dysfunction and death. Currently there are insufficient data on long-term renal dysfunction in patients after leptospirosis infection. Methods A prospective multicentre cohort study was conducted at 15 hospitals in the Sisaket province of Thailand. Confirmed leptospirosis patients admitted from 1 December 2015 to 30 November 2018 were followed between 1 February 2020 and 31 October 2020 (median 4.1 years after hospital discharge). The primary outcome was a composite of major kidney adverse events (MAKEs) including all-cause mortality, dialysis and new-onset chronic kidney disease (CKD). Results Of the 217 confirmed leptospirosis cases enrolled, 32.7% were classified as having severe leptospirosis. Fifteen cases (6.9%) were deceased at the time of hospital admission. After a median follow-up time of 4.18 years, 30 patients had died and 33 patients developed CKD. Patients with severe leptospirosis had a significantly higher risk of MAKEs {adjusted hazard ratio 2.45 [95% confidence interval (CI) 1.44–4.18]}. Patients with intensive care unit admission, pulmonary haemorrhage and acute kidney injury also had a higher risk of MAKEs and all-cause mortality. Participants with severe leptospirosis in the follow-up cohort showed a higher risk of developing CKD compared with non-severe leptospirosis [adjusted odds ratio 3.22 (95% CI 1.04–9.96)], especially renal magnesium and phosphate wasting. Conclusion Leptospirosis patients, especially severe leptospirosis, are associated with long-term kidney sequelae. Our finding reflects the importance of long-term follow-up and the urgent need for specific interventions. [ABSTRACT FROM AUTHOR]

Bartter Syndrome (BS) is a rare, inherited renal tubulopathy characterised by hypokalaemic, hypochloraemic metabolic alkalosis. Children present with the complaint of polyuria, dehydration, failure to thrive and normal blood pressure despite hyperreninemia and hyperaldosteronism. This is a series of eight children (2 months -1 years of age, 5 males and 3 females children) diagnosed with BS. Mean age of onset was five months with male predominance. Most common presentation was failure to thrive and polyuria. All children showed metabolic alkalosis with hyponatremia, hypokalemia and hypochloremia. Urinary losses of sodium, potassium and chloride were noted in all the eight children. Diagnosis was based on clinical manifestation and electrolyte abnormalities. All children were started on indomethacin and positive response was noted. On follow-up correction of electrolyte abnormalities along with adequate weight gain was seen. Although, it is a rare disease requiring high index of suspicion, but with prompt clinical diagnosis and early treatment, morbidity and mortality can be significantly reduced.

Background Dent's disease type 1 (DD1) is a rare X-linked nephropathy caused by CLCN5 mutations, characterized by proximal tubule dysfunction, including low molecular weight proteinuria (LMWP), hypercalciuria, nephrolithiasis–nephrocalcinosis, progressive chronic kidney disease (CKD) and kidney failure (KF). Current management is symptomatic and does not prevent disease progression. Here we describe the contemporary DD1 picture across Europe to highlight its unmet needs. Methods A physician-based anonymous international e-survey supported by several European nephrology networks/societies was conducted. Questions focused on DD1 clinical features, diagnostic procedure and mutation spectra. Results A total of 207 DD1 male patients were reported; clinical data were available for 163 with confirmed CLCN5 mutations. Proteinuria was the most common manifestation (49.1%). During follow-up, all patients showed LMWP, 66.4% nephrocalcinosis, 44.4% hypercalciuria and 26.4% nephrolithiasis. After 5.5 years, ≈50% of patients presented with renal dysfunction, 20.7% developed CKD stage ≥3 and 11.1% developed KF. At the last visit, hypercalciuria was more frequent in paediatric patients than in adults (73.4% versus 19.0%). Conversely, nephrolithiasis, nephrocalcinosis and renal dysfunction were more prominent in adults. Furthermore, CKD progressed with age. Despite no clear phenotype/genotype correlation, decreased glomerular filtration rate was more frequent in subjects with CLCN5 mutations affecting the pore or CBS domains compared with those with early-stop mutations. Conclusions Results from this large DD1 cohort confirm previous findings and provide new insights regarding age and genotype impact on CKD progression. Our data strongly support that DD1 should be considered in male patients with CKD, nephrocalcinosis/hypercalciuria and non-nephrotic proteinuria and provide additional support for new research opportunities. [ABSTRACT FROM AUTHOR]

