[Hypertension in patients with polycystic kidney disease -  incidence, pathogenesis, prognosis, therapy]. / Hypertenze u pacientu s polycystickými ledvinami -  incidence, patogeneze, prognóza, terapie.

Hypertension is common in patients with autosomal dominant polycystic kidney disease (ADPKD) very early usually already in adolescence and its occurrence precedes the decrease of glomerular filtration rate. Expansion of renal cysts causing local renal ischemia and activation of the reninangiotensin system is believed to play a decisive role in its pathogenesis. Hypertension in ADPKD leads to early development of left ventricle hypertrophy and definitely contributes to the progression of chronic renal insufficiency. In ADPKD optimal control of blood pressure dramatically decreases the risk of left ventricle hypertrophy and contributes to its regression, but the beneficial effect of optimal compared to standard blood pressure control on the progression of chronic renal insufficiency has yet to be unequivocally demonstrated. Angiotensin converting enzyme inhibitors and/ or angiotensin receptor blockers are the drugs of choice in the treatment of hypertension in ADPKD. New drugs blocking the growth of renal cysts (e. g. inhibitors of V2 vasopressin antagonists) may have in ADPKD positive impact not only of the growth of the cysts and kidney volume, but also on the rate of loss of glomerular filtration rate. The influence of these drugs on the control of blood pressure, if any, remains uncertain.

Mutational analysis of ACTN4, encoding α-actinin 4, in patients with focal segmental glomerulosclerosis using HRM method.

α-Actinin 4, encoded by ACTN4, is an F-actin crosslinking protein which belongs to the spectrin gene superfamily. It has a head-to-tail homodimer structure with three main domains. Mutations in ACTN4 are associated with idiopathic nephrotic syndrome (NS). However, until today only a few mutations have been described in this gene. We used genomic DNA of 48 patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) to screen for ACTN4 mutations by high-resolution melting analysis (HRM). Suspect samples were sequenced and compared with healthy controls. To investigate the prevalence and possible effect of some substitutions found in FSGS/MCD patients we also looked for these changes in patients with IgA nephropathy (IgAN) and membranous glomerulonephritis (MGN). We found 20 exonic and intronic substitutions in the group of 48 Czech patients. The substitution 2242A>G (p.Asn748Asp) is a candidate mutation which was identified in one patient but not in any of the 200 healthy controls. Exon 19 seems to be a variable region due to the amount of revealed polymorphisms. In this region we also found three unreported substitutions in IgAN patients, c.2351C>T (p.Ala784Val), c.2378G>A (p.Cys793Tyr) and c.2393G>A (p.Gly798Asp). These substitutions were not found in any tested healthy controls. To conclude, the ACTN4 mutations are not a frequent cause of FSGS/MCD in Czech adult patients. One new ACTN4 mutation has been identified.

TRPC6 gene variants in Czech adult patients with focal segmental glomerulosclerosis and minimal change disease.

Blood filtration and formation of primary urine in the kidney glomerulus is provided by a specialized membrane called slit diaphragm located between well-branched pedicels of podocytes. Actually, the slit diaphragm is a protein supercomplex, whose disruption can cause failure of renal filtration, and patients usually manifest nephrotic syndrome. Recently, familial forms of nephrotic syndrome have been described which arise from malfunction of mutated proteins making up the slit diaphragm. In 2005 it was found that one of the proteins present in this complex was non-selective cation channel TRPC6. The aim of this work was to screen mutations and polymorphisms of the TRPC6 gene in a group of 64 Czech patients with nephrotic syndrome and subsequently, on the basis of these data, evaluate the role of mutations in the TRPC6 gene in Czech population. The analysis was performed by the PCR method followed by direct sequencing and high-resolution melting method. We have not identified any mutations in our group of patients. Two additional single nucleotide polymorphisms - p.P15S and p.A404V - were detected along with nucleotide changes that did not result in amino acid changes and with a few intronic changes. P.P15S heterozygotes were more frequent in patients with steroid-resistant FSGS than in steroid- sensitive patients (29 % versus 12.1 %). To conclude, we did not find any probable disease-causing mutation in the TRPC6 gene in the cohort of 64 Czech patients. The p.P15S polymorphism might have some influence on the therapeutic response of FSGS patients.

Mutational analysis of the NPHS2 gene in Czech patients with idiopathic nephrotic syndrome.

