Samar Sabry

Genetic polymorphism of ACE and the angiotensin II type1 receptor genes in children with chronic kidney disease.

Aim and MethodsWe investigated the association between polymorphisms of the angiotensin converting enzyme-1 (ACE-1) and angiotensin II type one receptor (AT1RA1166C) genes and the causation of renal disease in 76 advanced chronic kidney disease (CKD) pediatric patients undergoing maintenance hemodialysis (MHD) or conservative treatment (CT). Serum ACE activity and creatine kinase-MB fraction (CK-MB) were measured in all groups. Left ventricular mass index (LVMI) was calculated according to echocardiographic measurements. Seventy healthy controls were also genotyped.ResultsThe differences of D allele and DI genotype of ACE were found significant between MHD group and the controls (p = 0.0001). ACE-activity and LVMI were higher in MHD, while CK-MB was higher in CT patients than in all other groups. The combined genotype DD v/s ID+II comparison validated that DD genotype was a high risk genotype for hypertension .~89% of the DD CKD patients were found hypertensive in comparison to ~ 61% of patients of non DD genotype(p = 0.02). The MHD group showed an increased frequency of the C allele and CC genotype of the AT1RA1166C polymorphism (P = 0.0001). On multiple linear regression analysis, C-allele was independently associated with hypertension (P = 0.04).ConclusionACE DD and AT1R A/C genotypes implicated possible roles in the hypertensive state and in renal damage among children with ESRD. This result might be useful in planning therapeutic strategies for individual patients.

Oxidative Stress Markers and C-Reactive Protein in Pediatric Patients on Hemodialysis

Background: Pediatric patients with end-stage renal disease undergoing hemodialysis (HD) are exposed to oxidative stress associated with an impairment of antioxidant defense and an overproduction of oxidative stress markers. Oxidative stress plays a significant role in the development of inflammation in these patients. Objectives: The high incidence of cardiovascular disease in HD pediatric patients is now well established and the involvement of oxidative stress has been hypothesized. This study focuses on a comparison of plasma total antioxidant capacity (TAC) and lipid peroxidation product and evaluates the relationship between these parameters and high-sensitivity C-reactive protein (hsCRP) in pediatric patients on HD. Subjects and Methods: Plasma TAC, lipid peroxidation products, malondialdehyde (MDA) as well as hsCRP were determined in 30 pediatric patients on HD and in 20 healthy controls (HC). Results: TAC and MDA levels were significantly higher in children on HD than in the HC (p < 0.001). The hsCRP values were also significantly higher in HD patients than in HC (p < 0.001). The percentage of HD pediatric patients with CRP >10 mg/l was 30%. The concentrations of TAC and MDA correlated positively with hsCRP in HD patients (TAC: r = 0.52, p < 0.08; MDA: r = 0.75, p < 0.04), but not in HC. Conclusion: Our study demonstrates an increase in oxidative stress in children on HD and that the susceptibility to oxidative stress is strongly related to the levels of MDA produced in plasma. hsCRP levels are higher in children on HD than in HC and this is indicative of a higher degree of inflammatory activity in the former patients. These profound disturbances in oxidative stress markers may provide an explanation for the cardiovascular complications in HD patients.

Effect of angiotensin-converting enzyme gene insertion/deletion polymorphism on steroid resistance in Egyptian children with idiopathic nephrotic syndrome

Introduction. The presence of the deletion (D) allele in the angiotensin-converting enzyme (ACE) gene has been reported as a probable genetic risk factor for idiopathic nephrotic syndrome (INS), but its role in determining resistance to steroid therapy remains to be evaluated. Methods. Fifty-one patients were enrolled in the study and received oral steroids. The pattern of response to steroid therapy was determined. A group of 50 healthy adults served as a control group. The genotypes for ACE insertion (I)/D polymorphism were analysed using a PCR-based method. Results. Twenty patients were steroid sensitive (SS) and 31 were non-SS. The presence of hypertension at presentation was significantly related to steroid unresponsiveness. Among the SS group, the frequencies of the II, ID, and DD genotypes of the ACE gene were 20% (n=4), 65% (n=13), and 15% (n=3), respectively, while the frequencies among the non-SS group were 19.4% (n=6), 74.2% (n=23), and 6.5% (n=2), respectively. The differences between the two groups were not statistically significant (Chi square=0.59). Conclusion. The current study on Egyptian children with INS reveals no association between the ACE gene I/D polymorphism and clinical parameters, histological findings, and steroid resistance.

