Risk factors for urolithiasis in children on the ketogenic diet

Kidney stones have been associated with use of the ketogenic diet in children with refractory seizure disorders. We performed a case-control study examining risk factors for the development of stones on the ketogenic diet, and prospectively followed children initiating the ketogenic diet to evaluate the incidence of urolithiasis. Clinical characteristics of 18 children presenting with stones (8 uric acid stones, 6 mixed calcium/uric acid stones, 1 calcium oxalate/phosphate stone, 3 stones not evaluated) were compared with characteristics of non-stone-forming children initiating the ketogenic diet at Johns Hopkins since July 1996. Since July 1996, 112 children initiating the ketogenic diet have been followed for development of stones. Follow-up times on the diet range from 2 months to 2.5 years. Of 112 children, 6 have developed stones (3 uric acid, 3 mixed calcium/uric acid stones) (0.8 children developing stones/ 100 patient-months at risk). Comparisons of children presenting with stones on the ketogenic diet with characteristics of the entire cohort initiating the ketogenic diet suggest younger age at diet initiation and hypercalciuria are risk factors for the development of stones. Prospective evaluation of children initiating the ketogenic diet revealed that almost 40% of patients had elevated fasting urine calcium: creatinine ratios at baseline; this increased to 75% after 6 months on the diet. Median urine pH was 5.5 at diet initiation, and remained at 6.0 thereafter. In a subset of patients tested, urinary citrate excretion fell from a mean of 252 mg/24 h pre diet initiation to 52 mg/24 h while on the diet. Uric acid excretion remained normal. Patients maintained on the ketogenic diet often have evidence of hypercalciuria, acid urine, and low urinary citrate excretion. In conjunction with low fluid intake, these patients are at high risk for both uric acid and calcium stone formation. Received: 28 May 1999 / Revised: 7 June 2000 / Accepted: 9 June 2000     

Bartter syndrome in a neonate: early treatment with indomethacin

The neonatal form of Bartter syndrome is characterized by intrauterine onset of polyuria leading to severe polyhydramnios. We report a patient with the early onset of the syndrome and a similar history in a previous sibling who died in early neonatal life. The patient is a female product of 33 weeks of gestation complicated by severe polyhydramnios. Her birth weight was 2,100 g. Polyuria led to severe dehydration on the 3rd day of life. Laboratory studies showed hypokalemia, hyponatremia, and elevated plasma levels of renin and aldosterone. Hypercalciuria was associated with echographic evidence of nephrocalcinosis. Indomethacin therapy resulted in a significant reduction in urine volume and correction of biochemical abnormalities. Growth and development are satisfactory after 4 years of indomethacin therapy, but nephrocalcinosis remains unchanged. Received: 22 December 1998 / Revised: 13 May 1999 / Accepted: 1 June 1999     

Atrial natriuretic peptide in children with idiopathic hypercalciuria

We measured plasma atrial natriuretic peptide (ANP) levels in 30 children with idiopathic hypercalciuria (IH) and 19 normal controls (NC). A calcium (Ca) loading test was performed in all patients to determine the type of IH. Subsequently plasma ANP, cAMP and renin activity (PRA), serum total and ionized Ca, intact parathyroid hormone, aldosterone, and 1,25-dihydroxyvitamin D as well as urine Ca, cAMP, and electrolytes were determined in all subjects. The mean (SD) plasma ANP levels were significantly lower in patients with renal hypercalciuria (RH) [21.4 (4.8) pg/ml] than in those with absorptive hypercalciuria (AH) [26.8 (7.6) pg/ml, P<0.05] and NC [27.6 (6.6) pg/ml, P<0.01]. PRA was significantly lower in AH [2.9 (1.3) ng/ml per hour] than in RH patients [7.8 (6.8) ng/ml per hour, P<0.01] and in NC [6.8 (4.6) ng/ml per hour, P<0.005]. Serum aldosterone values were significantly lower in AH [14.5 (11.4) ng/dl] than in RH patients [25.4 (14.1) ng/dl, P<0.05] and in NC [32.6 (20.5), P<0.001]. The lower plasma ANP levels in RH than in AH patients and in NC may be due to Ca depletion. The lower PRA and serum aldosterone levels in AH than in RH patients and in NC may be attributed to Ca excess. Received: 18 November 1998 / Revised: 4 October 1999 / Accepted: 5 October 1999     

