José Carlos Rodríguez-Pérez

Association of angiotensinogen m235t and a(-6)g gene polymorphisms with coronary heart disease with independence of essential hypertension: the procagene study

OBJECTIVES We examined the relationship between the angiotensinogen (AGT) gene M235T polymorphism, the variant promoter of the AGT gene A(-6)G and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary heart disease (CHD) in native Gran Canaria Island habitants, who have the highest rates of CHD in Spain. BACKGROUND Some studies subject that the ACE (I/D) polymorphism could be associated with CHD, while AGT (M235T) has been related to essential hypertension. METHODS We studied 304 subjects with angiographic evidence of coronary artery disease and a clinical diagnosis of myocardial infarction or unstable angina and 315 age- and gender-matched controls. Blood was drawn and DNA extracted. Angiotensin-converting enzyme (I/D) gene polymorphism was analyzed by polymerase chain reaction (PCR) and AGT gene polymorphisms by restriction fragment length polymorphism-PCR and mutagenically-separated PCR. RESULTS The ACE (I/D) polymorphism showed no association with CHD, whereas the frequency distribution of AGT (M235T) genotypes among patients and controls (235T: 29.1% and 19.0%; M235T: 48.5% and 50.2%; M235: 22.4% and 30.8%, respectively) was statistically different (p = 0.005) and not related to the presence of essential hypertension. Similar results were observed with the AGT A(-6)G polymorphism. In multiple logistic regression analysis, CHD odds ratio associated with 235T and M235 homozygotes were 1.7 (1.1 to 2.6) and 0.54 (0.36 to 0.82), respectively. CONCLUSIONS This study shows that genetic variation of the AGT (M235T), but not the ACE (I/D), genotypes contributes to the presence of CHD independently of blood pressure profile in a subset of the Spanish population with a high prevalence of cardiovascular disease.

Allelic Variants of the Human Scavenger Receptor Class B Type 1 and Paraoxonase 1 on Coronary Heart Disease: Genotype-Phenotype Correlations

Objective—The antioxidant properties of high-density lipoprotein (HDL) have been attributed to paraoxonase (PON) enzyme activity. Human scavenger receptor class B type 1 (SR-BI; CD36 and lysosomal integral membrane protein-II analogous-1 [CLA-1]) plays a central role in HDL-mediated native and oxidized cholesteryl ester uptake. We tested for a significant contribution of common variant of these genes to coronary heart disease (CHD) risk and hypothesized that genetic-mediated PON activity and CLA-1/SR-BI receptor functional properties jointly reduce plasma oxidation status. Methods and Results—We studied 304 cases and 315 controls. Polymorphisms were analyzed by polymerase chain reaction–restriction fragment analysis. CLA-1/SR-BI–relative expression levels and mRNA stability were analyzed by the comparative threshold cycle method. There was a significant difference in the male genotype distribution of the CLA-1/SR-BI exon 8 (C8/T8) variant between groups with an odds ratio of 1.7 (95% CI, 1.16 to 2.51). This significant risk was restricted to those subject carriers of Arg (R) and Leu (L) allele of the PON1 192 and 55 variants and was confirmed in multiple logistic regression analysis. CLA-1/SR-BI mRNA expression levels differed according to CLA-1/SR-BI genotypes. Conclusions—These data suggest a plausible genetic interaction between the CLA-1 exon 8 gene polymorphism and the risk of CHD in males.

Kidney transplants in HIV-positive recipients under HAART. A comprehensive review and meta-analysis of 12 series

BACKGROUND Kidney transplantation is being introduced gradually for the treatment of end-stage renal disease in patients who are human immunodeficiency virus (HIV) positive. Our aim was to review the outcomes of kidney transplantation in HIV-positive recipients who were being treated with highly active antiretroviral therapy (HAART). METHODS Eligible papers were English language manuscripts, published between July 2003 and April 2009 and available through Medline, that described three or more recipients of kidney transplants who were HIV positive and undergoing HAART. The regimens for induction and maintenance therapy, organ rejection, patient survival, CD4 counts, HIV progression, infectious complications and deaths were recorded. The survival at 1 year, organ rejection and infectious complications were evaluated using a random effects model with 95% confidence intervals (CI). RESULTS Twelve case series met the defined criteria. Induction therapy consisted most commonly of the administration of anti-CD25 monoclonal antibodies, and triple immunosuppressive therapy was used most commonly for maintenance. Among the 254 patients, 1-year survival was 0.93 (95% CI, 0.90-0.96), organ rejection was diagnosed in 0.36 (95% CI, 0.25-0.49) and infectious complications occurred in 0.29 (95% CI, 0.17-0.43). The CD4 counts decreased after transplantation but recovered later. Acquired immune deficiency syndrome (AIDS)-defining infections occurred in three patients. CONCLUSIONS Kidney transplantation appears to be safe in patients undergoing HAART. However, larger series of patients are needed to determine the best protocols for the induction and maintenance of immunosuppression.