Endothelial nitric oxide synthase gene intron4 VNTR polymorphism in patients with chronic kidney disease.

Nitric oxide production is reduced in renal disease, partially due to decreased endothelial nitric oxide production. Evidence indicates that nitric oxide deficiency contributes to cardiovascular events and progression of kidney damage. A polymorphism in intron 4 of the endothelial constitutive nitric oxide synthase (ecNOS) gene is a candidate gene in cardiovascular and renal diseases. We investigated a potential involvement of this polymorphism in chronic renal failure. A case–control study involved 78 children with chronic kidney disease (CKD) and 30 healthy controls. All participants were genotyped for the ecNOS4 polymorphism by the polymerase chain reaction (PCR). Dialyzed (maintenance hemodialysis) and conservative treatment children had significantly higher frequency of the aa genotype and ecNOS4a allele (P < 0.05) compared with controls. The combined genotype aa + ab vs. bb comparison validated that a allele is a high-risk allele for end-stage renal disease (ESRD) (P < 0.05). Serum nitric oxide level was found to be lower in carriers of the ecNOS 4a allele than in noncarriers (100.29 ± 27.32 vs. 152.73 ± 60.39 &mgr;mol/l, P = 0.04). Interestingly, 85.95% of the ecNOS 4a allele ESRD patients were found hypertensive in comparison to the 60.67% patients of non noncarriers (bb genotype) (P = 0.04). Also, 35.90% of the ecNOS 4a allele ESRD patients were found to have cardiovascular disease in comparison to the 5.13% patients of noncarriers (bb genotype) (P = 0.01). On multiple linear regression analysis, a allele was independently associated with hypertension (P = 0.03). There was a significantly higher frequency of the ecNOS4a allele carriers among CKD children, both on MHD and conservative treatment than in controls. This suggests that the ecNOS gene polymorphism may be associated with an increased risk of chronic renal failure.

Aluminium and lead abnormalities in children on haemodialysis: relationship with some medications.

Introduction The determination of toxic elements in the biological samples of human beings is an important clinical procedure. This study was performed to investigate the prevalence of abnormal blood contents of 2 trace elements (TEs), aluminum (Al),and lead (Pb) in hemodialysis (HD) patients and to analyze their relationship with the medications, such as CaCO3, Ca acetate, 1,25-dihydroxy vit. D3, and erythropoietin (EPO), as well as hematocrit level. Material and methods We included 43 patients on maintenance HD and they had continued the previously mentioned medications for at least 3 months. None of the patients were on Al containing phosphate binding agents. Results Serum aluminum and lead levels were significantly increased than in the healthy controls, but levels of both of them were far below toxic values. Male patients had higher mean levels of lead than did females. A strong positive correlation was found between serum Al and serum Pb levels among patients (r = 0.075, p = 0.0001).The serum level of Pb was positively correlated with the serum albumin in HD patients (r = 0.45, p = 0.03). Both serum aluminium and lead levels positively correlated with the EPO dose taken by the patients (r = 0.77, p = 0.0001 and r = 0.67, p = 0.0001 respectively). Conclusions The blood level of trace metals of these HD patients was not related to their medications except for the EPO dose. However, caution must be exercised in interpreting this result as dose and duration of medication may play an important role. Al and Pb over load may be considered from the causes of inadequate response to epoetin therapy.

Adiponectin: an adipocyte-derived hormone, and its gene encoding in children with chronic kidney disease.

