Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach.

AIMS/HYPOTHESIS: In the present study we investigated potential associations of a set of 45 single nucleotide polymorphisms (SNP) in 20 candidate genes on eight chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methodological approaches suitable for analysing susceptibility to complex traits: single- and multi-locus analyses. MATERIALS AND METHODS: The study comprised a total of 647 subjects in one of three groups: diabetes with or without DN, or no diabetes. Genotypes were detected by PCR-based methodology (PCR only, PCR plus RFLP, or allele-specific PCR). Haplotypes were inferred in silico. Set association (tested using SUMSTAT software) was used for multilocus analysis. RESULTS: After correction for multiple comparisons, only one SNP, in the gene encoding the receptor of advanced glycation end products, AGER 2184A/G (gene symbol formerly known as RAGE) showed a significant association with DN (p = 0.0006) in single-locus analysis. In multi-locus analysis, six SNPs exhibited a significant association with DN: four SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A and AGER -429T/C) and two SNPs on chromosome 7q (NOS3 774C/T and NOS3 E298D), omnibus p = 0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p = 0.0002); however, there were no significant difference in the frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression analysis identified SNPs AGER 2184A/G and NOS3 774C/T, together with diabetes duration and HbA1c, as significant predictors of DN. Testing for interactions between SNPs on chromosomes 6 and 7 did not provide significant evidence for epistatic interaction. CONCLUSIONS/INTERPRETATION: Using the set-association approach we identified significant associations of several SNPs on chromosomes 6 and 7 with DN. The single- and multi-locus analyses represent complementary methods.

[Diabetes mellitus and microalbuminuria]. / Diabetes mellitus a mikroalbuminurie.

Microalbuminuria is considered as an independent predictor of cardiovascular morbidity and mortality and is a general marker of endothelial dysfunction. Microalbuminuria is the indicator of the incipient phase of diabetic nephropathy in diabetes mellitus, and especially in the type 1 diabetes mellitus patients. Progressive continuously growing albumin secretion into the urine is a generally recognised criterion for determining the degree of diabetic renal affection. The modern definition of diabetic nephropathy therefore includes increased cardiovascular risk which--if not treated--is accompanied by progressive decrease in renal functions related to diabetic retinopathy. In the case of a positive microalbuminuria result, strict monitoring of diabetes compensation and of systemic pressure is necessary in order to prevent further progression of specific microvascular complications of diabetes. The article provides an overview of epidemiological data and current knowledge of etiopathogenesis of microalbuminuria in diabetic nephropathy.

[Risky medication and contrast media-induced nephropathy in patients with diabetes and hypertension]. / Riziková medikace a kontrastní látkou indukovaná nefropatie u pacientu s diabetem a hypertenzí.

Contrast media-induced nephropathy (CMIN) is accompanied by high morbidity, lengthy hospitalization, and a higher mortality rate. In proportion to the rising number of diagnostic and interventional radiological procedures, the prevalence of this complication is also rising The study briefly tackles the currently known pathophysiological mechanisms that lead to CMIN and deals with various risk factors which increase the probability of development of contrast nephropathy. Among these factors are, in the first place, diabetes mellitus, a pre-existing renal illness and hypertension. In addition, the risk of developing CMIN significantly increases in patients on risky medication. In our study, this medication was a combination of ACE-inhibitors (ACEI) and furosemide. Even though none of the patients met the criteria defined for CMIN, radiocontrast examination showed a significant statistical decline in glomerular filtration (GFR) and a rise in proteinuria (PU) in the sub-group which used this combination of medication. The risk level of this medication especially in patients with pre-existing nephropathy is also underlined by the suggested dependency of the relative rise in the serum levels of creatinine in terms of its input value. It is necessary, as early as the radiocontrast examination is being done, to bare in mind the possibility of CMIN occurring and avoid it also through the modification of the risk factors which can be influenced, e.g. elimination of risky medication and in indicated cases, taking preventive measures.

[Contrast medium induced nephropathy]. / Kontrastní látkou indukovaná nefropatie.

Contrast medium indicated nephropathy (CMIN) is a iatrogenic disorder by which patients become inflicted due to contrast medium exposure. Prevalence of this disorder might increase as more and more diagnostic and intervence radiology has been used. The article is focused on known pathofysiological mechanisms that are responsible for CMIN incidence. There are many risk factors guided by more frequent development of this complication, in particular diabetes mellitus, preexisting renal disease, hypertensis. Plus, the risk of CMIN is much higher in patients with risky medication. Measures to prevent contrast nephropathy coincidence are mentioned; however, some of them require more support and evidence in studies. The possible incidence of CMIN has to be taken into account and prevented by respective measures.

[Antihypertensives and their importance in the initial stages of diabetic nephropathy]. / Antihypertenziva a jejich význam v iniciálním stadiu diabetické nefropatie.

Diabetic nephropathy is a serious microangiopathic late complication of diabetes and is one of the most frequent causes of premature death of diabetic subjects. The main task of diabetologists and nephrologists in these patients is an attempt to arrest or at least delay progression of nephropathy. As to therapeutic possibilities, antihypertensive drugs are most suitable, i.e. angiotensin converting enzyme inhibitors, Ca blockers of the IInd generation and also blockers of AT1 receptors.

[Free oxygen radicals in patients with diabetes mellitus]. / Kyslíkové volné radikály u nemocných s diabetes mellitus.

Free oxygen radicals (FOR) are one of the factors which participate via lipoperoxides in the development of atherosclerosis. Atherosclerosis complications affect a large part of diabetic patients. The objective of the present work was to test whether in diabetic patients there is, as compared with healthy subjects, a difference in the FOR activity and in the lipoperoxide blood level. A total of 30 patients with insulin non-dependent diabetes and a control group of 31 healthy subjects were examined. The FOR formation in blood, the concentration of malondialdehyde (MDA) as a marker of lipid paroxidation and serum lipid concentrations were assessed. In patients with diabetes a statistically significant increase in the FOR formation in blood (p < 0.01) and an increased MDA serum concentration (p < 0.01) were found. The mean serum lipid concentrations in the two groups did not differ significantly. The results suggest a significant participation role of highly reactive oxygen species in the development of vascular atherosclerosis complications.

[Combined therapy with insulin/gliquidone (Glurenorm) in type 2 diabetes after treatment failure using oral antidiabetic agents]. / Kombinovaná lécba inzulín/gliquidon (Glurenorm) u diabetiku 2. typu po selhání lécbý perorálními antidiabetiky.

The authors evaluate treatment by a combination of insulin and gliquidone (Glurenorm) in 29 type 2 diabetics where long-term treatment with oral antidiabetics alone had failed. Within four months all patients were completely compensated from the metabolic aspect. HbA1c declined from 10.8 to 6.5, C peptide, on the other hand, increased from the original value of 1.2 ng/ml to 1.8 ng/ml. The authors did not observe any undesirable effects or hypoglycaemic states. Gliquidone is suitable for combined treatment because of its short-term effect; stimulation of endogenous secretion has a pulsed character and imitates an intensified regime. The prerequisite of success is a low dose of intermediary insulin to prevent inhibition of the central action of gliquidone.