Family history may be misleading in the diagnosis of Dent’s disease

The rare Dent’s disease manifests with medullary nephrocalcinosis, nephrolithiasis, hypercalciuria, low molecular weight proteinuria and other tubular dysfunctions, rickets or osteomalacia, and renal failure, in various combinations. It is a recessive X-linked condition. Clinicians consider family history a fundamental pointer to its diagnosis, but this is not invariably the case as clearly pointed out by the two reported cases.     

Evaluation of histologic changes in the urinary tract of hypercalciuric rats

Idiopathic hypercalciuria (IH) has been speculated to have a predisposing role in the development of urinary tract infection (UTI), due to the uroepithelial cell damage it leads to. In this study, we aimed to investigate the effects of hypercalciuria on the bladder, ureters, and kidneys in rats with experimentally induced hypercalciuria.Normocalcemic hypercalciuria was induced by furosemide (60 mg/100 mL of drinking water) administration to 16-week-old male Wistar Albino rats for 14 days. Calciuria (calcium/creatinine ratio, mg/mg, Ca/Cr) increased from 0.07±0.01 at the beginning of administration to 0.41±0.1 on day 14 (p=0.000). The Ca/Cr ratio was 0.14±0.06 at the beginning of the study and 0.25±0.06 on day 14 in the control group rats (p=0.002 vs. the hypercalciuric group rats on day 14). Bladder, ureter, and kidney specimens of the rats, dissected on the 14th day, were fixed in 10% formalin and 2.5% gluteraldehyde solutions for light and electron microscopic examination, respectively. Histopathological and ultrastructural examination of the hypercalciuric rats revealed proliferation and apical cytoplasmic vacuole formation in transitional epithelial cells, mitotic activity in the intermediate cell line, vasodilatation, edema, and separation of collagen fibers in the bladder and ureter specimens. Light microscopic examination of the kidney specimens revealed a lot of erythrocyte in the glomerular capillary lumen, while electron microscopy revealed vacuolization of proximal and distal tubules, tubular degeneration, interstitial edema, and vasodilatation.In this study, hypercalciuria was observed to have adverse effects on the cell architecture of the uroepithelium and disruption of the epithelial barrier of the bladder and ureters and all kidney structures, especially on the proximal epithelial cells.This research was presented as an oral presentation in the 39th Annual Meeting of the European Society for Pediatric Nephrology (ESPN) in Istanbul, Turkey, September 10–13, 2005.     

Hypercalciuria and recurrent urinary tract infections: incidence and symptoms in children over 5 years of age

Hypercalciuria is an important and common risk factor in the formation of renal stones. In this study we evaluated the incidence and the clinical presentation of hypercalciuria in 75 children over 5 years of age with the diagnosis of recurrent urinary tract infection (UTI). We measured random urinary calcium/creatinine value (three times), 24-h urinary calcium excretion, serum calcium, phosphorus, electrolytes, blood gas, blood urea nitrogen and creatinine levels. Hypercalciuria was found in 32 patients (43%). The mean urinary calcium/creatinine ratio for hypercalciuric patients was 0.50±0.21 mg/mg (min: 0.24, max: 2.60). The mean urinary calcium/creatinine ratio for the rest of the study population—those without hypercalciuria—was 0.10±0.04 mg/mg (min: 0.01, max: 0.18). Presenting symptoms of the hypercalciuric patients and normocalciuric patients were similar. History of familial urolithiasis was positive in 19 patients (59%). Predisposing urinary tract abnormalities in recurrent UTI was shown in 12 of the hypercalciuric patients (12/32, 37.5%) and 8 of the normocalciuric patients (8/43, 19%) without a statistically significant difference between. We conclude that hypercalciuria is not a rare finding among recurrent UTI cases in Turkish children. Hypercalciuria does not modify the clinical presentation of UTI, and we suggest the investigation of urinary calcium excretion in children with recurrent UTI.     

