POSTTRANSPLANT DIASTOLIC HYPERTENSION - ASSOCIATIONS WITH INTRAGRAFT TRANSFORMING-GROWTH-FACTOR-BETA, ENDOTHELIN, AND RENIN TRANSCRIPTION

Background Diastolic hypertension after renal transplantation leads 60 significant chronic morbidity and mortality, Recently, calcineurin ph osphatase inhibition by cyclosporine or tacrolimus has been postulated to lead to diastolic hypertension through the induction of transformi ng growth factor-beta (TGF-beta) and resultant endothelin-mediated ren al arteriolar vasospasm, Methods. To investigate this hypothesis in hu mans, the allografts of 40 stable renal allograft recipients were biop sied 2 to 3 years after transplantation. Both cyclosporine and tacroli mus patients were included. Biopsies were divided and processed for hi stology and RNA extraction, RNA was then converted to cDNA and evaluat ed by semiquantitative polymerase chain reaction (actin-standardized, high-performance liquid chromatography-quantitated) for TGF-beta, endo thelin, and renin transcription. Inflammatory cytokine gene transcript ion was also evaluated, Blood pressure was measured during the clinic check-in before biopsy. Variables were evaluated by Spearman rank corr elation coefficient (r(8)) analysis. Results. Diastolic hypertension w as prevalent in the study population, with 40% of individuals having d iastolic pressure>90 mmHg, TGF-beta and endothelin transcription were detected in 88% of biopsies studied, and renin transcription was detec ted in 91%, Intragraft transcription of TGF-beta (r(8)=0.61, P=0.0003) and endothelin (r(8)=0.43, P=0,0188) was strongly correlated with inc reasing transcription intragraft renin. in turn, renin transcription w as strongly correlated with increasing diastolic blood pressure (r(8)= 0.55, P=0.0015), Histological correlation of fibrosis score did not pr edict the degree of hypertension, nor did it correlate with TGF-beta t ranscription. Inflammatory cytokine transcription was not related to r enin transcription or diastolic hypertension but was correlated with h istological evidence of immune graft injury. Conclusions. These data s upport the hypothesis that posttransplant diastolic hypertension is a result of TGF-beta-induced, endothelin-mediated arteriolar vasoconstri ction and subsequent activation of the renin-angiotensin pathway. Thes e effects are independent of immune-mediated graft injury.