Nephrocalcinosis diuretics

Four children with the nephrotic syndrome developed transient hypercalciuria and intraluminal calcification in renal histopathological specimens without radiological evidence of renal calcification. These children were resistant to corticosteroids and were receiving furosemide plus albumin for the management of edema (10). This result stresses the pervasive effect of furosemide, and probably all loop diuretics, in increasing urinary calcium excretion, with resultant nephrocalcinosis. Whenever possible, steps should be taken to limit the hypercalciuric effect of loop diuretics. Such maneuvers could include limiting the sodium content of the diet and/or combining the loop diuretic with a thiazide diuretic. 

Diuretics have been shown to have variable effects in relationship to urinary calcium excretion and supersaturation, most notably including loop diuretic induced hypercalciuria and attenuation of urinary calcium excretion by thiazide diuretics. The factors contributing to nephrotoxicity are most commonly associated with multiple factors that favor calcium salt or uric acid deposition at the tubulo-interstitial level. Management of renal stone formation and nephrocalcinosis therefore presents a unique clinical challenge, balancing factors that increase risk for abnormal calcium salt deposition or crystallization, and factors that reduce this risk. 

Loop diuretic therapy has been implicated in the development of renal calcifications in both preterm and full-term infants [99-105]. In a study by Jacinto et al., nephrocalcinosis occurred in 20 of 31 (64%) of premature infants with birth weights less than 1500 g, with 65% of affected infants having received furo-semide [103]. Nephrocalcinosis was found in 14% of full-term infants with congestive heart failure receiving long-term furosemide therapy [104]- Furosemide may induce high urinary calcium excretion rates and low urinary citrate to creatinine ratio, risk factors for renal calcification [106]. 

Dose and length of therapy with loop diuretics may predict the likelihood of developing calcium deposits in the renal parenchyma. Ten premature infants developed nephrocalcinosis after receiving furosemide at a dose of at least 2 mg/kg per day for 12 days [102]. In a study by Saarela et al, infants who developed renal calcifications were receiving higher daily doses of furosemide than infants who had not developed this complication (1.9 + 0.6 vs. 1.3 + 0.4 mg/kg per day p value-0.01) [104]. Calcifications were diagnosed within a few months of initiating furosemide. 

Spontaneous resolution of nephrocalcinosis usually occurs within 6 months after discontinuation of loop diuretic therapy [106], but may persist for greater than 1 year [100, 104]. Measurement of serum calcium-to-creatinine ratio may be predictive of resolution when nephrocalcinosis is first diagnosed. Premature infants with unresolved nephrocalcinosis had mean calcium-to-creatinine ratios upon initial diagnosis that were approximately five-fold greater than ratios in infants with resolved nephrocalcinosis (2.23 0.99 vs. 0.34 +... 

Since unresolved nephrocalcinosis may lead to residual abnormalities in the kidney including microscopic hematuria, hypercalcemia, and impaired tubular function [100,104,105], renal ultrasonography within a few months of initiating loop diuretics may be warranted [100 104]. If long-term diuretic therapy is needed, a thiazide diuretic alone or in combination with furosemide may reduce the risk of renal calcifications by decreasing urinary calcium and oxalate excretion [100,102,104,107,108]. However, two studies of premature infants failed to show a reduction in either urinary oxalate or calcium excretion when thiazides were added to furosemide therapy [107,109]. 

Pope, IV JC,Trusler LA, Klein AM, Walsh WF, Yared A, Brock, III JW.The natural history of nephrocalcinosis in premature infants treated with loop diuretics. J Urol 1996 156 709-712. 

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