Stones, bones, and heredity

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine–glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined.

Conclusion

These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.     

Role of Medical Approach in the Management of Stone Disease

In the management of stone disease, the medical approach concerned with the prevention of stone recurrence is equally as important as the surgical removal of stones. The application of medical approach requires an understanding of the pathophysiology of stone formation. A wide variety of physiological or environmental disturbances have been identified in stone–forming patients. They include hypercalciuria, hypocitraturia, undue urinary acidity and hyperuricosuria. Reliable diagnostic protocols have been developed which are based on the presence of above derangements. The prophylactic treatment programs are directed at the correction or amelioration of underlying environmental disturbances. Conservative measures include a high fluid intake, dietary sodium and oxalate restriction, dietary calcium restriction (in absorptive hypercalciuria and primary hyperparathyroidism), and moderate animal protein restriction. Specific medical treatments chosen for discussion are thiazide, slow–release neutral potassium phosphate, potassium citrate and potassium magnesium citrate.     

SLC34A3 intronic deletion in a new kindred with hereditary hypophosphatemic rickets with hypercalciuria

Objective: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form of hypophosphatemia with hyperphosphaturia, hypercalciuria, and hypercalcemia. In two reports on six affected kindreds with HHRH, the disease was mapped to chromosome 9q34, which contains the SLC34A3 gene that encodes the renal type 2c sodium-phosphate cotransporter. Our objective was to define the clinical course of these cases in a family with HHRH and to screen for SLC34A3 gene in order to determine whether these mutations are responsible for HHRH.Methods: After clinical and biochemical evaluations, the entire SLC34A3 gene was screened using PCR amplification followed by direct sequencing technique. In this paper, we describe a new kindred with HHRH and a case of progressive and complicated HHRH presenting at age 27 years.Results: We found 101-bp deletion in intron 9 of the SLC34A3 gene. The index patient was homozygous for this mutation which has been previously reported in a Caucasian population. This is the first report for presence of SLC34A3 intron 9 deletion in an Iranian population.Conclusions: These data showed that HHRH can be easily missed or underdiagnosed. Genetic evaluation of patients with familial hypercalciuria, hypophosphatemia and nephrolithiasis is needed for further information on the prevalence and management of this rare disorder. Conflict of interest:None declared.     

Clinical presentation

Stones in the genitourinary tract commonly present with abdominal pain, hematuria, and dysuria. In certain cases, however, the diagnosis is not straightforward because of either the absence of the aforementioned symptoms or the various diseases that can present in a similar fashion. In those situations, the laboratory tests and ancillary procedures available, in addition to the actual clinical history and physical examination, are used in combination to establish the appropriate diagnosis. It must be pointed out that a great deal of knowledge of anatomy, particularly the genitourinary tract, is essential in understanding such varied clinical presentations. In this article, various disease entities, such as, polycystic kidney disease, medullary sponge kidney, and situations such as pregnancy, which are characterized by predispositions to formation of various types stones in the genitourinary tract, are also presented.     

Multicenter study of the clinical features and mutation gene spectrum of Chinese children with Dent disease

Dent disease is a rare X-linked recessive inherited tubular disease. In this multicenter study, the clinical presentation and genetic background of Chinese children with Dent disease are studied to improve the cognition and diagnostic ability of pediatricians. In this prospective cohort, we described the genotype and phenotype of a national cohort composed of 45 pediatric probands with Dent disease belonging to 45 families from 12 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system. The CLCN5 gene from 32 affected families revealed 28 different mutations. The OCRL gene from 13 affected families revealed 13 different mutations. The incidence of low-molecular-weight proteinuria (LMWP) in both Dent disease type 1 populations and Dent disease type 2 populations was 100.0%; however, the incidence of other manifestations was not high, which was similar to previously reported data. Therefore, LMWP is a key clinical feature that should alert clinicians to the possibility of Dent disease. A high amount of LMWP combined with positive gene test results can be used as the diagnostic criteria for this disease. The diagnostic criteria are helpful in reducing the missed diagnosis of this disease and are beneficial for protecting the renal function of these patients through early diagnosis and early intervention.     

