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Hypertension after renal transplantation and polymorphism of genes involved in essential hypertension: ACE, AGT, AT1
El-Essawy A Basset1, P Berthoux, S Cécillon
1Nephrology, Dialysis and Renal Transplantation Department, Hĵpital Nord, CHU de Saint-Etienne, France.
Insights
Genetic variations in endothelial nitric oxide synthase (ecNOS) may influence hypertension after kidney transplants. The ecNOS-a allele appears to protect against severe post-transplant hypertension, requiring fewer medications.
Area of Science:
- Nephrology
- Pharmacogenomics
- Cardiovascular Medicine
Background:
- Arterial hypertension (HT) is a common complication following renal transplantation (RTx), affecting up to 70% of recipients.
- This HT is often severe and linked to calcineurin inhibitor-induced vasoconstriction and fluid retention.
- Cyclosporine A (CsA) is a primary immunosuppressant contributing to post-transplant HT.
Purpose of the Study:
- To investigate the association between genetic polymorphisms in key hypertension-related genes and the development/severity of HT post-RTx.
- To identify genetic factors influencing CsA-induced HT in renal transplant recipients.
Main Methods:
- Retrospective analysis of 294 renal transplant recipients treated with CsA.
- Molecular biology study of polymorphisms in angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1-R), and endothelial constitutive nitric oxide synthase (ecNOS).
- Correlation of genetic data with HT prevalence and severity, defined by blood pressure and antihypertensive medication use.
Main Results:
- No significant differences in ACE, AGT, AT1-R, or ecNOS genotype distributions were found between recipients and controls.
- HT prevalence was high (72% at 5 years, 78% at 10 years) among functioning grafts.
- The ecNOS-a allele and non-bb genotype were significantly associated with less severe HT and reduced need for antihypertensive drugs (p=0.001).
Conclusions:
- Genetic polymorphisms in ACE, AGT, and AT1-R did not significantly impact HT development or severity in this CsA-treated RTx cohort.
- The ecNOS-a allele may offer a protective effect against severe post-transplant hypertension.
- This protective effect might be related to CsA-induced upregulation of ecNOS activity, though further research is needed.
Background:
Arterial hypertension (HT), secondary to cyclosporine A (CsA) used as main immunosuppressive treatment in renal transplantation (RTx), is very frequent (70%), usually severe and explained mostly by vasoconstriction of the glomerular afferent arteriole with secondary sodium and water retention.
Material And Methods:
In a retrospective study, we have analyzed 294 consecutive recipients receiving a first renal cadaveric allograft and all treated with CsA (the majority with triple therapy). We studied, by molecular biology, the polymorphism of genes previously implicated in essential HT such as: angiotensin-converting enzyme (ACE: II, ID and DD), angiotensinogen (AGT: MM, MT and TT), angiotensin II type 1 receptor (AT1-R: AA, AC and CC) and endothelial constitutive nitric oxide synthase (ecNOS: aa, ab and bb), and correlated the data to the prevalence and severity of post-Tx HT. This cohort included 195 (66%) males and 99 females with a mean age of 42 years at time of Tx. The presence and severity of post-Tx HT were indicated by initial persistent blood pressure over 140/90 mmHg with the need for at least one anti-hypertensive drug and by the number of anti-HT medications required to achieve its control.
Results:
The distribution of the specific alleles and genotypes for ACE, AGT, AT1-R, and ecNOS was not different in transplant recipients compared to 181 controls. At 5 years post-Tx, the prevalence of HT was 72% (169 out of 235) among functioning grafts. There was no significant difference for ACE, AGT, AT1R and ecNOS genotypes distribution between hypertensive vs non-HT recipients. The number of anti-hypertensive drugs prescribed was not different among ACE, AGT, and AT1-R genotypes. However, the a allele and the non-bb genotype (aa + ab) for ecNOS were significantly (p = 0.001) associated with a less severe HT, needing fewer anti-HT drugs. At 10 years post-Tx, the HT prevalence remained high 78% (67 out of 86) among functioning Tx. However, the limited numbers did not allow further correlation.
Conclusions:
This study produced mainly negative results except for ecNOS-a allele, which seems to protect against severe hypertension. The explanation remains speculative but probably relates to the known cyclosporine-induced upregulation of ecNOS gene and enzyme activity.
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