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Hypertension after renal transplantation and polymorphism of genes involved in essential hypertension: ACE, AGT, AT1R and ecNOS

A. Basset El-Essawy, P. Berthoux, S. Cécillon, C.Deprèle, D. Thibaudin, J.-P. De Filippis, E.Alamartine, and F. Berthoux

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Volume 57 (2002) p. 192 - 200

Abstract

A. Basset El-Essawy¹,², P. Berthoux¹,², S. Cécillon², C.Deprèle¹,², D. Thibaudin¹,², J.-P. De Filippis¹, E.Alamartine¹,² and F. Berthoux¹,²

¹Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, ²Research Group on Glomerulonephritides and Renal Transplantation, Faculty of Medicine, Saint-Etienne, France
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.

Original

A trial comparing local pain after subcutaneous injection of epoetin-b versus darbepoetin-a in healthy volunteers

F. Berthoux, J.-P. Ryckelynck, S. Rouanet, S. Gelu-Mantoulet, F. Montestruc, P. Mouchel and G. Choukroun on behalf of the PAINLESS investigators and coordinators

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Volume 70 (2008) p. 33 - 40

Abstract

F. Berthoux¹, J.-P. Ryckelynck², S. Rouanet³, S. Gelu-Mantoulet³, F. Montestruc⁴, P. Mouchel⁴ and G. Choukroun⁵ on behalf of the PAINLESS investigators and coordinators

¹Department of Nephrology, Dialysis and Renal Transplantation, North University Hospital Saint-Etienne, ²Department of Nephrology, Dialysis and Transplantation CHU de Caen, ³Therapharm Research Caen, ⁴F. Hoffmann-La Roche Ltd., Neuilly-sur-Seine, ⁵Department of Internal Medicine, Nephrology, Dialysis and Transplantation, CHU Amiens and Jules Verne University, Amiens, France
Background: The aim of this study was to compare local pain experienced with subcutaneous (s.c.) injection of epoetin-b vs. darbepoetin-a. Methods: 40 healthy volunteers were enrolled into this single-blind, crossover study. After receiving an injection of placebo, individuals were randomized to receive s.c. injections of epoetin-b 6,000 IU (0.3 ml) or darbepoetin-a 30 mg (0.3 ml), with a 1-week washout period between injections. Local pain was evaluated using a Visual Analog Scale (VAS) and a 6-item Verbal Rating Scale (VRS) immediately after (T₀) and 1 h after injection (T₁). Results: The respective mean (standard deviation) and median (range) VAS values at T0 were 1.2 (1.7) and 0.5 (0.0 – 6.9) for epoetin-b vs. 2.8 (2.4) and 1.9 (0.0 – 9.0) for darbepoetin-a (p<0.0001). At T0, VRS scores demonstrated that 51% of individuals experienced no pain after epoetin-b injection compared with 16% of those receiving darbepoetin-a. The percentage of individuals perceiving moderate or important pain was significantly greater with darbepoetin-a (38%) compared with epoetin-b (5%, p = 0.0005) and placebo (14%). Pain evaluation at T₁ showed no difference between treatment groups. Local tolerance was excellent except for a small hematoma with epoetin-b at T₁ and with darbepoetin-a at T0 which persisted at T₁. Conclusion: In healthy volunteers, s.c. injection of epoetin-b was significantly less painful than with darbepoetin-a and comparable with placebo. No significant pain was apparent at T₁ in any group.Correspondence to:
F. Berthoux, MD
Department of Nephrology, Dialysis and Renal Transplantation
Hôpital Nord CHU de Saint-Etienne
42055 Saint-Etienne Cedex 2, France
Email: [email protected]

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