Nephrocalcinosis, Hyperparathyroidism, and Renal Failure in Familial Hypophosphatemic Rickets Uri Alon, M.D. Helen B. Lovell, M.D. David L. Donaldson, M.D.

Introduction The

of familial hypophosphatemic rickets -JL. typically consists of large quantities of oral phosphate combined with active vitamin D metabolites.’ This treatment improves the bone status of patients and in some enhances growth. 2,3 In recent years it has become apparent that many children treated according to this protocol developed nephrocalcinosis.4-8 In all the cases reported so far, the nephrocalcinosis was detected only by ultrasonography, and kidney function remained normal or was only slightly deranged.¢s The clinical importnce of the finding of nephrocalcinosis in these patients has, therefore, been doubted.8 We report a child with familial hypophosphatemic rickets treated treatment

From the Division of Nephrology, The Children’s Mercy Hospital, University of Missouri, Kansas City, Missouri, and Divisions of Nephrology and Endocrinology,

Department of Pediatrics, University of Kansas Medical Center, Kansas

City, Kansas.

Address correspondence to: Uri Alon, M.D., The Children’s Mercy Hospital, 2401 Gillham Road Kansas City, MO 64108. Tel: (816) 234-3010


for nine years with phosphate and calcitriol who developed profound nephrocalcinosis and hyperparathyroidism associated with significant renal failure.

tion varied between 9.2 and 9.6

mg/dL; serum phosphate, 2.7 to 2.8 mg/dL; and serum creatinine 0.5 to 0.6 mg/dL. Estimated creatthe creatipatient’s height nine concentration&dquo;) was 91.2 to 106.7 mL/min/1.73 m2 and urine calcium/creatinine ratio was 0.03 (normal < 0.2 9). The child continued to be treated with oral phosphate 1,200 mg/day divided into six doses and calcitriol 1.0 f.1g1 day. He received the prescriptions for his medications from his local physician, although no biochemical studies were done until an office visit for evaluation of decreased appetite, when the hypercalcemia was detected. Upon admission the child’s height was 114.4 cm (-4.5 S.D.), weight 19.3 kg (-3.0 S.D.) and blood pressure 114/74 mm Hg. Physical examination revealed deinine clearance





A nine-year, nine-month-old white male was admitted with decreased appetite and a serum calcium concentration of 12.3 The was child mg/dL. diagnosed at the age of 10 months with famil-

ial At

hypophosphatemic rickets. diagnosis his length and weight

2.25 S.D. and 2.0 S.D. below the means for age, respectively, and his serum calcium concentration was 9.8 mg/dL, phosphate 2.8 mg/dL, alkaline phosphatase 593 LU. (normal 99-232), tubular reabsorption of phosphate 58%, and TmP/GFR 1.62 mg/dL.g Radiologic studies of his wrists, knees, and ankles demonstrated florid rickets. Both the child’s mother his and grandmother have hypophosphatemic rickets. Following diagnosis the child was treated continuously with varying oral doses of phosphate and calcitriol. At age six years and five months, when he was last seen in the follow-up clinic, his height was 99.5 cm (-4.0 S.D.) and weight was were

17.1 kg (-2.5 S.D.). During that year, his


calcium concentra-

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hydration, tremulousness, exaggerated deep tendon reflexes, and bowed legs with medial tibial torsion. Laboratory studies revealed a calcium concentration of mg/dL, phosphate 6.4 mg/dL, BUN 25 mg/dL, creatinine 1.0 mg/dL, creatinine clearance (based on 24-hour urine collection) 32.4 mL/min/1.73 m2, alkaline phosphatase 191 LU., urine calcium excretion 3.82 mg/kg/day, and serum PTH (inserum


Figure 1. A plain abdominal radiograph demonstrating right calcified kidney (arrows). The left kidney is partially obscured by intestinal gas. Note also the generalized osteodystrophy.

tact molecule) 50.9 pg/mL (normal 11.0-55.0 pg/mL). Skeletal films revealed healed rickets, but there was radiographic evidence of hyperparathyroidism. A plain abdominal radiograph disclosed calcified kidneys (Figure 1 ) . This finding was confirmed by renal

ultrasonography (Figure 2). Calcitriol and phosphate were discontinued, and the patient was

treated with saline and furosemide diuresis until his serum calcium decreased, his tremulousness resolved, and his deep tendon reflexes returned to normal. The child was then discharged, taken off all medications. Four weeks later when the patient was readmitted to the hospital, his serum calcium was 13.3 mg/dL, phosphate 4.5 mg/dL,

BUN 34 mg/dL, creatinine 1.7 mg/dL creatinine clearance 29.7 mL/min/ 1.73 m2, PTH 64.4 pg/mL, and 1,25-dihydroxyvitamin D3 8.9 pg/mL (normal 15-50 pg/mL). With the clinical diagnosis of tertiary hyperparathyroidism, the patient was referred for subtotal parathyroidectomy. Twelve days after surgery, PTH level declined to 3.4 pg/mL and serum calcium concentration to 10.0 mg/dL, serum creatinine concentration decreased to 1.2 mg/dL, and creatinine clearance increased to 39.4 mL/min/1.73 m2. Five months after surgery his serum calcium, phosphate, and creatinine concentrations were 10.7, 4.2, and 1.0 mg/dL, respectively, and his creatinine clearance was 47.4 mL/min/1.73 m2. Because of hypercalciuria of 9.4 mg Ca/kg/ 24 hr, he was placed on chlorothiazide 20 mg/kg/24 hr. Sixteen months after surgery, the child’s

height was 116.7 cm (-5.0 S.D.), weight 25.1 kg (-2.75 S.D.), serum creatinine 0.9 mg/dL, and creatinine clearance 68.7 mL/min/1.73 m2, calcium 8.7 mg/dL, phosphate 3.0 mg/dL, PTH 0.9 pg/mL

(normal 1.0-5.0), 1,25-dihydroxy

Figure 2. Ultrasound of the right kidney demonstrating hyperechogenic kidney (small arrows) compared to the echogenicity of the liver (arrow).

