Vitamin D receptor gene polymorphisms in chronic kidney disease Egyptian children: effect on biochemical markers of bone mineral disorders.

INTRODUCTION: The aim of this study was to assess the association between four vitamin D receptor (VDR) single nucleotide polymorphisms BsmI (rs1544410), ApaI (rs7975232), FokI (rs2228570) and TaqI (rs731236) and the susceptibility to chronic kidney disease (CKD) in Egyptian children and to evaluate their association with mineral status in these patients. MATERIAL AND METHODS: The current study included 305 patients with CKD and 100 apparently healthy children. We measured the serum vitamin D (VD), para-thyroid hormone (PTH) level and fibroblast growth factor 23 (FGF-23) levels by ELISA method. The genotyping of the four VDR gene variants was carried out by PCR-RFLP technique. RESULTS: The TaqI AG & the BsmI TT genotypes were associated with a significantly higher risk of CKD. The expression of 25-OH D serum level was decreased in patients with TaqI GG & AG genotypes groups and in patients with BsmI TT genotype group The expression of PTH serum level was increased in patients with BsmI CT genotype group. The expression of FGF-23 serum level was increased in patients with Taq1 AG genotype group. We found 3 specific haplotypes; AGCA, AGCC and GGCA for healthy controls. CONCLUSIONS: Our study showed an association between VDR TaqI, BsmI polymorphisms and the susceptibility to CKD. The existence of VDR vari-ants affected the protein expression of VD, FGF-23 and PTH. The AGCA, AGCC and GGCA haplotypes were considered as protec-tive factors against the development of renal nephropathy in our population.

Anti-apolipoprotein A-1 autoantibodies as risk biomarker for cardiovascular diseases in type 2 diabetes mellitus.

OBJECTIVE: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) represent an emerging prognostic cardiovascular marker in patients with myocardial infarction or autoimmune diseases associated with high thrombotic events. The aim of this work is to investigate the incidence of anti-apoA-1 autoantibodies in type 2 diabetes (T2DM) patients with and without CVD and to study potential association with disease risk and its effect on plasma lipid parameters. METHODS: Qualitative determination of anti-apoA-1 IgG was assayed in sera from 302 subjects classified into T2DM patients (n=102), T2DM+CVD (n=112) and healthy controls (n=88). RESULTS: The incidence of anti-apoA-1 IgG was significantly higher among CVD patients (35.7%) than T2DM patients (8.8%) or control subjects (6.1%), p<0.0001. A significant association with CVD was identified (p<0.0001) and subjects who were positive for anti-apoA-1 IgG were at 8.5 times increased risk to develop CVD when compared to controls. Diabetic patients who were positive for the antibodies showed 5.7 times increased CVD risk. ROC analysis indicated anti-apoA-1 IgG as a risk biomarker for CVD in T2DM patients with an AUC value of 0.76, sensitivity of 35.7% and specificity of 91.2%. Studying the effect on lipid parameters, anti-apoA-1 IgG associated with significantly higher serum concentrations of TC and non-HDL-C in all groups and with higher concentrations of LDL-C in diabetic patients and higher TC/HDL-C ratio in CVD patients. CONCLUSION: Our results indicate that anti-apoA-1 IgG is a cardiovascular risk biomarker in T2DM patients.

Soluble adhesion molecules as markers of native arteriovenous fistula thrombosis in children on uremia.

Vascular access represents a lifeline for children undergoing hemodialysis. A failure of vascular access among patients receiving regular hemodialysis is associated with increased morbidity, mortality and costs. We assessed the possibility of using soluble adhesion molecules as reliable predictors of vascular access failure in children on hemodialysis. Moreover, we evaluated whether there is an association among the different studied adhesion molecules in hemodialysis patients with thrombosed and non-thrombosed arteriovenous fistula fistulas (AVFs). This study included 55 hemodialysis children, 36 with good access and 19 with access failure, and 20 healthy volunteers. Forty-four patients had native AVFs and 11 patients had tunneled permanent catheter (11with thrombosed and 33 with non-thrombosed AVFs). Serum-soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin) and soluble P-selectin (sP-selectin) were measured using ELISA technique. A significant increase was found in the levels of sVCAM-1, sICAM-1, sE-selectin and sP-selectin versus controls and all hemodialysis patients, hemodialysis patients with good access and hemodialysis patients with access failure (P=0.001 for sVCAM-1 and sICAM-1 and P=0.0001 for sE-selectin and sP-selectin). A significant increase was found in the levels of sVCAM-1, sE-selectin and sP-selectin in both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs versus controls (P=0.0001 for all parameters). There was significant difference between both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs as regard to sVCAM-1 (54.64±30.82 versus 25.69±27.96ng/ml, P=0.04). Both sICAM-1 and sP-selectin were positively correlated with the erythropoietin (EPO) dose in hemodialysis children (r=0.31, P=0.04 and r=0.32, P=0.04, respectively). A significant positive association was found between E-selectin and sP-selectin in hemodialysis patients with thrombosed AVFs (r=0.83, P=0.04). There was a significant correlation between sVCAM-1 and EPO dose in thrombosed AVF group (r=0.84, P=0.01). The assessment of serum sVCAM-1 might be useful for the identification of the chronic hemodialysis patients at an increased risk for native AVFs thrombosis. The role of EPO in vascular access failure should be taken into consideration. The clinical relevance of these observations warrants further investigations.

Paraoxonase-1 gene Q192R and L55M polymorphisms and risk of cardiovascular disease in Egyptian patients with type 2 diabetes mellitus.

BACKGROUND: Increased oxidative stress or an impaired antioxidant defense mechanism may play a crucial role in the onset and progression of atherosclerosis. Recently, Paraoxonase -1 (PON1) which accounts for most of the antioxidant effect of high density lipoprotein (HDL) cholesterol has been presented as a potential therapeutic agent against atherosclerosis development. Allele frequencies for PON1 gene that influence enzyme concentration as well as activity differ greatly among ethnic groups and data from several studies showed ethnic variations in the interpretation of cardiovascular disease (CVD) associated with PON1 polymorphisms. In this work, we investigated PON1 Q192R and L55M polymorphisms in Egyptian patients with type 2 diabetes mellitus (T2DM) and its association with CVD. METHODS: The study included 184 subjects classified into 3 groups; T2DM, T2DM + CVD, and healthy controls. PON1 polymorphisms were genotyped by real-time PCR and PON1 concentration was assayed in serum by ELISA (enzyme linked immunesorbent assay). RESULTS: Genotype and allele frequencies of Q192R were significantly different between controls and diabetic patients. Frequency of QQ genotype was significantly higher in healthy controls, while QR and RR genotypes were significantly higher in diabetic patients (p = 0.02). Frequency of 55LL and LM genotypes were significantly higher in patients than in controls (p = 0.009). Q192R polymorphism associated with CVD in our diabetic patients (p = 0.01) and with low serum PON1 concentration (p = 0.04). Multiple logistic regression analysis revealed significant correlations between 192R and other independent CVD risk factors. CONCLUSION: PON1 192R and 55 L alleles are associated with T2DM. Q192R polymorphism is associated with CVD and lower serum enzyme concentration and might represents a novel risk factor for CVD in Egyptian patients with T2DM.

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

AIM AND METHODS: We 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. RESULTS: The 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). CONCLUSION: ACE 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.

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 CaCO(3), Ca acetate, 1,25-dihydroxy vit. D(3), 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.