Development of chronic allograft rejection and arterial hypertension in Brown Norway rats after renal transplantation

The cardiovascular and renal pathophysiology associated with chronic renal allograft rejection under triple drug immunosuppressive treatment was studi ed using a recently developed model (Brown Norway (BN) rats) in a 6-week ex periment. Renal transplantation was performed to 10-week-old rats in a rat strain combination of Dark Agouti (DA) --> BN. The right kidney was removed from another group of BN rats (uninephrectomized). A triple drug treatment comprising cyclosporine (10 mg/kg subcutaneously, s.c.), azathioprine (2 m g/kg s.c.) and methylprednisolone (1.6 mg/kg s.c.) was given to each rat da ily for 6 weeks. A control group underwent no operations nor drug treatment . After the transplantation, the systolic blood pressure in this group was increased from 116 +/- 2 to 166 +/- 2 mmHg, while in the uninephrectomized group the rise was from 115 +/- 4 to 146 +/- 4 mmHg, and no change was obse rved in the blood pressures of the control group. The vascular relaxation r esponses of mesenteric arterial rings in vitro to acetylcholine were inhibi ted in both the transplantation group and the uninephrectomized group as co mpared with the control group, but few significant differences were found i n the contraction responses to noradrenaline and potassium chloride. Graft histology was examined after 6 weeks, quantified by using the chronic allog raft damage index (CADI). Changes specific to a chronic rejection reaction were observed in the allografts (CADI mean 6.0) but no injuries were seen i n the rats' own kidneys (CADI mean 1.2). Our findings show that allograft r ejection in BN rats after renal transplantation is associated with the deve lopment of arterial hypertension. The combination of cyclosporine, methylpr ednisolone and azathioprine also rises blood pressure in uninephrectomized BN rats. The hypertensive effects of the drug treatment and graft rejection are associated with endothelial dysfunction.