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vitamin D3 14 pg/mL, and urine calcium excretion 3.4 mg/kg/day. Repeat skeletal survey revealed improved bone mineralization.





abdominal film and in the renal ultrasound. on


During the past decade, it has increasingly recognized that nephrocalcinosis is the most common complication observed in children with hypophosphatemic rickets.&dquo; All patients with nephrobeen

calcinosis have been treated according to the current recommended protocol of large oral doses of phosphate combined with active vitamin D metabolites.~ The pathophysiologic mechanisms associated with the development of nephrocalcinosis in these patients have not yet been fully clarified. Correlations between high doses of calcitriol and the development of nephrocalcinosis have been observed by Goodyer et al’ and Weber et a16; however, their patients were also treated with phosphate. In the Hyp mouse, the murine analog of the human disease, Meyer and Meyer&dquo; did not find histologic evidence of nephrocalcinosis in calcitrioltreated mice, whereas Marie et all’ found evidence of mild nephrocalcinosis only after treatment with high-dose calcitriol. The development of nephrocalcinosis may be related to the treatment with phosphate. In vitro studies demonstrated that high urine concentrations of phosphate can result in intratubular crystallization.13 Administration of large oral doses of phosphate to patients with hypophosphatemia results in high phosphate excretion and might consequently promote calcium phosphate precipitation in the kidney. Moreover, Reusz et al’


demonstrated that high phosphate intake in children with hypophosphatemic rickets is associated with absorptive hyperoxaluria, which can also contribute to the precipitation of calcium in the kidney. Administration of large oral doses of phosphate may also lower serum ionized calcium concentration, thereby stimulating the parathyroid glands, resulting in the development of secondary hyperpara-

thyroidism is known nephrocalcinosis.15 In a limited number of patients, it has been shown that subtotal parathyroidectomy or reduction in phosphate intake protected the kidneys from further damage. 16 In all cases of familial hypophosphatemic rickets and nephrocalcinosis described so far, the renal calcifications were detected by renal ultrasonography, which is regarded to be more sensitive than plain abdominal radiographs in the detection of nephrocalcinosis.’ Glomerular filtration rates in these patients remained normal or were only slightly reduced. In the present case, the nephrocalcinosis was detected by plain abdominal radiograph, indicating more extensive renal calcifications, and the glomerular filtration rate was markedly decreased. The presence of renal failure was evident also from the fact that our patient had a normal serum phosphate concentration due to the reduction in his glomerular filtration rate, whereas patients with hypophosphatemic rickets and secondary hyperparathyroidism have low serum phosphate concentrations.&dquo; It is possible that once renal failure developed in our patient, it by itself may have further contributed to the development of secondary or tertiary hyperparathyroidism and to the progression of nephrocalcinosis. Whereas the usual clinical practice


to cause

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in patients with renal failure is to reduce phosphate intake in order to suppress the activity of the parathyroid glands, the present patient continued to receive high oral phosphate doses, thus further stimulating the parathyroid glands. This resulted in high serum cal-

cium(Ca) and phosphate (P) concentrations and, hence, a high Ca X P product which might promote metastatic calcifications in the kidney, resulting in further deterioration in kidney function. 17

Interestingly, following subtotal parathyroidectomy and discontinuation of treatment with phosphate and vitamin D, the patient’s kidney function improved. This phenomenon could be related in part to the normalization of serum calcium concentration


surgery. Hypercalcemia has been shown to be associated with reduction in glomerular filtration rate which reversed upon correction of the hypercalcemia.2,1&dquo;19 However, based on the fact that the hypercalcemia-induced reduction in glomerular filtration rate is usually less severe than that observed in the present case 2,18 and the fact that the glomerular filtration rate remained decreased 16 months after surgery, it can be assumed that some of the renal damage was irreversible. Further long-term follow-up is required to observe the extent of permanent damage to the kidneys of our patient. This case demonstrates that children with hypophosphatemic rickets treated with oral phosphate and calcitriol must be followed closely. Routine studies should include frequent renal ultrasound examinations and continuous of serum calcium, monitoring phosphate, and PTH concentrations, as well as urine calcium excretion and creatinine clearance. Reusz et al5 suggests monitoring urine oxalate excretion as well.

Early detection of vitamin D intoxication, secondary hyperparathyroidism and nephrocalcinosis, and appropriate medical and surgical intervention might protect the kidneys from progressive failure, and might even enable reversibility of the renal damage. Moreover, in order to find a way to

prevent the development of

in this patient is an urgent there population, need for further studies addressing the mechanisms involved in the development of this complication.




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Nephrocalcinosis, hyperparathyroidism, and renal failure in familial hypophosphatemic rickets.

Nephrocalcinosis, Hyperparathyroidism, and Renal Failure in Familial Hypophosphatemic Rickets Uri Alon, M.D. Helen B. Lovell, M.D. David L. Donaldson,...
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