Focal segmental glomerulosclerosis and minimal change disease represent frequent histological patterns of renal injury in patients with nephrotic syndrome. Few cases carrying NPHS2 gene variants have been described to date. Mutational analysis of the NPHS2 gene was performed in 50 Czech adult patients with histologically proved FSGS/MCD. The common p.P20L and p.R229Q polymorphisms of the NPHS2 gene were tested in 169 patients with IgA nephropathy and in 300 individuals of the control group. No mutation in the NPHS2 gene in patients with adult onset was identified. One homozygous mutation p.V290M in a patient with onset in early childhood was found. One new heterozygous variant in the non-conservative area of the NPHS2 gene, p.G97S, was identified in a patient with childhood-onset FSGS. In one adult patient, there were two polymorphisms, p.P20L and p.R229Q, in trans-heterozygous state, which could contribute to steroid-resistant nephrotic syndrome. The most common polymorphism p.R229Q was identified in 12 % of FSGS/ MCD patients, in 11.8 % of IGAN patients and in 10% of controls. The heterozygosity of p.R229Q polymorphism was similar in the IGAN group, with non-significantly higher prevalence in IGAN patients with progressive form of the disease (15.9 % versus 9.4 %). The prevalence of p.P20L polymorphism was not significantly different among the groups (6 % in FSGS patients, 1.8 % in IGAN patients, 1 % in the control group). To conclude, NPHS2 mutations are rare in patients with adult onset of FSGS/MCD. The R229Q polymorphism is frequent in the Czech population and probably could have some influence on IGAN.

The influence of vascular endothelial growth factor (VEGF) polymorphism on the progression of chronic glomerulonephritides.

Vascular endothelial growth factor is an important mediator in maintaining normal kidney functions. In addition, several lines of evidence show that up-regulation of this mediator in glomeruli may be associated with or may directly cause renal dysfunction. We tried to assess the influence of the -2578 C/A and -1154 G/A polymorphisms in the regulatory region of the vascular endothelial growth factor gene upon progression of three primary chronic glomerulonephritides (minimal change disease/focal and segmental glomerulosclerosis, membranous nephropathy, immunoglobulin A nephropathy). We studied a cohort of 213 patients compared to 311 unrelated healthy controls. Analysis of the C/A polymorphism of vascular endothelial growth factor revealed an increased prevalence of CC genotype in the minimal change disease/focal and segmental glomerulosclerosis group in comparison with the other groups. A balanced distribution of G and A alleles among the respective types of chronic glomerulonephritides was shown in the analysis of -1154 G/A polymorphism. Finally, we have not proved any significant influence of the polymorphisms at positions -2578 C/A and -1154 G/A of the vascular endothelial growth factor gene promoter on the progression of chronic glomerulonephritides even though our study suggests a negative effect of CC genotype of -2578 C/A polymorphism on the clinical course of minimal change disease/focal segmental glomerulosclerosis.

DNA analysis of renal electrolyte transporter genes among patients suffering from Bartter and Gitelman syndromes: summary of mutation screening.

Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB. Clinical symptoms of these two diseases may overlap. Patients with clinical symptoms of antenatal form of Bartter syndrome were screened for mutations in two different genes: KCNJ1 and SLC12A1. The aim was to establish genetic mutation screening of Bartter/Gitelman syndrome and to confirm the proposed diagnosis. We have identified seven different causative mutations in the SLC12A3 gene, four in the CLCNKB gene, two in the SLC12A1 gene, and none in the KCNJ1 gene. Nine of these mutations are novel. In one case, genetic analysis led to re-evaluation of diagnosis between the Gitelman and classic form of Bartter syndrome.

Influence of VEGF polymorphism on progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). Dysregulation of vascular endothelial growth factor (VEGF) expression in the kidney has been demonstrated in a wide range of renal diseases. The aim of the present study was to assess the influence of the -2578 C/A and the -1154 G/A polymorphisms in the regulatory region of the VEGF gene upon the progression of ADPKD toward end-stage renal disease (ESRD). METHODS: The study was performed on 283 ADPKD patients (145 males, 138 females, mean age 51.7 +/- 10.3 years) who had reached ESRD. Patients were divided into three groups: (1) ESRD development later than in 63 years (slow progressors, n = 47), (2) ESRD development before 45 years (rapid progressors, n = 69), and (3) ESRD development between 45 and 63 years (intermediate progressors, n = 167). Genetically unrelated healthy Czech individuals were analyzed as a control group (n = 311, 153 males, 158 females, mean age 44.6 +/- 9.2 years). DNA samples were genotyped for the -2578 C/A and for the -1154 G/A polymorphisms of the VEGF gene promoter. The serum levels of VEGF were established in 111 healthy Czech individuals from the control group. RESULTS: The VEGF -2578 C/A and -1154 G/A genotype distribution showed no differences among the groups of slow, rapid and intermediate progressors. The age of ESRD with regard to different genotypes was not significantly different in all ADPKD patients. However, the AA genotype of the -2578 C/A polymorphism was associated with a significantly higher age of ESRD than other genotypes in rapid progressors (42.7 vs. 40.5 years, p = 0.01). The CG haplotype was found significantly more frequent in ADPKD rapid progressors than in slow progressors (p = 0.047). Serum levels of VEGF did not significantly differ in the control group, according to different genotypes of both polymorphisms. CONCLUSION: To conclude, AA genotype of the -2578 C/A polymorphism was related to better prognosis of the disease in a limited group of ADPKD patients. Classical genetic recessive and dominant model did not find significant influence of separate VEGF polymorphisms on the progression of ADPKD. Accordingly, CG haplotype was associated with earlier onset of ESRD in ADPKD patients.

