Scott J. Schurman

Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease

Hypercalciuria is the major risk factor promoting stone formation in Dents disease, also known as X-linked recessive nephrolithiasis, but the effects of diuretics on calcium excretion and other stone risk factors in this disease are unknown. This study examined urine composition in eight male patients with Dents disease, ages 6 to 49 yr, all of whom were hypercalciuric and had inactivating mutations of CLCN5. Eight males, ages 7 to 34 yr, with idiopathic hypercalciuria (IH) served as controls. Patients were instructed to maintain a consistent intake of sodium, potassium, calcium, and protein. Two consecutive 24-h urine collections were obtained after a baseline period and after 2 wk of chlorthalidone (25 mg), amiloride (5 mg), and the two diuretics in combination, with a week off drug separating the treatment periods in a randomized crossover design. Doses were reduced by half in boys under age 12 yr. Chlorthalidone alone (P < 0.002) and the combination of chlorthalidone and amiloride (P < 0.003) reduced calcium excretion significantly in either patient group. With chlorthalidone, calcium excretion fell to normal (<4.0 mg/kg per d) in all but one patient in each group. Amiloride alone had no significant effect on urinary calcium excretion, in either patient group. In patients with Dents disease during chlorthalidone therapy, the supersaturation ratios for calcium oxalate and calcium phosphate fell by 25% and 35%, respectively. Mean citrate excretion was reduced by chlorthalidone (P <.04) and by chlorthalidone in combination with amiloride (P <.02). There were no significant differences in the responses to these diuretics between the patient groups in any of the urinary parameters. The intact hypocalciuric response to a thiazide diuretic indicates that inactivation of the ClC-5 chloride channel does not impair calcium transport in the distal convoluted tubule and indicates that thiazides should be useful in reducing the risk of kidney stone recurrence in patients with Dents disease.

Factors influencing short-term and long-term pediatric renal transplant survival☆☆☆★

OBJECTIVE To determine the patient and donor characteristics important for short-term and long-term renal transplant survival at Cincinnati Childrens Hospital Medical Center. METHODS Cumulative transplant survival was calculated and univariate analysis of graft survival performed on 206 transplants done since 1970 in 148 pediatric patients. Grafts to black recipients were analyzed separately. Short-term graft survival is defined as 1-year allograft survival and long-term graft survival as graft half-life (t1/2) survival for allografts functioning after the first posttransplant year. RESULTS One-year graft survival of living-related donor (LRD) and cadaver donor (CAD) transplants was 77% and 62%, respectively. Graft t1/2 was 11.2 years for LRD and 9.8 years for CAD grafts. The CAD 1-year graft survival when the recipient or donor was younger than 7 years was 36% and 41%, respectively. The LRD 1-year graft survival to children younger than 7 years was 88% versus 75% in older children. Graft survival at 1 year was similar for CAD primary and retransplants (60% vs 65%), but graft t1/2 better for CAD primary grafts (17.8 years vs 5.0 years, P < 0.001). Preemptive LRD grafts performed similarity at 1 year and better over the long term compared with patients who had long-term dialysis (85% vs 74%, P = NS; and 16.9 years vs 8.0 years, p < 0.001). Preemptive CAD grafts did poorly, with 1-year graft survival of 38%. Administration of Cyclosporine A (CsA) improved CAD 1-year graft survival (76% vs 54%, p < 0.001) but not long-term survival. Thirty grafts to 24 black children had a 1-year survival of 48%, with no graft surviving more than 5 years. CONCLUSIONS Living-related donor transplantation should be aggressively pursued for young children. If a LRD is unavailable and the young childs medical condition is stable, delay in CAD transplantation should be considered, with dialysis before transplant. Use of CsA improves 1-year pediatric graft survival, but does not improve graft survival after 1 year at the Childrens Hospital Medical Center. New strategies to improve graft survival in black children should be pursued.

X-linked recessive nephrolithiasis: Presentation and diagnosis in children☆☆☆★★★

We report a new X-linked recessive nephrolithiasis kindred. X-linked recessive nephrolithiasis is a recently described disease characterized by recurrent nephrolithiasis, nephrocalcinosis, and progressive renal failure, associated with mutations in a renal chloride channel gene, chloride channel number 5. Screening individuals at risk with renal ultrasonography and measurement of urinary excretion of low molecular weight proteins and calcium will exclude boys without X-linked recessive nephrolithiasis kindred and identify boys likely to have the disease.

Neonatal Bone Mineral Uptake Is Measurably Affected by Local pH and Concentrations of Inorganic Phosphate, Ionized Calcium and Ionized Magnesium

Neonatal Bone Mineral Uptake Is Measurably Affected by Local pH and Concentrations of Inorganic Phosphate, Ionized Calcium and Ionized Magnesium

Contrasting Phenotypes of Children with Different Bartter's Syndrome (BS) Gene Defects |[dagger]| 483

BS describes a phenotype of renal sodium wasting, hypokalemic metabolic alkalosis, elevated plasma renin and aldosterone with normal blood pressure, and normal serum magnesium. To date, mutations in 3 genes encoding thick ascending limb transporters have been identified in BS; NKCC2, ROMK, and CLCNKB. Children with NKCC2 and ROMK defects are premature with polyhydramnios, hypercalciuria and nephrocalcinosis. In contrast, children with CLCNKB defect are premature with polyhydramnios, but do no have nephrocalcinoisis.