BackgroundThe prevalence of cardiovascular disease (CVD) and inflammation is high in patients with chronic kidney disease (CKD). Adiponectin (ADPN) is an adipocytokine that may have significant anti-inflammatory and anti-atherosclerotic effects. Low adiponectin levels have previously been found in patients with high risk for CVD.MethodsOn seventy eight advanced CKD (stages 4 and 5) pediatric patients undergoing maintenance hemodialysis( MHD) or conservative treatment (CT) the following parameters were studied: body mass index, left ventricular mass index(LVMI), serum adiponectin , cholesterol, HDL-cholesterol, high sensitivity C-reactive protein (hs CRP),interleukin 6(IL6) and single-nucleotide polymorphisms (SNPs) in the ADIPOQ gene at positions 45, and 276. Seventy age-and gender-matched healthy subjects served as control subjects.ResultsMarkedly (P = 0.01) elevated plasma adiponectin levels were observed in CKD patients, especially CT patients, compared to control subjects. The wild type of ADIPOQ 45T > G (T) allele is the main gene for patients and controls. MHD and CT patients had significantly higher frequency of the TT genotypes of +276G > T gene (P = 0.04) compared with control subjects. A significant positive correlation was observed between plasma adiponectin and IL6 level, whereas negative correlations were found between adiponectin level, cholesterol, HDL cholesterol and hs CRP. In a stepwise backward multiple regression model only IL6 (P = 0.001) was independently associated with plasma adiponectin levels. The adiponectin gene the 276 GT+TT genotypes were associated with a higher level of adiponectin .ConclusionsThe present study demonstrated that ADPN is related to several metabolic and inflammatory CV risk factors in a manner consistent with the hypothesis that this protein might have a protective role against these factors. We observed an association between the +276G>T SNP in the adiponectin gene and CKD in children. Genetic variation of +276 gene seemed to have a positive impact on circulating adiponectin levels in CKD patients.

Plasma Total Nitric Oxide and Endothelial Constitutive Nitric Oxide Synthase (ecNOS) Inron 4 Gene Polymorphism: A Study in Children with Chronic Kidney Disease

Considerable progress has been made in the treatment of end-stage renal disease over the past 20 yr. Nonetheless, the dialysis population continues to carry an excess mortality from fatal cardiovascular events [Baylis et al., 2006]. One possible explanation derives from the association of uremia and accelerated atherosclerosis [Tripathi et al., 2008]. The latter may be related to pre-dialysis factors such as preceding arterial hypertension, glucose intolerance, secondary hyperparathyroidism, dyslipidemia, and others. However, dialysis itself may further contribute to atherosclerosis by oxidative stress, cytokine stimulation, and other events inherent to hemodialysis (HD). Endothelial dysfunction has been shown recently to be a major initiating factor in atherosclerosis [Kone et al., 1997]. Endothelial dysfunction is associated primarily with decreased nitric oxide (NO). However, endothelial dysfunction of uremia has received little attention. Among the various factors involved in the deterioration of renal function, changes in the hemodynamic are thought to be important. Nitric oxide (NO), an important endothelium derived relaxing factor, is synthesized in the vascular endothelium by the NO synthase. NO is a potent regulator of intrarenal hemodynamics [Baylis et al., 2006 and Tolins et al., 1990]. At the release site it mediates local vasodilatation, antagonizes platelet aggregation, inhibits vascular smooth muscle cell proliferation and also, regulates some vessel-platelet interactions, limits the oxidation of atherogenic low density lipoproteins and has a vasoprotective effect by scavenging superoxide radicals and suppresses leukocyte adhesion to endothelial vessel wall. Multiple lines of evidence have suggested that NO plays a protective role in various important events during atherogenesis. Reduced NO levels are involved in the pathogenesis of the vascular endothelium due to the loss of its vasodilatory effect [Schmidt et al., 1994]. In the kidney, NO dilates renal blood vessels and modulates renin secretion [Kone et al., 1997 and Tripathi et al., 2008]. An impairment of NO production

