Background: Urinary concentration impairment is a major feature of cyclosporine nephrotoxicity. Methods: We explored two possible mechanisms that may underlie cyclosporineinduced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II). Results: In Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88 ±3%, p<0.05). Conclusion Both water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Background: Urinary concentration impairment is a major feature of cyclosporine nephrotoxicity. Methods: We explored two possible mechanisms that may underlie cyclosporineinduced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II). Results: In Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88 ±3%, p<0.05). Conclusion Both water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Three cases of hisiocytic medullary reticulosis occurring in children aged 6 years, 9 years and 14 years, are described. In all children the diagnosis was based on anemia, granulocytopenia, thrombocytopenia and marked erythrophagocytosis by bone marrow and lymph node atypical histiocytes. They all showed immediate remission with combined chemotherapy of vinblastine and prednisolone, but Case 1 eventually died at 6 months after onset of this rapidly progressive, fatal illness and Case 2, 3 are alive 14 months after onset of their illness.
Agranulocytosis ; Anemia ; Bone Marrow ; Child ; Diagnosis ; Drug Therapy ; Histiocytes ; Humans ; Lymph Nodes ; Prednisolone ; Thrombocytopenia ; Vinblastine