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Kidney tubules are responsible for the preservation of fluid, electrolyte and acid-base homeostasis via passive and active mechanisms. These physiological processes can be disrupted by inherited or acquired aetiologies. The net result is a tubulopathy. It is important to make a prompt and accurate diagnosis of tubulopathies in children and young adults. This allows timely and appropriate management, including disease-specific therapies, and avoids complications such as growth failure. Tubulopathies can present with a variety of non-specific clinical features which can be diagnostically challenging. In this review, we build from this common anatomical and physiological understanding to present a tangible appreciation of tubulopathies as they are likely to be clinically encountered among affected children and young adults. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a toxic metal that accumulates in kidneys, especially in the proximal tubular epithelial cells, where virtually all proteins in the glomerular ultrafiltrate are reabsorbed. Here, we analyzed archived data on the estimated glomerular filtration rate (eGFR) and excretion rates of Cd (ECd), total protein (EProt), albumin (Ealb), β2-microglobulin (Eβ2M), and α1-microglobulin (Eα1M), which were recorded for residents of a Cd contamination area and a low-exposure control area of Thailand. Excretion of Cd and all proteins were normalized to creatinine clearance (Ccr) as ECd/Ccr and EProt/Ccr to correct for differences among subjects in the number of surviving nephrons. Low eGFR was defined as eGFR ≤ 60 mL/min/1.73 m2, while proteinuria was indicted by EPro/Ccr ≥ 20 mg/L of filtrate. EProt/Ccr varied directly with ECd/Ccr (β = 0.263, p < 0.001) and age (β = 0.252, p < 0.001). In contrast, eGFR values were inversely associated with ECd/Ccr (β = −0.266, p < 0.001) and age (β = −0.558, p < 0.001). At ECd/Ccr > 8.28 ng/L of filtrate, the prevalence odds ratios for proteinuria and low eGFR were increased 4.6- and 5.1-fold, respectively (p < 0.001 for both parameters). Thus, the eGFR and tubular protein retrieval were both simultaneously diminished by Cd exposure. Of interest, ECd/Ccr was more closely correlated with EProt/Ccr (r = 0.507), Eβ2M (r = 0.430), and Eα1M/Ccr (r = 0.364) than with EAlb/Ccr (r = 0.152). These data suggest that Cd may differentially reduce the ability of tubular epithelial cells to reclaim proteins, resulting in preferential reabsorption of albumin. [ABSTRACT FROM AUTHOR]

Abstract Background Gitelman Syndrome (GS) is a hereditary tubulopathy associated with a biallelic inactivating mutations of the SLC12A3 gene encoding the thiazide-sensitive sodium-chloride cotransporter (NCCT). The typical clinical manifestation is a hypokalemic metabolic alkalosis with significant hypomagnesemia, and low urinary calcium excretion. Hypocalciuria is widely believed to be a hallmark of GS that distinguishes it from Barter’s syndrome, presenting as hypercalciuria. The pathomechanism of hypocalciuria in GS is not fully elucidated. Up to date, a clinical course of GS with normocalciuria has been reported only in men, while women have a milder course of the disease with typical hypocalciuria, which is believed as the result of sex hormone. Additionally, there is a growing evidence that calcium channels of the distal nephron could be regulated by a variety of hormones, including aldosterone (Aldo). Case presentation We present the case of a 28-year-old Caucasian woman with asymptomatic, chronic hypokalemia, hypomagnesemia, hypochloremic alkalosis and normal urinary calcium excretion. A high renin levels with normal concentration of Aldo in serum have also been found. The values of blood pressure were low. Based on genetic studies, two heterozygous mutations in the trans position were confirmed: c.2186G>T (p.Gly729Val) and c.1247G>C (p.Cys416Ser) in the SLC12A3 gene, which ultimately confirmed the diagnosis of GS. Conclusions We report here the first case of genetically confirmed GS manifested as normocalciuria in a Caucasian woman. Thus, our result does not confirm a role of sex hormones on the level of calciuria. Based on the results of normal Aldo concentration despite high renin level in our patient, we hypothesized that Aldo may be connecting with the level of urinary calcium excretion in patients with the GS.