Spanish guidelines for the management of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on renal replacement therapy (RRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a consensus statement presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence found were C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and RRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are not provided since no drug has regulatory approval for this indication.

The Effect of Methylenetetrahydrofolate Reductase C677T Common Variant on Hypertensive Risk Is Not Solely Explained by Increased Plasma Homocysteine Values

The C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene causes a moderate increase in total plasma homocysteine (tHcy). We studied the effect of MTHFR TT homozygosity and mild hyperhomocysteinemia on arterial hypertension. Normotensive controls (n = 223) and hypertensive subjects (n = 235) were matched for age, gender, and history of cardiovascular disease. Homocysteine levels were measured by a fluorescense polarization immunoassay method. Methylenetetrahydrofolate reductase genotypes were determined by polymerase chain reaction and restriction fragment analysis. Hypertensives showed elevated tHcy compared to normotensive group in men (P = 0.039). Homocysteine values higher than 15 µmol/L were associated with increased hypertensive risk in the male population [odds ratios (OR) = 1.63; 95% confidence interval (CI) = 1.06–2.52; P = 0.027]. In multivariate analysis, TT genotype was associated with an increased risk of hypertension in males (OR = 2.27; 95% CI = 1.12–4.60; P = 0.022). An increased hypertensive risk was observed in those TT males with tHcy levels higher than 15 µmol/L (OR = 2.78; 95% CI = 1.05–7.3; P = 0.032) but not in those non‐TT males with tHcy levels higher than 15 µmol/L (P = 0.33). Our findings do not support the possibility that mild hyperhomocysteinemia may solely account for the hypertensive risk associated to the TT genotype.

Improvement in Renal Function After Late Conversion to Sirolimus-Based Immunosuppression in Composite Tissue Allotransplantation

1. Abraham G, Shroff S, Matcha J, et al. Deceased donor renal transplantation program in India. Kidney Int 2010; 77: 378. 2. Li R, Chen G, Guo H, et al. Prolonged cardiac allograft survival in presensitized rats after a high activity Yunnan-cobra venom factor therapy. Transplant Proc 2006; 38: 3263. 3. Mansy H, Filobbos P, Aly TF, et al. Massive haemorrhage and rupture of renal transplant from a donor who died of snake bite. Nephrol Dialysis Transplant 1998; 13: 1018.

Rosiglitazone but not losartan prevents Nrf-2 dependent CD36 gene expression up-regulation in an in vivo atherosclerosis model

BackgroundThiazolidinediones exert anti-inflammatory and anti-oxidative roles and attenuate atherosclerosis by mechanisms partially independent of their metabolizing actions. High doses of angiotensin type 1 receptor (AT1R) blocker losartan (LST) seem to promote fat cell formation by preserving PPARγ activity.MethodsC57BL/6J diet-induced atherosclerotic susceptible mice randomly received a normal or a high-fat high-cholesterol (HFHC) diet and were treated with rosiglitazone (RG), LST or a vehicle for 12 weeks.ResultsHFHC was associated with increased PPARγ gene expression without an over regulation of PPARγ responsive genes, whereas RG and LST treatments were found to maintain PPARγ activity without resulting in increased PPARγ gene expression. A better anti-inflammatory and antioxidant profile in mice treated with RG regarding LST was observed in spite of a similar PPARγ preserved activity. Chromatin immunoprecipitation (ChIP) assays revealed that animals under HFHC diet treated with RG showed a significant nuclear factor erythroid 2-like 2 (Nrf2)-dependent down-regulation of the expression of the CD36 gene.ConclusionThe PPARγ agonist RG exerts antioxidant properties that significantly reduced Nrf-2-dependent CD-36 up-regulation in mice under HFHC diet. Because LST treatment was also associated with a preserved PPARγ activity, our data suggests that these RG antioxidant effects are partially independent of its PPARγ metabolizing properties.

Sensorimotor recovery after partial facial (mystacial pad) transplantation in rats.