CLDN16 基因突变致家族性低镁血症高钙尿症与肾钙质沉着症1 例报告并文献复习

目的探讨家族性低镁血症高钙尿症和肾钙质沉着症(FHHNC)的临床特征和致病基因特点。方法分析1例2月龄FHHNC女性患儿的临床资料。结果患儿血镁低,尿钙高;肾脏超声提示肾髓质回声增强;多次尿培养大肠埃希菌。基因测序显示患儿CLDN16基因2处杂合变异c.324+1GC,c.317CT(p.Ser 106 Phe)。予抗感染及25%硫酸镁、门冬氨酸钾镁、10%枸橼酸钠口服治疗,病情好转。结论 FHHNC罕见且预后差,目前除肾移植外无特殊治疗方法,基因检测有助于早期诊断。     

High urinary excretion of uric acid combined with high excretion of calcium links kidney stone disease to familial hypertension.

BACKGROUND: Past studies identified an association between kidney stone disease (KSD) and hypertension. We recently reported a high occurrence of hypertension in families of patients with hyperuricosuric KSD. As hypercalciura frequently coexists with hyperuricosuria and high urinary excretion of calcium is found in patients with hypertension, we hypothesized that hyperuricosuria that is accompanied by hypercalciuria better describes the familial association between KSD and hypertension. METHODS: Four hundred and eighty-six KSD patients, aged 18-50 years, attending a lithotripsy unit collected a 24-h urine sample for metabolic analysis and provided information on family history of hypertension. The familial occurrence of hypertension was compared among four groups of patients: those who had combined elevation of both urinary calcium and uric acid excretions ("combined" abnormality, n=56), those who had hyperuricosuria without concomitant hypercalciuria ("pure" hyperuricosuria, n=67), those who had hypercalciuria without concomitant hyperuricosuira ("pure" hypercalciuria, n=52), and a control KSD patient group ("other" abnormality, n=311). The prevalence of treated hypertension in patients from the four groups was 16%, 12%, 2%, 10%, respectively. RESULTS: Thirty-four per cent of the patients with the "combined" abnormality had a positive family history of hypertension, defined as two or more first-degree relatives with treated hypertension, that was significantly higher than in patients with either "pure" hyperuricosuira (15%, P<0.02), "pure" hypercalciuria (8%, P<0.001), or patients with "other" abnormality (10%, P<0.001). The adjusted OR for positive family history of hypertension in the "combined" abnormality group compared to the control KSD patient group was 5.6 (2.39-13.30). The prevalence of hypertension in siblings of patients with the "combined" abnormality (13%) was significantly higher than in siblings of patients with either "pure" hyperuricosuria (3%, P<0.001), "pure" hypercalciuria (1%, P<0.001), or siblings of control patients with "other" abnormality (4%, P<0.001). The adjusted OR for hypertension in siblings of a patient with "combined" abnormality compared to a control KSD patient was 3.4 (1.97-5.91). Patients in the "combined" abnormality group were also characterized by significantly elevated urinary sodium, phosphorus, citrate and potassium excretions. CONCLUSIONS: Our data suggest that there is a strong, independent association between familial occurrence of hypertension and the phenotype characterized by combined elevation of both urinary uric acid and calcium excretions. The association is not present in those with "pure" hyperuricosuria or "pure" hypercalciuria. Ascertainment of patients based on this phenotype may identify more homogeneous populations for genetic analysis of hypertension.     

中西医结合治疗儿童特发性高钙尿症

目的:以中西医结合的方法治疗儿童特发性高钙尿症.方法:将高钙尿症72例区分为吸收型和肾漏型.随机分成三组治疗,西医组26例以西药氢氯噻嗪加枸橼酸钾治疗;中医组24例以中药健脾、益肾、通淋方剂治疗;中西医组22例两种方法结合治疗.疗程均为6周.以血尿减少程度和尿钙变化情况判断疗效.结果:西医组总有效率76.9%,中医组62.5%,中西医组95.5%.中西医组与西医、中医组比较,P均＜0.05.结论:中药治疗儿童特发性高钙尿症有效,中西医结合治疗疗效更好.