Beta-thalassemia syndromes are the most common inherited monogenic disorders worldwide. The most common pathophysiologic and clinical renal disease manifestations of in β-TM patients is the tubular dysfunctions related to iron overload, chronic anemia, and the need for chronic iron chelation therapy. The aim of this pilot study is to apply an innovative ultrasound and Doppler technique to assess the Renal Functional Reserve (RFR) in β-TM patients, and to evaluate its reliability in iron overload tubulopathy. Ultrasound assessment of intra-parenchymal renal resistive index variation (IRRIV) has recently been proposed as a safe and reproducible technique to identify RFR presence. We define the preserved RFR when the Delta Renal Resistive Index (RRI) is >0.05 (baseline RRI—minimum RRI value during stress) in the Renal Stress Test (RST). Nineteen β-TM patients were enrolled for this study. In our series, we found a strong negative correlation between mean ferritin values and Delta RRI (R = −0.51, p = 0.03). This pilot study suggested the RST as reliable tool for assessing the RFR by ultrasound. Specifically, RST could help in clinical practice suggesting the patient's management and iron chelation therapy. [ABSTRACT FROM AUTHOR]

BackgroundNephrotoxicity is the most frequent serious adverse effect associated with amphotericin B deoxycholate treatment, for this reason, in recent years it has been relegated from routine clinical practice and replaced by the new liposomal formulations that have less nephrotoxicity. Nevertheless, dyselectrolytemia are a frequent adverse effect of the use of liposomal amphotericin B that usually are resolved with the withdrawal of the drug.Case presentationWe present a preterm neonate of 25 weeks gestation, with preserved renal function and most electrolytes within normal limits for gestational age except for mild hyponatremia in the first month of life. Due to an infection of the central nervous system and growth of Candida albicans, he required treatment with endovenous liposomal amphotericin B as well as intrathecal amphotericin B deoxycholate showing severe hydroelectrolyte disturbances and clinical worsening compatible with possible tubulopathy showing hypokalemia and severe hyponatremia a few days after starting treatment that persisted over time even after withdrawal of both drugs. Subsequently to the main alterations described, hypomagnesemia, hypophosphatemia, glycosuria and tubular proteinuria were also observed. Calcium levels remained stable after amphotericin B administration and did not require supplementation. In preterm or low birth weight newborns who present unjustified, severe and difficult to correct hydroelectrolyte disturbances despite the usual treatment, a possible tubulopathy should be considered, whether hereditary, primary or secondary to toxins or drugs.What Is New and ConclusionWe present the first case reported in a neonate in whom dyselectrolithemia has been maintained over time after withdrawal of liposomal amphotericin B.

Kidney tubuloids are cell models that are derived from human or mouse renal epithelial cells and show high similarities with their in vivo counterparts. Tubuloids grow polarized in 3D, allow for long-term expansion, and represent multiple segments of the nephron, as shown by their gene expression pattern. In addition, human tubuloids form tight, functional barriers and have been succesfully used for drug testing. Our knowledge of mouse tubuloids, on the other hand, is only minimal. In this study, we further characterized mouse tubuloids and differentiated them towards the collecting duct, which led to a significant upregulation of collecting duct-specific mRNAs of genes and protein expression, including the water channel AQP2 and the sodium channel ENaC. Differentiation resulted in polarized expression of collecting duct water channels AQP2 and AQP3. Also, a physiological response to desmopressin and forskolin stimulation by translocation of AQP2 to the apical membrane was demonstrated. Furthermore, amiloride-sensitive ENaC-mediated sodium uptake was shown in differentiated tubuloids using radioactive tracer sodium. This study demonstrates that mouse tubuloids can be differentiated towards the collecting duct and exhibit collecting duct-specific function. This illustrates the potential use of mouse kidney tubuloids as novel in vitro models to study (patho)physiology of kidney diseases.

Background: Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. Methods: 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. Results: 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). Conclusion: 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 [ABSTRACT FROM AUTHOR]

Bartter Syndrome (BS) is a rare, inherited renal tubulopathy characterised by hypokalaemic, hypochloraemic metabolic alkalosis. Children present with the complaint of polyuria, dehydration, failure to thrive and normal blood pressure despite hyperreninemia and hyperaldosteronism. This is a series of eight children (2 months -1 years of age, 5 males and 3 females children) diagnosed with BS. Mean age of onset was five months with male predominance. Most common presentation was failure to thrive and polyuria. All children showed metabolic alkalosis with hyponatremia, hypokalemia and hypochloremia. Urinary losses of sodium, potassium and chloride were noted in all the eight children. Diagnosis was based on clinical manifestation and electrolyte abnormalities. All children were started on indomethacin and positive response was noted. On follow-up correction of electrolyte abnormalities along with adequate weight gain was seen. Although, it is a rare disease requiring high index of suspicion, but with prompt clinical diagnosis and early treatment, morbidity and mortality can be significantly reduced. [ABSTRACT FROM AUTHOR]

The review article describes the current data on the etiology, pathogenesis, clinical features, genetic diagnosis, and treatment tactics for hypoaldosteronism in children and adolescents. Phenotypic signs typical for this syndrome are described.

