Veronika Dvořáková

Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus

AIMS The aims of the study were (i) to ascertain prognostic value of serum uric acid (SUA) for diabetic kidney disease (DKD) progression and major adverse cardiovascular event (MACE) in a cohort of T2DM patients, (ii) to ascertain eventual protective effect of allopurinol treatment, (iii) to determine the effect of genetic variability in UA transporters on DKD progression, and (iv) to define optimal cut-off values for SUA in patients with DKD. METHODS Study comprised 422 subjects with diabetes duration at least 15years followed-up for a median of 43 [IQR 22-77] months. Participants were categorized into stable or progressors according to their change in albuminuria or chronic kidney disease (CKD) stage. At baseline, 68% patients had hyperuricemia (SUA≥420μmol/l for men and ≥360μmol/l for women and/or allopurinol treatment). Five SNPs in the SLC2A9 and ABCG2 genes were determined by PCR. RESULTS Time-to-event analysis with subgroups defined by the presence/absence of initial hyperuricemia revealed significant differences in all three end-points (P<0.0001 for DKD progression, P=0.0022 for MACE and P=0.0002 for death, log-rank test). Subjects with normal SUA not requiring allopurinol had median time to DKD progression 49months compared with remaining subjects (32months, P=0.0002, log-rank test). Multivariate Cox regression model revealed hyperuricemia (i.e. high SUA and/or allopurinol treatment) significant predictor of DKD progression independent of baseline CKD stage. Optimal cut-off values identified by ROC analysis for T2DM subjects were ≤377.5μmol/l for men and ≤309.0μmol/l for women. We found no differences in allele or genotype frequencies in selected SNPs between patients with and without hyperuricemia (all P>0.05). CONCLUSIONS Our study demonstrated that initial hyperuricemia or need for allopurinol is an independent risk factor for DKD progression and that SUA levels in diabetic subjects conferring protection against DKD progression might be lower than current cut-offs for general population.

Association of the Arg72Pro Polymorphism in p53 with Progression of Diabetic Nephropathy in T2DM Subjects

Objective: In addition to its anticancer function, p53 (regulated by murine double minute 2 oncoprotein, MDM2) has recently been shown to control intracellular metabolic processes. It participates in the regulation of glucose, fatty and amino acid and purine metabolism, influences mitochondrial integrity and oxidative phosphorylation, insulin sensitivity, antioxidant response and autophagy. With respect to the possible impact of genetic variability in p53 and MDM2 on metabolic compensation the aim of the study was to analyse the effect of common germ line Single Nucleotide Polymorphisms (SNPs) - Arg72Pro in the TP53 and SNP309 in the MDM2 - on the progression of Diabetic Nephropathy (DN), cardiovascular morbidity and mortality and all-cause mortality in Type 2 Diabetes Mellitus (T2DM) subjects. Methods: The cross-sectional study comprised a total of 309 (a sum of 155 and 154) unrelated Caucasian diabetic patients with diabetes duration at least 10 years and variable renal function at baseline (309, mean age was 67.2 ± 10.8 years). The stage of diabetic nephropathy was defined according to the urinary albumin excretion and glomerular filtration rate. Patients were followed-up for median 37 (20-59) months. The following end-points were considered: (a) progression of DN, (b) major cardiovascular event (non-fatal or fatal myocardial infarction or stroke, limb amputation, revascularization), (c) all-cause mortality. Genotypes were determined by PCR-based methodology. Time-to-event analysis using Kaplan-Meier curves and log-rank test was used. Results: We found significant difference between CG+GG vs. CC genotypes of the p53 Arg72Pro SNP for DN progression (P=0.046, log-rank test). Carriers of genotypes containing G allele (previously associated with susceptibility to T2DM) had faster progression of DN than CC genotype carriers. We did not find any significant difference between genotypes of MDM2 SNP for any of the end-points studied. Conclusions: Presented findings in general support the role of p53 in the pathogenesis of metabolic diseases, namely progression of hyperglycemia-related morbidity. Nevertheless, further studies are warranted to elucidate the eventual causal involvement of p53 pathway in the development of diabetic complications.

NOS3 894G>T Polymorphism is Associated With Progression of Kidney Disease and Cardiovascular Morbidity in Type 2 Diabetic Patients: NOS3 as a Modifier Gene for Diabetic Nephropathy?

Background/Aims: We have previously associated SNP 894G>T in the NOS3 gene with diabetic nephropathy (DN) using multi-locus analysis. Variant 894G>T has been widely studied as a DN susceptibility factor with contradictory results. In the present study we genotyped 894G>T in the cohort of prospectively followed type 2 diabetics with the aim to investigate its possible role in the progression of DN and development of morbidity and mortality associated with diabetes. Methods: 311 subjects with defined stage of DN were enrolled in the study and followed up for a median of 38 months. We considered three end-points: progression of DN, major cardiovascular event and all-cause mortality. Results: Considering baseline GFR, age at enrolment and diabetes duration as confounders, Cox regression analysis identified 894GT genotype as a risk factor for DN progression (HR = 1.843 [95% CI 1.088 - 3.119], P = 0.023) and 894TT genotype as a risk factor for major cardiovascular event (HR = 2.515 [95% CI 1.060 - 5.965], P = 0.036). Conclusion: We ascertained the significant effect of the NOS3 894G>T variant on DN progression and occurrence of major cardiovascular event in T2DM subjects. Based on these results NOS3 can be considered a modifier gene for DN.

Resting Heart Rate Does Not Predict Cardiovascular and Renal Outcomes in Type 2 Diabetic Patients

Elevated resting heart rate (RHR) has been associated with increased risk of mortality and cardiovascular events. Limited data are available so far in type 2 diabetic (T2DM) subjects with no study focusing on progressive renal decline specifically. Aims of our study were to verify RHR as a simple and reliable predictor of adverse disease outcomes in T2DM patients. A total of 421 T2DM patients with variable baseline stage of diabetic kidney disease (DKD) were prospectively followed. A history of the cardiovascular disease was present in 81 (19.2%) patients at baseline, and DKD (glomerular filtration rate < 60 mL/min or proteinuria) was present in 328 (77.9%) at baseline. Progressive renal decline was defined as a continuous rate of glomerular filtration rate loss ≥ 3.3% per year. Resting heart rate was not significantly higher in subjects with cardiovascular disease or DKD at baseline compared to those without. Using time-to-event analyses, significant differences in the cumulative incidence of the studied outcomes, that is, progression of DKD (and specifically progressive renal decline), major advanced cardiovascular event, and all-cause mortality, between RHR </≥65 (arbitrary cut-off) and 75 (median) bpm were not found. We did not ascertain predictive value of the RHR for the renal or cardiovascular outcomes in T2DM subjects in Czech Republic.