Chapter 42 – Inherited Magnesium Disorders

The molecular basis for a number of inherited disorders of magnesium homeostasis has been elucidated through discovery of genes encoding proteins critical to renal magnesium reabsorption in the thick ascending limb and distal convoluted tubule of the nephron. In the thick limb, mutations in claudins-16 and -19 impair paracellular cation transport and result in familial hypomagnesemia with hypocalcemia and nephrocalcinosis. In the distal convoluted tubule a number of disorders impair active transcellular transport of magnesium. Mutation in the TRPM6 apical magnesium channel impairs gut absorption, as well as renal reabsorption, and causes hypomagnesemia severe enough to alter parathyroid-regulated calcium metabolism, producing hypomagnesemia with secondary hypocalcemia. The potassium channels Kv1.1 and Kir4.1 are expressed in brain, as well as in distal renal tubule; and mutations not only cause renal magnesium wasting and hypomagnesemia but also neurologic impairment including ataxia. Hypomagnesemia also results from inherited defects in distal tubule basolateral membrane proteins EGF, the γ subunit of the Na/K ATPase, and the calcium-sensing receptor, as well as the sodium chloride cotransporter mutated in Gitelman syndrome, each of which is important in the pathway for transcellular magnesium transport.

Zoledronic acid for neonatal subcutaneous fat necrosis

Subcutaneous fat necrosis (SFN) in infants producing severe hypercalcemia is a life‐threatening emergency. Pathophysiology may include enhanced gastrointestinal calcium absorption and bone resorption. We treated an infant with SFN and serum calcium of 15 mg/dL with prednisolone and low‐dose zoledronic acid. Serum calcium promptly normalized without rebound hypocalcemia, and redosing of zoledronic acid was not necessary.

Inherited Magnesium Disorders

The molecular basis for a number of inherited disorders of magnesium homeostasis has been elucidated through discovery of genes encoding proteins critical to renal magnesium reabsorption in the thick ascending limb and distal convoluted tubule of the nephron. In the thick limb, mutations in claudins 16 and 19 impair paracellular cation transport and result in familial hypomagnesemia with hypocalcemia and nephrocalcinosis. In the distal convoluted tubule, a number of disorders impair active transcellular transport of magnesium. Mutation in the TRPM6 apical magnesium channel impairs gut absorption as well as renal reabsorption, and causes hypomagnesemia severe enough to alter parathyroid-regulated calcium metabolism, producing hypomagnesemia with secondary hypocalcemia. The potassium channels Kv1.1 and Kir4.1 are expressed in brain as well as distal renal tubule, and mutations not only cause renal magnesium wasting and hypomagnesemia but also neurologic impairment including ataxia. Hypomagnesemia also results from inherited defects in distal tubule basolateral membrane proteins EGF, the γ-subunit of the Na/K ATPase, and the calcium-sensing receptor, as well as the sodium chloride co-transporter mutated in Gitelman syndrome, each of which is important in the pathway for transcellular magnesium transport.

X-LINKED NEPHROLITHIASIS (XLN): A NEW KINDRED. 2198

XLN was recently described in a large kindred in NY State. Affected males had recurrent calcium nephrolithiasis/nephrocalcinosis, proteinuria, hematuria, and variable renal insufficiency in older patients. We have evaluated 2 half-brothers (same mother) ages 4 and 6 yrs both presenting with microhematuria/proteinuria on routine exam. Renal ultrasounds showed nephrocalcinosis. Further evaluation showed mild hypercalciuria(4.2&4.7mg/kg/day), non-nephrotic range tubular pattern proteinuria, and hematuria. Normal studies included serum Ca, Phos, Alk Phos, PTH, lytes, Cr, urinary excretion of oxalate, Mg, citrate, and uric acid, first A.M. urine pH<5.5, and audiograms. Growth was normal with no evidence for acidosis, rickets or bone demineralization. Both have an elevated serum 1,25-OH Vit. D and testing of one showed some reduction in urinary Ca on low Ca/Na diet (4.2 to 3mg/kg/day).

HYPERCALCEMIA IN AN ADOLESCENT WITH CONNECTIVE TISSUE DISEASE (CTD): EVIDENCE FOR INTERLEUKIN-1 (IL-1) MEDIATED SERUM BONE RESORBING ACTIVITY. 2347

HYPERCALCEMIA IN AN ADOLESCENT WITH CONNECTIVE TISSUE DISEASE (CTD): EVIDENCE FOR INTERLEUKIN-1 (IL-1) MEDIATED SERUM BONE RESORBING ACTIVITY. 2347