Abstract Background Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients. Patients and methods In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI. Results Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m2 (23.3 to 105 mL/min/1.73 m2). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m2. No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m2 and 37 ± 22 mL/min/1.73 m2. Conclusion CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved.

Objective: To describe the clinical presentation and management of a critically ill dog with profound renal tubular acidosis (RTA) with proximal and distal renal tubular dysfunction. Case Summary: A 3‐year‐old neutered female Border Terrier was presented with frequent regurgitation resulting from acute pancreatitis with severe ileus. Venous acid–base analysis and complete urinalysis confirmed the presence of normal anion gap metabolic acidosis with inappropriately alkaline urine (pH 8), consistent with distal RTA. Urinalysis, urine amino acids, and urinary fractional excretion of electrolytes revealed glycosuria (with normoglycemia), aminoaciduria, and increased fractional excretion of sodium, calcium, and phosphate consistent with generalized proximal renal tubulopathy or Fanconi syndrome. The dog responded well to supportive care and alkaline therapy and made a complete recovery. New or Unique Information Provided: To the authors' knowledge, this is the first description of RTA with proximal and distal renal tubular dysfunction in the veterinary literature. Furthermore, the authors hypothesize that the transient RTA was a manifestation of acute kidney injury secondary to acute pancreatitis, the first report of this in the literature. [ABSTRACT FROM AUTHOR]

La leptospirose est une anthropozoonose dont le tableau clinique est polymorph e et de gravité variable, allant du syndrome pseudo-grippal à l'insuffisance rénale aiguë menaçante. Cette maladie à forte incidence dans les régions tropicales voit son incidence augmenter en France métropolitaine et à la Réunion. L'objectif de cette étude était d'identifier les caractéristiques épidémiologiques, cliniques, biologiques et thérapeutiques des formes pédiatriques de la leptospirose en France métropolitaine et à la Réunion. Nous avons mené une étude de cohorte des cas de leptospirose pédiatriques hospitalisés dans les centres hospitaliers dans lesquels exercent des membres de la Société de néphrologie pédiatrique (SNP) entre janvier 2008 et décembre 2020. Parmi les centres répondeurs, six avaient eu des cas de leptospirose, un centre en avait eu un en consultation mais dont les données étaient insuffisantes, et dix n'en ont pas retrouvés. Vingt-et-un cas ont été recensés dans six centres hospitalo-universitaires français (âge moyen 13,4 ± 3,4 ans), majoritairement des garçons (ratio 6:1). Parmi les 21 enfants, 95 % avaient de la fièvre, 71 % avaient des myalgies, 81 % avaient une thrombopénie et 76 % ont présenté des symptômes digestifs. Sur le plan rénal, 18 patients (86 %) présentaient une insuffisance rénale, dont 19 % avec oligoanurie, mais aucun n'a nécessité de dialyse. Environ 30 % des patients présentaient des signes biologiques de tubulopathie comprenant une hypophosphatémie, une hypokaliémie ou une protéinurie tubulaire. Il n'y a eu aucun décès. La prise en charge thérapeutique correspondait aux recommandations avec une antibiothérapie par amoxicilline ou céphalosporine de 3e génération associée à un traitement symptomatique de l'atteinte rénale. Lorsqu'il y a eu un contrôle biologique après la sortie, on observait une décroissance de la créatinine. Dans cette étude rétrospective multicentrique, nous rapportons 21 cas d'infection par leptospirose, avec une proportion importante d'insuffisance rénale, dont l'évolution était favorable. L'évolution vers l'insuffisance rénale chronique ne semble pas être le cas chez les enfants, mais le suivi à distance n'a pas été systématiquement réalisé. Par rapport à des études menées chez les adultes, le pronostic global est meilleur et l'ictère est plus rare. Par rapport à d'autres études pédiatriques, la conjonctivite n'est pas un signe fréquent, mais les atteintes rénales et la survie sont similaires. On pourrait parler de formes rénales anictériques révélatrices. Le recueil de cas n'était pas exhaustif et ne comprenait pas les autres territoires d'outre-mer alors qu'ils regroupent la plus grande proportion d'infection par la leptospirose. La leptospirose est une infection qui peut être responsable d'une défaillance multiviscérale avec une atteinte rénale conditionnant le pronostic vital. Malgré un meilleur pronostic chez l'enfant, il reste important de diagnostiquer rapidement cette infection afin de mettre en place l'antibiothérapie adaptée et un suivi néphrologique en cas d'atteinte rénale. Leptospirosis is an anthropozoonosis with polymorphic clinical symptoms and a high variability of severity, ranging from flu-like syndrome to severe acute kidney injury. This disease is highly incident in tropical regions but there is a trend towards increasing incidence in metropolitan France and in Reunion Island. The objective of this study was to describe the epidemiological, clinical, laboratory and therapeutic characteristics of the pediatric leptospirosis in metropolitan France and in Reunion Island. We performed a retrospective analysis of leptospirosis cases hospitalized in University hospitals where members of the Paediatric Nephrology Society work in France between January 2008 and December 2020, 6 centers reported leptospirosis cases, one center had one patient in consultation but lack of available data and 10 centers did not find any case. A total of 21 cases were reported (mean age 13.4 ± 3.4 years), mostly boys (ratio 6:1). Out of 21 patients, 95% had fever, 71% were presenting with myalgia, 81% with thrombocytopenia, and 76% with gastrointestinal symptoms. Regarding kidney impairment, 18 patients (86%) had acute kidney injury, including 4 (19%) with oligoanuria, but none of them required acute dialysis. About 30% of patients had biological signs of tubulopathy including hypophosphatemia, hypokalemia, or tubular proteinuria. No death due to the disease occurred. The therapeutic management followed the current guidelines with the use of antibiotic therapy by amoxicillin or 3rd generation cephalosporins with symptomatic treatment. When there was biological control after exit, creatinine decreased. In this multicenter retrospective study, we report 21 children with leptospirosis with a significant proportion of acute kidney injury, the outcome was favorable. Children do not seem to be at high risk of chronic kidney disease progression but nephrology follow-up has not been systematically carried out. Compared to studies performed in adults, the prognosis was better and hepatic impairment was rare. Compared to other pediatric studies, conjunctivitis was not a common symptom but kidney injury and survival appeared to be similar. Children were presenting with anicteric renal presentation. The casebook wasn't exhaustive and didn't include the other overseas territories, which account for the highest proportion of leptospirosis infection. Leptospirosis is an infection which may lead to multivisceral failure with kidney involvement conditioning the outcome. Despite a better prognosis in children, it remains important to quickly diagnose this infection in order to start appropriate antibiotic therapy and perform a kidney function monitoring. [ABSTRACT FROM AUTHOR]

