Zinc nutritional status modifies renal osteodystrophy in uremic rats.
BACKGROUND
Previous studies from our laboratories suggested that zinc depletion reduces the circulating level of 1,25-dihydroxycholecalciferol (1,25(OH)2D, calcitriol) in calcium- and phosphorus-depleted rats with normal renal function, and rats with uremia. Since calcitriol synthesis is in part dependent on renal function, we studied levels of circulating vitamin D metabolites, PTH response, mineral balance and bone histomorphometry in animals with different zinc nutritional and renal functional status.


METHODS
Fifty-eight male Sprague-Dawley rats were pair-fed zinc-replete (+) or -deplete (-) diets for two weeks. Thereafter, half of each paired group underwent nephrectomy (N), while half had sham (S) operations. Animals were observed for eight weeks after surgery. External mineral balances of zinc, calcium, phosphate and magnesium were determined before surgery, and 1, 2 and 7 weeks after surgery. Plasma creatinine, zinc, calcium, phosphorus, magnesium, 25-hydroxycholecalciferol, calcitriol and PTH were determined at sacrifice. Static and dynamic bone histomorphometry was determined by standard techniques.


RESULTS
After an 8-week observation period, zinc-depleted animals had lower plasma zinc levels, and nephrectomized animals had lower creatinine clearances than respective controls at sacrifice. Plasma calcium and phosphorus 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 between mean PTH concentration in sham-operated animals, regardless of zinc nutritional 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 balance, however, there was no consistent effect of nephrectomy on external calcium, phosphorus, or magnesium balance, when nephrectomized groups of different zinc nutritional status were compared. Nephrectomized animals had histomorphometric changes indicative of higher bone turnover and abnormal mineralization. Zinc deficiency was associated with less evidence of increased parathyroid hormone activity on bone in nephrectomized rats.


CONCLUSIONS
Zinc depletion limits the increase in plasma PTH concentration and the expression of secondary hyperparathyroid bone disease during the development of renal insufficiency in the renal ablation model of uremia in rats. The mechanism underlying this effect is unknown, but may involve a direct effect of zinc on the synthesis, release, metabolic clearance, and/or action of PTH on the cellular level, on the interrelationship of calcitriol and PTH, or a direct effect of zinc on bone mineral metabolism. These data highlight the potential relevance of zinc nutritional status to mineral metabolism in patients with chronic renal insufficiency and end-stage renal disease.
Kimmel
P L
PL
Department of Medicine, George Washington University Medical Center, Washington, DC 20037, USA.
Langman
C B
CB
Bognar
B
B
Faugere
M C
MC
Chawla
L S
LS
Watkins
D W
DW
Malluche
H H
HH
D000818:Animals; D002117:Calcitriol / Q000097:blood*; D002118:Calcium / Q000097:blood; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000209:etiology / Q000378:metabolism*; D008274:Magnesium / Q000097:blood; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism; D014511:Uremia / Q000150:complications / Q000378:metabolism*; D015032:Zinc / Q000172:deficiency*
D010281:Parathyroid Hormone; D002117:Calcitriol; D008274:Magnesium; D015032:Zinc; D002118:Calcium