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Posttransplant diastolic hypertension: associations with intragraft transforming growth factor-beta, endothelin, and
A D Kirk1, L M Jacobson, D M Heisey
1Division of Transplantation, University of Wisconsin School of Medicine, Madison 53792, USA.
Insights
Post-transplant diastolic hypertension in renal allograft recipients is linked to transforming growth factor-beta (TGF-beta) and endothelin-mediated vasoconstriction, activating the renin-angiotensin system. This pathway is independent of immune graft injury.
Area of Science:
- Nephrology
- Transplantation Immunology
- Cardiovascular Physiology
Background:
- Diastolic hypertension is a significant complication post-renal transplantation, contributing to morbidity and mortality.
- Calcineurin inhibitors like cyclosporine and tacrolimus are suspected to induce hypertension via TGF-beta and endothelin pathways, causing renal arteriolar vasospasm.
Purpose of the Study:
- To investigate the role of transforming growth factor-beta (TGF-beta) and endothelin in post-transplant diastolic hypertension in humans.
- To determine the correlation between TGF-beta, endothelin, renin transcription, and blood pressure in renal allograft recipients.
Main Methods:
- Renal allograft biopsies were obtained from 40 stable recipients (cyclosporine and tacrolimus users).
- Semiquantitative PCR was used to assess intragraft transcription of TGF-beta, endothelin, and renin.
- Blood pressure was measured, and correlations with gene transcription and histology were analyzed using Spearman rank correlation.
Main Results:
- Diastolic hypertension was prevalent (40% >90 mmHg).
- TGF-beta and endothelin transcription strongly correlated with renin transcription, which in turn correlated with diastolic blood pressure.
- Intragraft TGF-beta and endothelin levels were associated with renin activation, not fibrosis or immune injury.
Conclusions:
- The study supports the hypothesis that post-transplant diastolic hypertension results from TGF-beta-induced, endothelin-mediated vasoconstriction and renin-angiotensin system activation.
- These vascular effects appear independent of immune-mediated graft injury.
Background:
Diastolic hypertension after renal transplantation leads to significant chronic morbidity and mortality. Recently, calcineurin phosphatase inhibition by cyclosporine or tacrolimus has been postulated to lead to diastolic hypertension through the induction of transforming growth factor-beta (TGF-beta) and resultant endothelin-mediated renal arteriolar vasospasm.
Methods:
To investigate this hypothesis in humans, the allografts of 40 stable renal allograft recipients were biopsied 2 to 3 years after transplantation. Both cyclosporine and tacrolimus patients were included. Biopsies were divided and processed for histology and RNA extraction. RNA was then converted to cDNA and evaluated by semiquantitative polymerase chain reaction (actin-standardized, high-performance liquid chromatography-quantitated) for TGF-beta, endothelin, and renin transcription. Inflammatory cytokine gene transcription was also evaluated. Blood pressure was measured during the clinic check-in before biopsy. Variables were evaluated by Spearman rank correlation coefficient (rs) analysis.
Results:
Diastolic hypertension was prevalent in the study population, with 40% of individuals having diastolic pressure >90 mmHg. TGF-beta and endothelin transcription were detected in 88% of biopsies studied, and renin transcription was detected in 91%. Intragraft transcription of TGF-beta (rs=0.61, P=0.0003) and endothelin (rs=0.43, P=0.0188) was strongly correlated with increasing transcription intragraft renin. In turn, renin transcription was strongly correlated with increasing diastolic blood pressure (rs=0.55, P=0.0015). Histological correlation of fibrosis score did not predict the degree of hypertension, nor did it correlate with TGF-beta transcription. Inflammatory cytokine transcription was not related to renin transcription or diastolic hypertension but was correlated with histological evidence of immune graft injury.
Conclusions:
These data support the hypothesis that posttransplant diastolic hypertension is a result of TGF-beta-induced, endothelin-mediated arteriolar vasoconstriction and subsequent activation of the renin-angiotensin pathway. These effects are independent of immune-mediated graft injury.