Background: Fanconi syndrome (FS) can be of primary or secondary origin. Some cases of FS secondary to the use of sodium valproate (VPA) have been described, mostly in children with severe psychomotor retardation who are fed by feeding device. The objetive of this study was to describe patients treated for this entity in our center, comparing them against the published literature.Methods: Descriptive study of our patients and those found in the literature. Epidemiologic and clinical data were collected.Results: We describe seven patients (three to 17 years old) with severe psychomotor retardation and undergoing treatment with VPA. Four presented pathologic fractures before the diagnosis of FS, and in three patients the diagnosis was reached due to abnormal laboratory findings. A review of the published cases was carried out and, including our sample, a total of 42 patients were studied: 51.3% were male, and the median age at diagnosis of FS was 6 years. Severe psychomotor retardation was found in 92.8% of patients, 78% carried a feeding device, and 77.5% received treatment with several antiepileptic drugs. The mean duration of VPA treatment was 5.7 years (range 2 to 7.5 years). Fifteen patients (37.5%) had bone complications. The resolution time of FS after discontinuation of drug therapy ranged from two to 19 months (median 4 months).Conclusions: FS related to VPA is a rare complication, but it should be considered in patients with epilepsy, especially if they have severe psychomotor retardation, are users of feeding devices, and receive other antiepileptic treatments in addition to VPA. [ABSTRACT FROM AUTHOR]

Abstract Background Primary adrenal insufficiency (Addison's disease) is a rare medical condition usually associated with hyperkalemia or normokalemia. We report a rare case of Addison's disease, coexisting with hypokalemia, requiring treatment. Case presentation In this case, a 42-year-old man was admitted to the intensive care unit with a history of loss of consciousness and severe hypoglycemia. His blood tests showed metabolic acidosis, low concentrations of cortisol 6 nmol/L (normal 68–327 nmol/L), and high plasma adrenocorticotropic hormone 253 pmol/L (normal 1.6–13.9 pmol/L), and he was diagnosed with primary adrenal insufficiency. Surprisingly, his serum potassium was low, 2.3 mmol/L (normal 3.5–5.1 mmol/L), requiring replacement over the course of his admission. Computed tomography scan of the adrenal glands showed features suggestive of unilateral adrenal tuberculosis. Investigations confirmed renal tubulopathy. The patient responded favorably to cortisol replacement, but never required fludrocortisone. Conclusions Coexistence of hypokalemia with Addison’s disease is unusual. We recommend investigation of the cause of hypokalemia in its own right, if it occurs with primary adrenal insufficiency.

