Hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a complex disorder in need of precision medicine.

Hereditary hypophosphatemic rickets with hypercalciuria is an autosomal recessive phosphate-wasting disorder, associated with kidney and skeletal pathologies, which is caused by pathogenic variants of SLC34A3. In this issue, Zhu et al. describe a pooled analysis of 304 individuals carrying SLC34A3 variants. Their study underscores the complexity of hereditary hypophosphatemic rickets with hypercalciuria, as kidney and bone phenotypes generally do not coexist, heterozygous carriers of SLC34A3 variants also can be affected, and the response to oral phosphate supplementation is dependent on the genetic status.

Family analysis and literature study of hereditary hypophosphatemic rickets with hypercalciuria.

BACKGROUND: Hereditary hypophosphatemia rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterised by reduced renal phosphate reabsorption leading to hypophosphataemia, rickets and bone pain. Here, we present a case of HHRH in a Chinese boy. CASE PRESENTATION: We report a 11-year-old female proband, who was admitted to our hospital with bilateral genuvarum deformity and short stature. Computed Tomography (CT) showed kidney stones, blood tests showed hypophosphatemia, For a clear diagnosis, we employed high-throughput sequencing technology to screen for variants. Our gene sequencing approach encompassed whole exome sequencing, detection of exon and intron junction regions, and examination of a 20 bp region of adjacent introns. Flanking sequences are defined as ±50 bp upstream and downstream of the 5' and 3' ends of the coding region.The raw sequence data were compared to the known gene sequence data in publicly available sequence data bases using Burrows-Wheeler Aligner software (BWA, 0.7.12-r1039), and the pathogenic variant sites were annotated using Annovar. Subsequently, the suspected pathogenic variants were classified according to ACMG's gene variation classification system. Simultaneously, unreported or clinically ambiguous pathogenic variants were predicted and annotated based on population databases. Any suspected pathogenic variants identified through this analysis were then validated using Sanger sequencing technology. At last, the proband and her affected sister carried pathogenic homozygous variant in the geneSLC34A3(exon 13, c.1402C > T; p.R468W). Their parents were both heterozygous carriers of the variant. Genetic testing revealed that the patient has anLRP5(exon 18, c.3917C > T; p.A1306V) variant of Uncertain significance, which is a rare homozygous variant. CONCLUSION: This case report aims to raise awareness of the presenting characteristics of HHRH. The paper describes a unique case involving variants in both theSLC34A3andLRP5genes, which are inherited in an autosomal recessive manner. This combination of gene variants has not been previously reported in the literature. It is uncertain whether the presence of these two mutated genes in the same individual will result in more severe clinical symptoms. This report shows that an accurate diagnosis is critical, and with early diagnosis and correct treatment, patients will have a better prognosis.

An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

A previously healthy 3-year-old female with hypertension, proteinuria, and hypercalciuria.

A 3-year-old female patient with no significant medical history presented to her pediatrician with foamy urine. Initial testing revealed moderate proteinuria on qualitative testing, although she was incidentally noted to have severe hypertension (240/200 mmHg). Physical examination of the carotid and femoral areas revealed significant systolic vascular murmurs. Labs showed elevated serum creatinine, hypokalemia, metabolic alkalosis, elevated renin and aldosterone and hypercalciuria. Echocardiography identified ventricular hypertrophy. Computed tomography (CT) of the abdomen and magnetic resonance angiography of the head showed multiple tortuous or interrupted arteries and multiple calcifications in the renal sinus area. B-mode ultrasonography suggested thickening of the carotid and femoral artery walls, with numerous spotted calcifications. Genetic testing revealed that ABCC6 had a complex heterozygous mutation (exon 24: c.3340C > T and intron 30: c.4404-1G > A). Our panel of experts reviewed the evaluation of this patient with hypertension, proteinuria, hypercalciuria, and vascular abnormalities as well as the diagnosis and appropriate management of a rare disease.

Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC.

Fluconazole in hypercalciuric patients with increased 1,25(OH)2D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial.

