Histological long-term outcome of furosemide-induced nephrocalcinosis in the young rat

Abstract

The long-term prognosis of furosemide-associated nephrocalcinosis in the infant is still unclear. Although discontinuation of the diuretic often results in radiological resolution of the calcifications, functional abnormalities may persist. The natural history of the renal histopathology of these patients is yet unknown. In the present study we investigated the histological long-term outcome of furosemide-induced nephrocalcinosis in the young rat. Thirty-six weanling male Sprague-Dawley rats were divided into three groups: A controls, B furosemide given for 8 weeks, and C furosemide given for 2 weeks followed by 6 weeks of observation. Metabolic studies at the end of the experiment demonstrated a significant diuretic and natriuretic effect in group B. Kidney histology showed nephrocalcinosis scores (mean +/- SD) of 0.0 +/- 0.0 in A, 2.6 +/- 1.5 in B, and 0.8 +/- 0.6 in C, with B significantly higher than A and C, and C greater than A. Kidney calcium content in B (3,421.9 +/- 2,558.7 micrograms/g dry tissue) was significantly greater than in A (310.4 +/- 21.3) and C (1470.1 +/- 932.2). Another group of 6 rats receiving 2 weeks treatment of furosemide showed a nephrocalcinosis score of 2.2 +/- 1.5, not different from group B, and an additional group of 6 rats treated with furosemide for 2 weeks and observed for another 12 weeks showed a score of 1.3 +/- 0.4, not different from group C. We conclude that most of the renal calcifications induced by furosemide occur during the early days of treatment and that up to 12 weeks after discontinuation of the diuretic, the resolution of the calcifications is only partial.

Development of an animal model of nephrocalcinosis via selective dietary sodium and chloride depletion

“…furosemide for four weeks (27). Furthermore, as previous clinical data also suggest, calcifications do not resolve in all animals after discontinuation of furosemide treatment (17). However, in the present and previous studies we found that rats fed selective sodium deficient diet did not develop NC (21).…”

“…A prior model using i.p. furosemide alone in weanling rats on a control diet was able to induce NC (17), however these changes could not be reproduced in our preliminary experiments. Also, furosemide has not been shown to induce NC in adult rats fed control diets (18).…”

Nephrocalcinosis in full-term infants receiving furosemide treatment for congestive heart failure: a study of the incidence and 2-year follow up

“…One explanation for this may be that the active growth of these infants would have caused a reduction of furosemide relative to body weight with time. Nevertheless, the early manifestation of nephrocalcinosis after onset of furosemide administration has also been supported by an animal model [4]. Our ®nding thus indicates that whenever possible non-calciuric diuretics should be used from the very beginning of treatment of infants in heart failure.…”

“…Many preterm infants are prone to increased urinary calcium excretion [1], which may be further aggravated by factors such as metabolic acidosis, prolonged immobility, reduced urinary output followinḡ uid restriction, and also by the possible use of xanthines and glucocorticoids [1,2,9,12,17]. Human and animal studies nevertheless suggest that the development of nephrocalcinosis does not always require hypercalciuria [4,14], but that alterations in urinary inhibitors of crystal formation, urinary excretion of oxalate and urine pH, for example, may also play a role [1,2,12].…”

Resolution of medullary nephrocalcinosis in children with metabolic bone disorders

“…Downing et al [18] demonstrated abnormal (urine-blood) pCO2 in all ten children in whom furosemide-related NC had resolved. A possible explanation for the persistence of functional abnormalities was provided in our animal model of furosemide-induced NC, in which after stopping the diuretic there was a significant decrease in the magnitude of renal calcifications, but they did not completely resolve even up to 12 weeks after discontinuation of the medication [19]. Renal calcifications as the etiology of tubular acidification defect was demonstrated by Bonilla-Felix et al [20] in children with hypercalciuria.…”