BackgroundInvolving pediatric nephrological input in the clinical diagnostic work-up of children with short stature, gave rise to the hypothesis that the presence of an underlying renal tubular disorder in children with short stature is possibly underestimated. This study focussed on the added value of calculated urinary fractional excretion (FE) in the early detection of tubular disorders in children with growth failure.MethodsThis trial was designed as an observational study analyzing the medical files of children between 5 and 16 years who had been referred for short stature to the pediatric endocrinology outpatient clinic at the University Hospital Antwerp between 25/01/2015 and 01/03/2019. Based on the laboratory results of the simultaneously taken blood and urine sample, the fractional excretions of Sodium, Chloride, Potassium, Calcium, Phosphate, and Magnesium were calculated.ResultsOf the 299 patients, 54 patients had at least one deviating fractional excretion value, requiring further investigation (control sample of blood and urine, kidney ultrasound or 24 h urine collection). Genetic screening for tubulopathies was performed in 19 patients. In 5 patients (1.7% of the total population) a tubulopathy was confirmed based on genetic analysis.ConclusionThis study explored the possibility of using fractional excretions as a screening test to obtain an earlier diagnosis of tubular disorders in children with short stature. Of the 299 patients, 5 patients were diagnosed with a genetically confirmed tubulopathy. Based on these results, we propose a flowchart for an additional work-up in all children with a deviating fractional excretion.

Monogenic causes of paediatric nephrocalcinosis are associated with extensive phenotypic variability. We report a 14-year-old male who presented at 8 years of age with incidentally identified nephrocalcinosis alongside growth impairment and dental anomalies. Extensive genetic investigation confirmed a molecular diagnosis of Bartter syndrome type II. This is exceptional in both late presentation and the presence of amelogenesis imperfecta, a very rare association of inherited tubulopathies. Details of the nephrocalcinosis gene panel analysed and associated phenotypes are presented to highlight the utility of a phenotype-driven genetic panel in resolving an atypical presentation of nephrocalcinosis, allowing precise diagnosis, tailored therapy and prognostication. [ABSTRACT FROM AUTHOR]

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Background and Objective: The registries and guidelines for kidney diseases in children mostly do not include the Asian population and hence, its applicability is questionable. As a first step to address this question, the tubular and inherited disease working group of the Asian Pediatric Nephrology Association aimed to assess the current situation of pediatric tubular and inherited disorders in Asia. Methods: Our group conducted an online survey among the members of AsPNA from September to October 2020. Data collected included demographics, number of patients each physician cares for per year, methods of diagnosis, and access to genetic tests. Descriptive analysis was performed. Results: A total of 299 pediatric nephrologists from 21 countries in Asia participated. Distal renal tubular acidosis, Bartter syndrome, autosomal dominant polycystic kidney disease, autosomal recessive kidney disease, and Alport syndrome were the commonly reported diseases. Around 70% employed clinical history, radiologic imaging, and biochemical tests for diagnosis. More than half (55.4%) of the institutions have access to genetic testing. For future collaborative projects, 88% expressed interest to participate. Conclusions: The results highlight the diversity of disease prevalence, diagnostic practices, capability, and access to genetic tests across Asia. The data gathered from this preliminary survey can be used to address knowledge gaps, and improve management and outcomes. [ABSTRACT FROM AUTHOR]