BACKGROUND: Hypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels. METHODS: The FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double-blind trial. A total of 60 patients (10-60 years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/day), increased 1,25(OH)2D levels (> 150 pmol/L), and 25-OH-D levels >20 nmol/L will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-h calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-h calciuria in patients who still display at W16 a 24-h hypercalciuria. DISCUSSION: The current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the "off-label" use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04495608 . Registered on July 23, 2020.

A Novel Mutation in CLDN16 Gene Causing Familial Hypomagnesemia, Hypercalciuria, Nephrocalcinosis in An Iranian Family.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is characterized by renal magnesium wasting, hypercalciuria and eventually kidney failure which mostly affects children and young aged adults. Mutation of genes of claudin-16 and claudin-19 are involved in the pathogenesis of this disorder, which leads to renal magnesium and calcium wasting. A 35-year-old man with end-stage kidney disease (ESKD) was referred to our clinic due to bilateral nephrocalcinosis, detected by ultrasonographic study, for further evaluation. Detailed investigations revealed that his siblings had also similar presentations of hypomagnesemia, hypercalciuria, nephrocalcinosis and chronic kidney disease (CKD). Sanger sequencing showed a novel mutation (c.338G > A: p.C113Y) at the second exon of the CLDN16 gene. The patient underwent kidney transplantation and his siblings received only medical treatment. In young patients with ESKD and concomitant nephrocalcinosis, especially where there is a family history of CKD/ESKD, genetic evaluation is strongly recommended.  DOI: 10.52547/ijkd.6845.

AN INFANT WITH IDIOPATHIC HYPERCALCIURIA AND NEPHROLITHIASIS ASSOCIATED WITH CYP24A1 ENZYME POLYMORPHISM: A CASE REPORT.

CYP24A1 is an enzyme that inactivates vitamin D and encodes vitamin D 24-hydroxylase. Mutations in this enzyme have been linked with idiopathic infantile hypercalcemia, nephrolithiasis, and nephrocalcinosis. Genetic testing for this mutation should be considered in the presence of calciuria, elevated serum calcium, elevated 1,25- dihydroxyvitamin D, and suppressed parathyroid hormone. We present a previously healthy eight-month-old male infant with macrohematuria, hypercalciuria (6 mg/kg/24 h), albuminuria (54 mg/24 h) and left-sided nephrolithiasis found on urinary tract ultrasound. The values of alpha 1 microglobulin, parathyroid hormone, vitamin D, serum electrolytes, amino acids, glycols, oxalates and citrates in urine, as well as coagulation tests were normal. Genetic testing excluded suspected Dent's disease but confirmed heterozygous missense variant CYP24A1 c.469C>T, p.(Arg157Trp) classified as polymorphism. He was treated with hydrochlorothiazide and potassium citrate. Children presenting with hypercalcemia, hypercalciuria and nephrolithiasis should be tested because of the importance of recognition, genetic diagnosis and proper treatment of CYP24A1 mutations that can present with a wide range of phenotypic presentations, from asymptomatic to chronic renal disease.

Hypocalcemia as the Initial Presentation of Type 2 Bartter Syndrome: A Family Report.

CONTEXT: Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Type 2 BS results from a defect in the renal outer medullary potassium channel encoded by the KCNJ1 gene. Type 2 BS presents with polyhydramnios, intrauterine growth retardation, prematurity, failure to thrive, polyuria, hypercalciuria, and life-threatening episodes of dehydration. Hypocalcemia is a very rare presenting symptom of BS, with only a few published cases reporting it as the initial manifestation of type 2 BS. OBJECTIVE: To describe a child who presented with hypocalcemic seizure at the age of 2.3 years that was first related to vitamin D deficiency and high-phosphate soft drink consumption. METHODS: Whole exome sequencing (WES) was used to evaluate the biochemical abnormalities of the proband. RESULTS: We identified a previously described homozygous missense mutation c.212C>T, p.T71M in the KCNJ1 gene associated with type 2 BS. Six additional family members with the same mutation and diagnosed clinically with BS are also reported, 2 presenting with hypocalcemia associated with vitamin D deficiency. CONCLUSION: This report expands the clinical spectrum associated with KCNJ1 mutations and emphasizes the role of WES in unsolved cases of hypocalcemia when genetic disease is suspected. It also highlights the hazardous effects of phosphate-containing soft drinks on calcium metabolism.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features.

Biallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.

Variable Clinical Presentation of Children with Hereditary Hypophosphatemic Rickets with Hypercalciuria: A Case Series and Review of the Literature.

INTRODUCTION: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare condition of renal phosphate wasting due to SLC34A3 mutations [Am J Hum Genet. 2006;78(2):193-201]. Patients exhibit low serum phosphorus, high 1,25-dihydroxyvitamin D, and inappropriately high urine phosphate and calcium. However, symptoms vary, and little is known about specific phenotype-genotype correlations. METHODS: We report 3 HHRH cases in unrelated 12-year-old, 9-year-old, and 14-year-old patients and perform a systematic literature review. RESULTS: All 3 patients exhibited labs typical of HHRH. Yet, their presentations differed, and 2 novel SLC34A3 variants were identified. As found in the literature review, bone symptoms are most common (50%), followed by renal symptoms (17%), combined bone and renal symptoms (18%), and asymptomatic (9%). CONCLUSION: These 3 cases highlight the variability of presenting signs and symptoms among individuals with HHRH. An accurate diagnosis is critical as treatment differs from other disorders of phosphate wasting, urinary stones, and mineralization defects.

Identification of p.Arg205Cys in CASR in an autosomal dominant hypocalcaemia type 1 pedigree: A case report.

RATIONALE: Autosomal dominant hypocalcaemia type 1 (ADH1) is a genetic disease characterized by benign hypocalcemia, inappropriately low parathyroid hormone levels and mostly hypercalciuria. It is caused by the activating mutations of the calcium-sensing receptor gene (CASR), which produces a left-shift in the set point for extracellular calcium. PATIENT CONCERNS: A 50-year-old man presenting with muscle spasms was admitted into the hospital. He has a positive familial history for hypocalcemia. Auxiliary examinations demonstrated hypocalcemia, hyperphosphatemia, normal parathyroid hormone level and nephrolithiasis. A missense heterozygous variant in CASR, c 613C > T (p. Arg205Cys) which has been reported in a familial hypocalciuric hypercalcemia type 1 patient was found in the patient's genotype. It is the first time that this variant is found associating with ADH1. The variant is predicted vicious by softwares and cosegregates with ADH1 in this pedigree. CASR Arg205Cys was deduced to be the genetic cause of ADH1 in the family. DIAGNOSIS: The patient was diagnosed with ADH1 clinically and genetically. INTERVENTIONS: Oral calcitriol, calcium and hydrochlorothiazide were prescribed to the patient. OUTCOMES: After the treatments for 1 week, the patient's symptom was improved and the re-examination revealed serum calcium in the normal range. A 3-month follow-up showed his symptom was mostly relieved. LESSONS: The variant of CASR Arg205Cys, responsible for ADH1 in this family, broadened the genetic spectrum of ADH1. Further and more studies are required to evaluate the correlation between genotype and phenotype in ADH1 patients.

Heterogeneity is a common ground in familial hypomagnesemia with hypercalciuria and nephrocalcinosis caused by CLDN19 gene mutations.

BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare tubulopathy caused by mutations in the CLDN16 or CLDN19 genes. Patients usually develop hypomagnesemia, hypercalciuria, nephrocalcinosis and renal failure early in life. Patients with CLDN19 mutations may also have ocular abnormalities. Despite clinical variability, factors associated with kidney function impairment, especially in patients with CLDN19 mutations, have not been addressed. METHODS: Retrospective multicenter study of 30 genetically confirmed FHHNC Spanish patients. We analyzed kidney function impairment considering as outcomes chronic kidney disease (CKD) stage 3 and annual estimated glomerular filtration rate (eGFR) decline, to identify factors associated with the different phenotypes. RESULTS: Of thirty patients, 27 had mutations in the CLDN19 gene (20 homozygous for the p.G20D mutation) and 3 in the CLDN16. Age at diagnosis was 1.71 (0.67-6.04) years and follow-up time was 8.34 ± 4.30 years. No differences in CKD stage 3-free survival based on CLDN19 mutation (p.G20D homozygous vs. other mutations) or gender were found, although females seemed to progress faster than males. Patients with more pronounced eGFR decline had higher PTH levels at diagnosis than those with stable kidney function, despite similar initial eGFR. Approximately 60% of CLDN19 patients presented ocular abnormalities. Furthermore, we confirmed high phenotypic intrafamilial variability. CONCLUSIONS: In a contemporary cohort of FHHNC patients with CLDN19 mutations, females seemed to progress to CKD-stage 3 faster than males. Increased PTH levels at baseline may indicate a more severe renal course. There was high phenotype variability among patients with CLDN19 mutations and kidney function impairment  differed even between siblings.

