Hypercalcemic nephropathy: chronic disease with predominant medullary inner stripe injury

Because of the recently observed augmentation of medullary hypoxic injury by calcium in isolated perfused rat kidneys (Kidney Int 34:186-194, 1988), renal morphology of chronic, prolonged hypercalcemia was investigated in vivo. Rats were treated with repeated injections of vitamin D2 (400,000 units/week) for two to eight weeks. Chronic elevation of plasma calcium from 2.1 to 2.8 mmol/liter (P less than 0.001) was associated by a fall in maximal urine osmolality with no change in glomerular filtration rate. The most significant morphological alterations occurred in the inner stripe of the outer medulla; these changes were characterized by a sequence of active injury with subsequent destruction and atrophy of the medullary thick ascending limbs, fibroblastic and lymphocytic infiltration, and secondary dilatation of collecting ducts. Similar changes occurred in the medullary rays. These alterations were accompanied by increased renal prostanoid production and a predisposition to acute kidney failure from indomethacin. Because of its selective occurrence in zones of poorest oxygen supply, this inner stripe injury may derive from vulnerability to hypoxia and may play a role in some chronic nephropathies.