Glutaric aciduria type I (GA-I, OMIM # 231670) is an autosomal recessive inborn error of metabolism caused by deficiency of the mitochondrial enzyme glutaryl-CoA dehydrogenase (GCDH). The principal clinical manifestation in GA-I patients is striatal injury most often triggered by catabolic stress. Early diagnosis by newborn screening programs improved survival and reduced striatal damage in GA-I patients. However, the clinical phenotype is still evolving in the aging patient population. Evaluation of long-term outcome in GA-I patients recently identified glomerular filtration rate (GFR) decline with increasing age. We recently created the first knock-in rat model for GA-I harboring the mutation p.R411W (c.1231 C>T), corresponding to the most frequent GCDH human mutation p.R402W. In this study, we evaluated the effect of an acute metabolic stress in form of high lysine diet (HLD) on young Gcdh ki/ki rats. We further studied the chronic effect of GCDH deficiency on kidney function in a longitudinal study on a cohort of Gcdh ki/ki rats by repetitive 68Ga-EDTA positron emission tomography (PET) renography, biochemical and histological analyses. In young Gcdh ki/ki rats exposed to HLD, we observed a GFR decline and biochemical signs of a tubulopathy. Histological analyses revealed lipophilic vacuoles, thinning of apical brush border membranes and increased numbers of mitochondria in proximal tubular (PT) cells. HLD also altered OXPHOS activities and proteome in kidneys of Gcdh ki/ki rats. In the longitudinal cohort, we showed a progressive GFR decline in Gcdh ki/ki rats starting at young adult age and a decline of renal clearance. Histopathological analyses in aged Gcdh ki/ki rats revealed tubular dilatation, protein accumulation in PT cells and mononuclear infiltrations. These observations confirm that GA-I leads to acute and chronic renal damage. This raises questions on indication for follow-up on kidney function in GA-I patients and possible therapeutic interventions to avoid renal damage. [ABSTRACT FROM AUTHOR]

There is a growing recognition that children with Lowe syndrome are at risk of nephrocalcinosis and nephrolithiasis from hypercalciuria. Increased fluid intake and correction of metabolic acidosis have remained the focus for intervention but are not always successful. Thiazide diuretics, which reduce urinary calcium excretion, have not been used in these children, due to concerns that (i) they may not work as a result of the underlying tubular abnormalities and (ii) their risk may outweigh the potential benefits they have to offer. Herein we report a child with Lowe syndrome who was successfully treated with thiazides in managing his hypercalciuria.

Background: Proximal renal tubulopathy (PRT) is an infrequent complication of tenofovir disoproxil fumarate (TDF). It remains to be established whether tenofovir alafenamide (TAF) can be safely administered to individuals who experienced PRT on TDF. Methods: Individuals with a history of TDF-associated PRT and current estimated glomerular filtration rate (eGFR) over 30 mL/min/1.73 m² initiated TAF and were followed for 96 weeks. The primary outcome of interest was recurrent PRT. Secondary outcomes were changes in kidney biomarkers, bone biomarkers, and bone mineral density (BMD). Data were analyzed using multilevel mixed-effects linear regression models. The trial was registered under EudraCT 2016-003345-29. Results: All 31 participants [median age 55 (inter-quartile range 51, 60) years, 97% men, 87% White ethnicity] remained on TAF at week 96, and none developed glycosuria or recurrent PRT. Participants experienced small declines in eGFR-creatinine [-1.9 (95% confidence interval: -3.5 to -0.3) mL/min/1.73 m²/yr; P = 0.024], but not in eGFR-cystatin C [-0.9 (-2.1 to 0.4) mL/min/1.73 m²/yr; P = 0.16]. Ten (32%) and 5 (16%) participants experienced rapid (>5 mL/min/1.73 m²/yr) decline in eGFR-creatinine and eGFR-cystatin C. No significant change in other kidney biomarkers, bone turnover, or BMD was observed (P > 0.2). Conclusions: In individuals with a history of PRT on TDF, 96 weeks of TAF was not associated with recurrent PRT or adverse effects on renal tubular function, bone turnover, or BMD. These data suggest that TAF is a treatment option for this vulnerable population. [ABSTRACT FROM AUTHOR]

The clinical recommendations on management of children with Gitelman syndrome developed by the experts of the Union of pediatricians of Russia are presented in this article. Gitelman syndrome is a dysfunction of distal renal tubules with further development of hypomagnesemia, hypocalciuria and secondary aldosteronism which determine hypokalemia and metabolic alkalosis. Features of epidemiology, etiology and pathogenesis, disease progression, differential diagnostics and evidence-based treatment are presented.

The review article considers current data on the etiology, pathogenesis, clinical picture, genetic diagnostics of hyperaldosteronism in children and adolescents. Phenotypic signs characteristic of this syndrome are described. Diagnostic methods and treatment strategies are presented.