Litiasis renal en niños / Renal lithiasis in children

Resumen Justificación y objetivo: La litiasis renal se debe a la precipitación de cristales por un desequilibrio en la orina entre sustancias promotoras y las sustancias inhibitorias. Es una patología con una prevalencia entre 2-10% en la población pediátrica, con una incidencia que ha aumentado en los últimos 25 años; razón por la cual este estudio pretende conocer la prevalencia, las manifestaciones clínicas y metabólicas de la litiasis renal en la población pediátrica del Hospital Nacional de Niños de Costa Rica. Métodos: Es un estudio retrospectivo, descriptivo y observacional, mediante la revisión de expedientes de pacientes menores a 18 años con el diagnóstico de litiasis renal, atendidos en el Hospital Nacional de Niños, en el periodo comprendido entre enero del año 2000 al 2018. Resultados: Se incluyeron un total de 106 pacientes. El 57,5% hombres, la edad promedio al diagnóstico de 6,6 ± 3,8 años; la frecuencia de casos se ha incrementado en 5,5 veces en los últimos 5 años. Factores de riesgo detectados: anormalidades del tracto urinario 22,6% y antecedentes familiares de litiasis 17,9%. El análisis metabólico mostró un gasto urinario bajo en el 74,3%, hiperfosfaturia en un 43,2%, hipomagnesuria 39,2% e hipercalciuria 37,8%. Etiologías determinadas: metabólica 54,7%, malformaciones de las vías urinarias 16% e idiopática en un 30,9%. La litotricia intracorpórea se aplicó en un 61,2%. La recidiva se observó en el 28,5% de los casos, se encontró relación entre la incidencia de recidiva con el tamaño del lito (p = 0,001) y el tratamiento quirúrgico. (p = 0,010). Conclusiones: Existe un aumento en la frecuencia de casos de litiasis pediátrica con una etiología multifactorial en el Hospital Nacional de Niños de Costa Rica.

Abstract Background and aim: Renal lithiasis is due to the precipitation of crystals due to an imbalance in the urine between promoter substances and inhibitory substances. It is a pathology with a prevalence between 2-10% in the pediatric population, with an incidence that is increasing in the last 25 years, because of that, this study pretend to know the prevalence, the clinical and metabolic, manifestation of the renal lithiasis in the pediatric population. Methods: It is a retrospective, descriptive and observational study, by reviewing records of patients under 18 years of age with a diagnosis of renal lithiasis, treated at the Hospital Nacional de Niños, in the period of 2000 to 2018. Results: A total of 106 patients were included, 57,5% men, the average age at diagnosis of 6,6+- 3,8 years, the frequency of cases has increased 5,5 times in the last 5 years. Risk factors detected: urinary trac abnormalities 22,6% and family history of nephrolithiasis 17,9%. The metabolic analysis showed a low urinary flow rate in 74,3%, hyperphosphaturia in 43,2%, hypomagnesuria 39,2% and hypercalciuria 37,8%. Etiologies determined: metabolic 54,7%, malformations of the urinary trac 16% and idiopathic in 30,9%. Intracorporeal lithotripsy was applied in 61,2%. Recurrence was observe in 28,5 % of cases, a relationship was found between the incidence of recurrence with the size of litho (p= 0.001) and surgical treatment (p= 0.01). Conclusions: There is a significant increase in the incidence of pediatric lithiasis cases with a multifactorial etiology.

Metabolic Evaluation: Place of the Calcium Load Test: How, When, For Whom, and Why?