Bone mineral density and bone turnover in patients with Bartter syndrome

The aim of this investigation was to evaluate bone mineral density (BMD), by use of DXA, and bone turnover, in patients with Bartter syndrome (BS). Ten patients (2 with BS type II and 8 with BS type III) were included in the procedure. Age at study varied between 2 and 30 years. During the studies usual treatment with indomethacin, spironolactone, and potassium chloride was maintained. Results were compared with those obtained in the 20 asymptomatic parents. Height of the patients at the time of the study did not differ from reference values (Z-score –1.2 to +0.8). Three patients (1 with BS type II and 2 with BS type III) presented reduced lumbar spine BMD or overt osteopenia (BMD Z-scores: –2.3, –1.3, and –1.1). BMD did not correlate significantly with age. Paternal and maternal femoral neck BMD values correlated significantly with lumbar spine BMD of the patients (r=0.65, P<0.05, and r=0.80, P<0.01). Lumbar spine BMD Z-scores correlated negatively with urinary Ca excretion when values both from patients and parents were jointly analyzed (r=–0.43, P<0.05). Plasma calcium concentration was significantly higher (P<0.001) and plasma phosphate Z-score was significantly lower (P<0.05) in the patients than in the parents. However, no significant differences were observed in values for intact PTH, 1,25 (OH)₂D₃ and 25 (OH)D₃. Intact PTH values correlated positively with BMD Z-scores at lumbar spine (r=0.45, P<0.05) and at femoral neck (r=0.63, P<0.01). Age-corrected biochemical markers of bone formation (plasma alkaline phosphatase and osteocalcin concentrations) were normal whereas age-corrected markers of bone reabsorption (urinary PYD and DPD excretion) were significantly higher than parental values (P<0.01 and <0.05, respectively). We conclude that: (1) reduced BMD is not an exclusive feature of neonatal BS and it can be also observed in classic BS; (2) the loss of bone mineral is not progressive, probably because of the hypocalciuric effect of indomethacin therapy; and (3) this study did not determine whether loss of bone mass is the cause or the consequence of hypercalciuria although the beneficial effect of indomethacin therapy implies the latter.     

Paracellin-1 gene mutation with multiple congenital abnormalities

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive renal tubular disorder characterized by renal magnesium wasting, hypercalciuria, advanced nephrocalcinosis and progressive renal failure. Mutations in the paracellin-1 (CLDN16) gene have been defined as the underlying genetic defect. The tubular disorders and progression in renal failure are usually resistant to magnesium substitution and hydrochlorothiazide therapy, but hypomagnesemia may improve with advanced renal insufficiency. We present a patient with a homozygous truncating CLDN16 gene mutation (W237X) who had early onset of renal insufficiency despite early diagnosis at 2 months. He also had additional abnormalities including horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis. To the best of our knowledge, this is the youngest case diagnosed as familial hypomagnesemia with hypercalciuria and nephrocalcinosis and the first case having such additional congenital abnormalities independent of the disease itself.     

Urinary calcium excretion in healthy children and adolescents

Urinary calcium (Ca) excretion was determined in 1,578 24-h urine samples from 507 healthy children and adolescents (252 boys, 255 girls; 2.8–18.4 years) participating in the DONALD Study and is presented for 32 different age and sex groups. Calciuria values related to body weight (mg/kg per day) were relatively constant except for a transient decrease during puberty in all centiles, with a later onset in boys than girls. Distribution of calciuria (mg/kg per day) was best normalized by log transformation, with an almost constant standard deviation of the log-transformed values. Ca excretion was ≥4 mg/kg per day in 8.6% and ≥6 mg/kg per day in 1.5% of the urine samples. Based on Ca excretion rates of 1,080 pairs of 24-h urine samples from 364 children and adolescents, sensitivity, specificity, and the predictive value for hypercalciuria (≥4 mg/kg per day) in the next urine sample were calculated at three test levels classifying calciuria of the initial urine sample. In summary, this study presents normal values of urinary Ca excretion related to age and sex in a population of healthy German children and adolescents consuming a typical western-style diet. A high level of calciuria in a random urine sample is important in the diagnosis of hypercalciuria. Received: 25 February 1997 / Revised: 28 April 1999 / Accepted: 3 May 1999