Most research in facial transplantation has been conducted in rats. This skill demanding model has a steep learning curve and is accompanied by high mortality rates. Investigations were carried out to minimize these disadvantages and a whiskers flap properly named mystacial pad flap, was developed. The mystacial pad contains the whiskers follicles of the rat, and our aim was to investigate the effect of repairing the nerves on the whiskers function after mystacial pad allotransplantation in rats.A total of 56 animals were studied in 6 groups. In the main study group (VI), 16 semi-allogenic vascularized mystacial flaps were transplanted from Lewis-Brown-Norway (RT1l+n) to Wistar-Lewis (RT1l) rats. This group was divided in 2 subgroups; in subgroup VIa (nonneurotized alloflap transplant group, n = 8), alloflaps were transplanted without nerve repairs, whereas in subgroup VIb (neurotized alloflap transplant group, n = 8) the facial and trigeminal nerves were repaired. Animals were kept under tapered doses of tacrolimus immunosuppression monotherapy. Clinical and neurophysiological explorations were performed to evaluate sensitivity and motor voluntary activity of the mystacial region after 6 weeks. Animals were euthanized after 8 weeks and histologic studies were performed.In group VI, each procedure required an average of 3.5 hours, and 87.5% of the recipients survived for 8 weeks. Sensitivity, motor activity, and histologic signs of recovery were found in the mystacial pad allotransplants after 6 weeks.Mystacial pad allotransplants in which nerves were repaired showed clinical, neurophysiological, and histologic signs of recovery. A functional facial subunit was successfully transplanted and sensorimotor function recovery could be demonstrated in rats.

A Synergistic Association of ACE I/D and eNOS G894T Gene Variants with the Progression of Immunoglobulin A Nephropathy – A Pilot Study

Background: Individual variability in the natural history and response to therapy of immunoglobulin A nephropathy (IgAN) suggests a complex multifactorial pathogenesis. We investigated whether single nucleotide polymorphisms (SNPs) involved in the non-immunologic progression of renal disease are related with disease progression. Methods: This is a pilot historic cohort study of 64 Caucasian patients with biopsy-proven IgAN and a median follow-up of 70 months. Three SNPs of the renin-angiotensin system genes (angiotensin I converting enzyme insertion/deletion (ACE I/D), angiotensinogen (AGT) M235T, and angiotensin II type 1 receptor (AT1R) 1166A/C), 2 of the endothelial nitric oxide synthase (eNOS), 4a/b and G894T, and 1 of the bradykinin 1 receptor, G–699C, were genotyped. The primary outcome was ‘kidney survival’ defined as a 30% decrease of baseline creatinine clearance; annualized decrease of glomerular filtration rate was also calculated. Results: Proteinuria, histological lesions, and mean arterial pressure were related to an unfavorable outcome. The simultaneous presence of the DD and GG variants of the ACE and eNOS genes was related to an unfavorable outcome as compared with other combinations [hazard ratio ranging from 4.7 (95% CI 1.52–14.33) to 8.4 (95% CI 2.45–29.10)] after controlling for proteinuria, mean arterial pressure and baseline histological lesions. Conclusion: This study suggests that in our population with IgAN, an interaction between ACE and eNOS polymorphisms may be a prognostic factor for renal function deterioration.

Combination therapy with an angiotensin II receptor blocker and an HMG-CoA reductase inhibitor in experimental subtotal nephrectomy

BACKGROUND Angiotensin receptor 1 blockers (ARB) are standard nephroprotective drugs in chronic kidney disease. There is less evidence for a nephroprotective effect of HMG-CoA reductase inhibitors (statins) and much less is known about potential benefits of combination therapy. We evaluated the therapeutic potential of a statin alone or in combination with an ARB in experimental chronic kidney disease. METHODS Subtotally nephrectomized (5/6 Nx) rats were treated early with vehicle, losartan, cerivastatin or losartan/cerivastatin. Expression of messenger RNA (mRNA) was assessed by real-time reverse transcription-polymerase chain reaction. Tissue proteins were localized by immunohistochemistry. Nuclear factor-κB (NF-κB) activation was measured in whole kidneys. RESULTS In contrast to the sham group, at 6 weeks, vehicle-treated 5/6 Nx rats displayed renal lesions, albuminuria and increased blood pressure, serum creatinine and total kidney NF-κB p65 DNA-binding activity and preproendothelin-1, fibronectin and type I and III collagen mRNA. NF-κB activation correlated with albuminuria and histological renal injury. Losartan or combination therapy preserved renal function, abrogated albuminuria and improved glomerular and interstitial histology. Cerivastatin alone preserved renal function and improved interstitial injury but did not influence albuminuria, glomerular histology or NF-κB activation. Losartan/cerivastatin normalized kidney NF-κB activation and extracellular matrix mRNA expression pattern. The effect of losartan alone on these parameters was less intense. All treatments decreased preproendothelin-1 mRNA and preserved interstitial capillaries. CONCLUSIONS In a chronic kidney disease model, early treatment with either an ARB or a statin preserved renal function although the mechanisms differed. Combination therapy with an ARB and a statin did not confer clear-cut advantages on biochemical and histological parameters over ARB alone, although it further improved the kidney NF-κB and gene expression profile.