Zinc nutritional status modifies renal osteodystrophy in uremic rats

Background: Previous studies from our laboratories suggested that zinc depl etion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25( OH)(2)D, calcitriol) in calcium- and phosphorus-depleted rats with normal r enal function., and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D me tabolites, PTH response,, mineral balance and bone histomorphometry in anim als with different zinc nutritional and renal functional status. Methods: F ifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -depl ete (-) diets for two weeks. Thereafter, half of each paired group underwen t nephrectomy (N), while half had sham (S) operations. Animals were observe d for eight weeks after surgery. External mineral balances of zinc, calcium , phosphate and magnesium were determined before surgery, and 1, 2 and 7 we eks after surgery. Plasma creatinine,, zinc, calcium, phosphorus, magnesium . 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrific e. Static and dynamic bone histomorphometry was determined by standard tech niques. Results: After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels. and nephrectomized animals had lower creatini ne clearances than respective controls at sacrifice. Plasma calcium and pho sphorus concentrations were similar in all four groups at sacrifice. Plasma magnesium concentrations were similar in groups with renal insufficiency, regardless of zinc nutritional status. Plasma 25-hydroxycholecalciferol and calcitriol levels were similar in all groups, There was no difference betw een mean PTH concentration in sham-operated animals, regardless of zinc nut ritional status. Although nephrectomized groups' PTH levels were increased compared to S controls, PTH levels were increased in +Zn/N animals compared to the -Zn/N group. Zinc-deplete groups had consistent negative net zinc b alance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of di fferent zinc nutritional status were compared. Nephrectomized animals had h istomorphometric changes indicative of higher bone turnover and abnormal mi neralization. Zinc deficiency was associated with less evidence of increase d parathyroid hormone activity on bone in nephrectomized rats. Conclusions: Zinc depletion limits the increase in plasma PTH concentration and the exp ression of secondary hyperparathyroid bone disease during the development o f renal insufficiency in the renal ablation model of uremia in rats. The me chanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PT H on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight t he potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.