BACKGROUND FK506 is a useful agent in the prevention of allograft rejection but has recently been shown to be nephrotoxic. METHODS Sprague-Dawley rats (n = 40) were divided into four groups: control (C); low-salt (LS); FK506, 3 mg/kg daily by gavage (FK); and FK506-low-salt (FK-LS). After 6 weeks, the animals underwent physiologic studies and were sacrificed with perfusion fixation of the kidneys. Semiquantitative analysis of morphologic injury was performed as well as grading of juxtaglomerular apparatus (JGA) granularity (1-micron plastic sections). Computer-assisted morphometry was used to measure medullary thick ascending limb (mTAL) size within the inner stripe. RESULTS Serum creatinine and plasma renin activity were significantly elevated only in the FK-LS group, but both FK groups had significantly increased fractional excretion of Mg. Tubular atrophy and fibrosis involving medullary rays and inner stripe (areas of low oxygen availability) was minimally present in FK, but prominent in FK-LS (P < 0.001). Injury correlated with decreased function (P < 0.001). Variance of mTAL size, an expression of co-existent tubular atrophy and hypertrophy was significantly greater in FK-LS and correlated with decreased renal function and urine osmolality (P < 0.001). JGA granularity was increased by FK506 (P < 0.006) with the highest values in FK-LS (P < 0.001), and strongly correlated with injury (P < 0.001). JGA granularity did not correlate with circulating renin activity levels, suggesting local activation of a renin-angiotensin system. CONCLUSIONS FK506 compromises renal parenchymal zones which are known to have limited oxygen availability (medullary ray and inner stripe), a pattern that has been observed with other nephrotoxins. The injury is potentiated by salt depletion and may be mediated by the renin-angiotensin system. Furthermore, these findings illustrate the close correlation between the medullary injury that was observed and the impaired function that was documented.