Calcium phosphate supersaturation regulates stone formation in genetic hypercalciuric stone-forming rats

Background Hypercalciuria is the most common metabolic abnormality observed in patients with nephrolithiasis. Hypercalciuria raises urine supersaturat ion with respect to the solid phases of calcium oxalate and calcium phospha te, leading to an enhanced probability for nucleation and growth of crystal s into clinically significant stones. However, there is little direct proof that supersaturation itself regulates stone formation. Through successive inbreeding of the most hypercalciuric progeny of hypercalciuric Sprague-Daw ley rats, we have established a strain of rats, each of which excrete abnor mally large amounts of urinary calcium and each of which forms calcium phos phate kidney stones. We used these hypercalciuric (GHS) rats to test the hy pothesis that an isolated reduction in urine supersaturation, achieved by d ecreasing urine phosphorus excretion, would decrease stone formation in the se rats. Methods. Thirty 44th-generation female GHS rats were randomly divided into three groups. Ten rats received a high-phosphorus diet (0.565% phosphorus), 10 a medium-phosphorus diet (0.395% phosphorus), and 10 a low-phosphorus d iet (0.225% phosphorus) for a total of IX weeks. The lowered dietary phosph orus would be expected to result in a decrease in urine phosphorus excretio n and a decrease in urinary supersaturation with respect to the calcium pho sphate solid phase. Every two weeks, 24-hour urine collections were obtaine d. All relevant ions were measured, and supersaturation with respect to cal cium oxalate and calcium hydrogen phosphate were determined. At the conclus ion of the experiment, each rat was killed, and the kidneys, ureters, and b ladder were dissected en block and x-rayed to determine whether any stones formed. A decrease in stone formation with a reduction in urinary supersatu ration would support the hypothesis that supersaturation alone can regulate stone formation. Results. Decreasing the dietary phosphorus intake led to a progressive decr ease in urine phosphorus excretion and an increase in urine calcium excreti on, the latter presumably caused by decreased intestinal calcium phosphate binding anti increased calcium absorption. With decreasing dietary phosphor us intake, there was a progressive decrease in saturation with respect to t he calcium phosphate solid phase. Fifteen of the 20 kidneys from the 10 rat s fed the high-phosphorus diet had radiographic evidence of kidney stone fo rmation, whereas no kidneys from the rats fed either the medium- or low-pho sphorus diet developed kidney stones. Conclusions. A decrease in urine phosphorus excretion not only led to a dec rease in urine supersaturation with respect to the calcium phosphate solid phase but to an elimination of renal stone formation. The results of this s tudy support the hypothesis that variation in supersaturation alone can reg ulate renal stone formation. Whether a reduction of dietary phosphorus will alter stone formation in humans with calcium phosphate nephrolithiasis rem ains to be determined.