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The clinical course of chronic renal diseases and their progression to ESRD is highly variable. The strongest predictors of poor outcome of IgAN involve hypertension, severe proteinuria and elevated serum creatinine level. Different candidate gene polymorphisms have been advocated as possible modulators of the progression of IgAN. Megsin belongs to the serpin superfamily and was mapped to chromosome 18q21.3. Megsin plays a role in the regulation of a wide variety of processes in mesangial cells, such as matrix metabolism, cell proliferation, and apoptosis. Overexpression of Megsin might lead to mesangial dysfunction, and impair degradation of the mesangial matrix and disposal of immune complexes. The expression of Megsin is upregulated in a variety of glomerular diseases with mesangial injury in humans and in animal models. We investigated a possible association of two C2093T, C2180T polymorphisms of the megsin gene with the progression of IgAN towards ESRD, as well as the haplotype reconstruction of megsin gene polymorphisms and clinical manifestation of IgAN. We examined a group of 197 pts with histologically proven IGAN (84 pts with normal renal function, 113 pts with progressive renal insufficiency); as a control group we used 61 genetically unrelated healthy subjects. DNA samples from collected blood were genotyped for two singlenucleotide polymorphisms of megsin C2093T, C2180T by means of PCR with defined primers, electrophoresis on 2% agarose gel, UV light visualization and direct sequencing. The megsin genotype distribution showed no differences among the groups of IgAN with normal renal function, progressive renal insufficiency and the control group. According to haplotype analysis, the TT haplotype (defined as T-2093, T-2180 alleles) was substantially more frequent in pts with IgAN and normal renal function (Table 1, P = 0.025; Table 3, P = 0.062). Pts in the progressive group showed significantly higher levels of 24-h UP (3.53 +/- 2.80 vs 2.06 +/- 2.06, P = 0.042; Table 10), diastolic blood pressure (92.89 +/- 15.66 vs 84.93 +/- 10.43, P = 0.047; Table 10) and almost significantly systolic blood pressure (150.79 +/- 32.88 vs 135.21 +/- 14.88, P = 0.058; Table 10). We confirmed the negative prognostic influence of hypertension and proteinuria on the progression of IgAN in Czech pts. We found out that the TT haplotype (defined as T-2093, T-2180 alleles) could play a protective role in the progression of IgAN. In our Czech population, we excluded the negative influence of the 2093C-2180T haplotype, which was proposed by Chinese studies.

The clinical course of chronic renal diseases and their progression to ESRF is highly variable. Different candidate gene polymorphisms have been advocated as possible modulators of ESRF progression. Moreover, ET-1 has been suggested as a major promoting factor in renal disease. However, limited data are available regarding an association of three ET-1 SNP K198N, T- 1370G and 3A/4A with the progression of IgAN to ESRF. We examined a group of 122 pts with histologically proved IgAN (91 pts with normal renal function, 31 pts with ESRF), as a control group we used 132 genetically unrelated healthy subjects. Patients' DNAs were genotyped for three ET-1 SNP: K198N, T-1370G and 3A/4A by means of PCR. The frequencies of different genotypes and ET-1 gene haplotypes were compared among control group, IgAN pts with normal renal function and IgAN pts with ESRF. The ET-1 genotype distribution showed no differences among the groups of IgAN with normal renal function (1. K198N - 63.74% KK, 32.97% KN, 3.3% NN; 2. TT - 68.13% TT, 28.57% TG, 3.3% GG; 3. 3A/4A - 42.22% 3A/3A, 50.0% 3A/4A, 7.69% 4A/4A ), IgAN with ESRF (1. K198N - 74.19% KK, 25.81% KN, 0% NN; 2. TT - 77.42% TT, 22.58% TG, 0% GG, 3. 3A/4A - 56.25% 3A/3A, 37.5% 3A/4A, 6.25% 4A/4A ) and the control group (1. K198N - 66.67% KK, 31.82% KN, 1.52% NN, 2. TT - 76.51% TT, 22.72% TG, 0.76% GG, 3. 3A/4A - 43.94% 3A/3A, 44.70% 3A/4A, 11.36% 4A/4A ). The analysis of haplotypes showed that the frequency of G-198, G-1370 and 4A allele combination was significantly higher in comparison with the control group (P=0.0056). We excluded the effect of K198N, T-1370G and 3A/4A polymorphisms of the ET-1 gene in single-gene analysis on the progression of IgAN to ESRF. A significant association of the GG4A haplotype with IgAN, demonstrated by haplotype reconstruction of the ET-1 gene, could suggest a role in the pathogenesis of IgAN.

ADPKD is the most common hereditary renal disease. IGAN is a mesangial proliferative glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A. ET-1 has been suggested to be a major disease-promoting factor in renal diseases. The vasoconstrictor effect of ET-1 is mediated by the ET-A receptor. We have investigated the influence of C/T polymorphism in exon 8 of the EDNRA gene. A total number of 193 patients (87 males, 106 females) with ADPKD entered into this study. Patients were divided into three groups: 1. 47 pts with ESRD later than in 63 years (slow progressors), 2. 49 pts with ESRD before 45 (rapid progressors) and 3. 97 pts with ESRD between 45-63 years. Moreover, we examined a group of 153 pts with histologically proven IGAN (116 males, 37 females). Pts were divided into two groups: 1. 79 pts with ERSD during 5 years of the study (IGAN rapid progressors) and 2. 74 patients with normal renal function (IGAN slow progressors). As a control group we used 100 genetically unrelated healthy subjects. The distribution of C/T polymorphism did not significantly differ between rapid and slow progressors of ADPKD and IGAN. The comparison of ESRD ages showed that CC females with ADPKD failed significantly later than CT heterozygotes: CC (57.4 +/- 8.1 years), CT (53.0 +/- 9.1 years) and TT (54.5 +/- 6.4years) (t-test, P = 0.018). To conclude, the CC genotype could be protective in ADPKD females. This genotype was described to be associated with lower pulse pressure.