Background: Chronic kidney disease (CKD) is one of the main long-term prognosis factors in methylmalonic acidemia (MMA), a rare disease of propionate catabolism. Our objective was to precisely address the clinical and biological characteristics of long-term CKD in MMA adolescent and adult patients.Patients and Methods: In this retrospective study, we included MMA patients older than 13 years who had not received kidney and/or liver transplantation. We explored tubular functions, with special attention to proximal tubular function. We measured glomerular filtration rate (mGFR) by iohexol clearance and compared it to estimated glomerular filtration rate (eGFR) by Schwartz formula and CKD-EPI.Results: Thirteen patients were included (M/F = 5/8). Median age was 24 years (13 to 32). Median mGFR was 57 mL/min/1.73 m2 (23.3 to 105 mL/min/1.73 m2). Ten out of 13 patients had mGFR below 90 mL/min/1.73 m2. No patient had significant glomerular proteinuria. No patient had complete Fanconi syndrome. Only one patient had biological signs suggestive of incomplete proximal tubulopathy. Four out of 13 patients had isolated potassium loss, related to a non-reabsorbable anion effect of urinary methylmalonate. Both Schwartz formula and CKD-EPI significantly overestimated GFR. Bias were respectively 16 ± 15 mL/min/1.73 m2 and 37 ± 22 mL/min/1.73 m2.Conclusion: CKD is a common complication of the MMA. Usual equations overestimate GFR. Therefore, mGFR should be performed to inform therapeutic decisions such as dialysis and/or transplantation. Mild evidence of proximal tubular dysfunction was found in only one patient, suggesting that other mechanisms are involved. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many potentially fatal complications. Renal involvement in various forms is common in addition to serum electrolyte disturbances. Early reports suggest that hypokalaemia may frequent those with SARS-CoV-2 infection and various aetiological factors may cause this electrolyte disturbance. A Chinese retrospective study has demonstrated renal potassium wasting in patients infected with SARS-CoV-2, however, it is not known if these patients were receiving diuretic therapy which may be a contributing factor. This case report illustrates an example of renal potassium wasting in SARS-CoV-2 infection in the absence of diuretics and extra-renal mechanisms with important lessons learned.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with many potentially fatal complications. Renal involvement in various forms is common in addition to serum electrolyte disturbances. Early reports suggest that hypokalaemia may frequent those with SARS-CoV-2 infection and various aetiological factors may cause this electrolyte disturbance. A Chinese retrospective study has demonstrated renal potassium wasting in patients infected with SARS-CoV-2, however, it is not known if these patients were receiving diuretic therapy which may be a contributing factor. This case report illustrates an example of renal potassium wasting in SARS-CoV-2 infection in the absence of diuretics and extra-renal mechanisms with important lessons learned.

Background: Primary adrenal insufficiency (Addison's disease) is a rare medical condition usually associated with hyperkalemia or normokalemia. We report a rare case of Addison's disease, coexisting with hypokalemia, requiring treatment.Case Presentation: In this case, a 42-year-old man was admitted to the intensive care unit with a history of loss of consciousness and severe hypoglycemia. His blood tests showed metabolic acidosis, low concentrations of cortisol 6 nmol/L (normal 68-327 nmol/L), and high plasma adrenocorticotropic hormone 253 pmol/L (normal 1.6-13.9 pmol/L), and he was diagnosed with primary adrenal insufficiency. Surprisingly, his serum potassium was low, 2.3 mmol/L (normal 3.5-5.1 mmol/L), requiring replacement over the course of his admission. Computed tomography scan of the adrenal glands showed features suggestive of unilateral adrenal tuberculosis. Investigations confirmed renal tubulopathy. The patient responded favorably to cortisol replacement, but never required fludrocortisone.Conclusions: Coexistence of hypokalemia with Addison's disease is unusual. We recommend investigation of the cause of hypokalemia in its own right, if it occurs with primary adrenal insufficiency. [ABSTRACT FROM AUTHOR]

Genetic kidney disease is common but often unrecognized. It accounts for most cystic kidney diseases and tubulopathies, many forms of congenital abnormalities of the kidney and urinary tract (CAKUT), and some glomerulopathies. Genetic kidney disease is typically suspected where the disease usually has a genetic basis or there is another affected family member, a young age at onset, or extrarenal involvement, but there are also many exceptions to these "rules". Genetic testing requires the patient's written informed consent. When a patient declines testing, another later conversation may be worthwhile. Genetic testing not only indicates the diagnosis but also the inheritance pattern, likely at-risk family members, disease in other organs, clinical course, and possibly effective treatments. Sometimes genetic testing does not identify a pathogenic variant even where other evidence is strong. A variant of uncertain significance (VUS) may be reported but should not be used for clinical decision making. It may be reclassified after more information becomes available without necessarily retesting the patient. Patients should be provided with a copy of their genetic test report, the results explained, and at-risk family members offered "cascade" testing. A referral to a clinical geneticist or genetic counselor helps identify affected family members and in providing advice to assist with reproductive decisions., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.