Acknowledgement to the 2009 Reviewers

Helmut Heseker, Paderborn, Germany Manfred Hüttinger, Vienna, Austria Mohsen Janghorbani, Isfahan, Iran Miroslaw Jarosz, Warsaw, Poland Majken K. Jensen, Boston, Mass., USA Alex Johnstone, Aberdeen, UK Anthony Kafatos, Heraklion, Greece Andre Pascal Kengne, Camperdown, N.S.W., Australia Arthur Klatsky, Oakland, Calif., USA Nanne Kleefstra, Zwolle, The Netherlands Marlena Kruger, Palmerston North, New Zealand Anura Kurpad, Bangalore, India Denis Lairon, Marseille, France Wolfgang Langhans, Zürich, Switzerland Mark Lawrence, Melbourne, Vic., Australia Donald K. Layman, Urbana, Ill., USA James V. Leonard, London, UK Lars Libuda, Dortmund, Germany Xu Lin, Shanghai, China Jakob Linseisen, Munich, Germany Dieter Luetjohann, Bonn, Germany Silvia Maggini, Basel, Switzerland Philippe Marmillot, Washington, D.C., USA Franscesco Marotta, Milano, Italy Eva Martos, Budapest, Hungary Velimir Matkovic, Columbus, Ohio, USA Regis Moreau, Corvallis, Oreg., USA Luis A. Moreno, Zaragoza, Spain Yuji Naito, Kyoto, Japan Serge Nef, Geneva, Switzerland Hee Young Paik, Seoul, Korea Mihalis I. Panagiotidis, Reno, Nev., USA Sun Ming Park, Asan-si, Korea Kristina Pentieva, Ulster, UK Carmen Perez-Rodrigo, Bilbao, Spain Nancy M. Petry, Farmington, Conn., USA John M. Pettifor, Johannesburg, South Africa Spencer Proctor, Edmonton, Alta., Canada Ana Maria Proenza Arenas, Palma de Mallorca, Spain Giuliano Ramadori, Göttingen, Germany Aune Rehema, Tartu, Estonia Lajos Rethy, Budapest, Hungary Gerald Rimbach, Kiel, Germany Glorimar Rosa, Rio de Janeiro, Brazil Catherine A. Ross, University Park, Pa., USA Elaine Rush, Auckland, NZ Lydia Afman, Wageningen, The Netherlands Tasnime Akbaraly, London, UK Anthony Alberg, Baltimore, Md., USA Hooman Allayee, Los Angeles, Calif., USA James W. Anderson, Lexington, Ky., USA Bahram Arjmandi, Tallahassee, Fla., USA Georgianne L. Arnold, Rochester, N.Y., USA Benoit Arsenault, Québec, Qué., Canada Fereidoun Azizi, Tehran, Iran Matthias Baum, Kaiserslautern, Germany Giorgio Bedogni, Milano, Italy Joe Begley, Poole, UK Aloys Berg, Freiburg, Germany Renate Bergmann, Berlin, Germany Odilia I. Bermudez, Boston, Mass., USA Francisco Blanco-Vaca, Barcelona, Spain William S. Blaner, New York, N.Y., USA Pontus Boström, Göteborg, Sweden Regina Brigelius-Flohé, Nuthetal, Germany Veronika Butterweck, Gainesville, Fla., USA Anette Buyken, Dortmund, Germany Philip C. Calder, Southampton, UK Dexter Canoy, Manchester, UK Namsoo Chang, Seoul, Korea Supranee Changbumrung, Bangkok, Thailand Marie-Aline Charles, Villejuif, France Armand B. Christophe, Ghent, Belgium Nain-Feng Chu, Taipei, Taiwan Dolores Corella, Valencia, Spain Lindsey Darrow, Atlanta, Ga., USA Tamás Decsi, Pécs, Hungary Antonio Di Stefano, Chieti, Italy Marie-Claude Dop, Rome, Italy Klaus Eder, Freising, Germany Mathias Fasshauer, Leipzig, Germany Annie Ferland, Québec, Qué., Canada Jose Fernandez, Birmingham, Ala., USA Nicola Fuiano, Foggia, Italy Claudio Galli, Milano, Italy Dieter Genser, Vienna, Austria Frank Greer, Madison, Wisc., USA M.H. Hamdaoui, Tunis, Tunisia Igor Harsch, Erlangen, Germany Hans Hauner, Munich, Germany Alan S. Hazell, Montréal, Qué., Canada Erik Hemmingsson, Stockholm, Sweden