Most human urinary stones are calcium-based and are often associated with hypercalciuria. A simple test described in 1975 by Pak et al allows for pathogenic classification of hypercalciuria: the calcium load test (CLT). The CLT explores calcium homeostasis after a low-calcium diet and then a calcium load (typically oral administration of 1 g of elemental calcium). Only simple laboratory equipment is required. Inadequate calcium excretion after a calcium-free diet or a calcium load is suggestive of resorptive or absorptive hypercalciuria, respectively. The CLT is particularly valuable in diagnosing primary hyperparathyroidism, even in most early stages of this disease. PATIENT SUMMARY: Kidney stone formation can be linked to calcium metabolism. When high calcium levels are found in urine despite adequate diet changes, a calcium load test may help to understand the underlying mechanisms. Urine and blood levels are explored during a low-calcium diet phase, and after a calcium load phase in the test. The calcium load test is particularly advantageous for revealing abnormally high function of the parathyroid gland, which is called hyperparathyroidism.

A survey of hypercalciuria during chemotherapy in acute lymphoblastic leukemia.

BACKGROUND: Urolithiasis is an extremely rare complication in childhood acute lymphoblastic leukemia (ALL), and some reports have implicated corticosteroids during chemotherapy as a risk factor for it. However, only a few reports have analyzed urinary electrolytes in this context. METHODS: We retrospectively analyzed 55 patients with ALL who underwent chemotherapy between October 2007 and January 2019. Their median age was 9.3 years (range, 0.3-24.0 years) with 30 males and 25 females. Lineages were B-cell precursor ALL (BCP-ALL) in 42 patients, T-cell in nine and others in four patients. All patients received chemotherapy based on the Berlin-Frankfurt-Münster regimen. RESULTS: Forty-nine out of the 55 ALL patients exhibited hypercalciuria at least once during chemotherapy. Moreover, 36 patients with BCP-ALL, who were receiving identical Berlin-Frankfurt-Münster-based regimens, exhibited significantly high urinary calcium excretion immediately following high-dose glucocorticoid administration. Among the 55 ALL patients, urolithiasis was observed in one patient, a 6-year-old boy with BCP-ALL who developed urolithiasis at reinduction chemotherapy just after cessation of high-dose dexamethasone administration. CONCLUSIONS: Nearly 90% of the ALL patients studied developed hypercalciuria during chemotherapy in strong association with corticosteroid administration.

Utility of blood tests in screening for metabolic disorders in kidney stone disease.

OBJECTIVES: To determine the clinical utility of blood tests as a screening tool for metabolic abnormalities in patients with kidney stone disease. SUBJECTS AND METHODS: Clinical and biochemical data from 709 patients attending the Oxford University Hospitals NHS Foundation Trust for assessment and treatment of kidney stones were prospectively collected between April 2011 and February 2017. Data were analysed to determine the utility of serum calcium, parathyroid hormone (PTH), urate, chloride, bicarbonate, potassium and phosphate assays in screening for primary hyperparathyroidism, normocalcaemic hyperparathyroidism, hyperuricosuria, distal renal tubular acidosis (dRTA) and hypercalciuria. RESULTS: An elevated serum calcium level was detected in 2.3% of patients. Further investigations prompted by this finding resulted in a diagnosis of primary hyperparathyroidism in 0.2% of men and 4.6% of women for whom serum calcium was recorded. An elevated serum PTH level in the absence of hypercalcaemia was detected in 15.1% of patients. Of these patients, 74.6% were vitamin D-insufficient; no patients were diagnosed with normocalcaemic hyperparathyroidism. Hyperuricosuria was present in 21.6% of patients and hypercalciuria in 47.1%. Hyperuricaemia was not associated with hyperuricosuria, nor was hypophosphataemia associated with hypercalciuria. No patient was highlighted as being at risk of dRTA using serum chloride and bicarbonate as screening tests. CONCLUSION: This study indicates that individuals presenting with renal calculi should undergo metabolic screening with a serum calcium measurement alone. Use of additional blood tests to screen for metabolic disorders is not cost-effective and may provide false reassurance that metabolic abnormalities are not present. A full metabolic assessment with 24-h urine collection should be undertaken in recurrent stone formers and in those at high risk of future stone disease to identify potentially treatable metabolic abnormalities.