The influence of two megsin polymorphisms on the progression of IgA nephropathy.

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 influence of endothelin-A receptor gene polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy.

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.

The influence of three endothelin-1 polymorphisms on the progression of IgA nephropathy.

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.

Long-term outcome of patients with idiopathic membranous nephropathy.

Although idiopathic membranous nephropathy (iMN) is a common glomerular disease, its therapy still remains controversial. The aim of our study was to analyse the outcome of patients with iMN diagnosed and treated in our center. We retrospectively studied 82 patients with iMN that were diagnosed between January 1991 and June 2002. The group consisted of 57 males (69.5%) and 25 females (30.5%) with a mean age of 53 years. The mean follow-up was 56 +/- 38 months. Remission was achieved in 59.2% of patients treated with chlorambucil, 71.4% treated with cyclophosphamide, 85.7% treated with cyclosporine and in 71.4% of those who were left untreated intentionally. However, the proportion of patients in the different treatment subgroups differed significantly (60% vs. 8.5% vs. 8.5% vs. 23%, respectively). The relapse rate was 31.3%. The second-line treatment was effective in a majority of the patients. At the end of follow-up, almost 70% of the patients were in remission with the parameters of nephrotic syndrome significantly improved and renal function unchanged. The renal survival was 100%. Immunosuppressive therapy is effective in iMN, but spontaneous remissions occur as well. Although relapses are frequent, almost 70% of the patients were in remission at the end of follow-up. The renal survival in our group of iMN patients was very good, probably due to preserved renal function at diagnosis.

The pathogenetic aspects and gene polymorphisms of IgA nephropathy.

Immunoglobulin A nephropathy is an immune-complex-mediated glomerulonephritis characterized by diffuse mesangial deposition of immunoglobulin A or IgA--containing immune complexes. Although its most common clinical presentation is macroscopic hematuria provoked by upper respiratory tract infection, this is neither universal nor necessary for the diagnosis. The patients with IgA nephropathy manifest with variable clinical symptoms (e.g., microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The pathogenetic mechanisms include the abnormality of O-glycosylation of the IgA1 molecule, genetic factors, environmental factors and various inflammatory mediators. The source of mesangial IgA deposits is total circulating serum IgA but the response of the mesangium and the mesangial cells to the deposited IgA is critical to the development of IgAN. Without a genetic predisposition to IgAN, IgA deposition can cause no risk for triggering glomerulonephritis. If generic progression risk factors of an unfavourable outcome coincide (e.g. hypertension, severe proteinuria, elevated serum creatinine level), this will increase the likelihood of progressive renal impairment. Further studies are needed to disclose the precise pathogenetic mechanisms involved in primary IgA nephropathy and to facilitate the development of newer therapeutic possibilities.

Influence of endothelin-1 gene polymorphisms on the progression of autosomal dominant polycystic kidney disease.

BACKGROUND/AIM: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. Endothelin-1 (ET-1) has been suggested to be a major promoting factor in renal diseases. The role of the ET-1 gene locus (EDN1) in the renal function in the general nondiabetic population was evaluated. We examined the influence of three single-nucleotide polymorphisms of the ET-1 gene (EDN1)--K198N, 3A/4A, and T-1370G--on the progression of ADPKD towards end-stage renal disease (ESRD). METHODS: Two hundred and five ADPKD patients (113 males and 92 females) who had reached ESRD were analyzed. The patients were divided into three groups: (1) 48 patients (23 males and 25 females) with ESRD later than 63 years of age (slow progressors), (2) 74 patients (41 males and 33 females) with ESRD before 45 years of age (rapid progressors), and (3) 83 patients (49 males and 34 females) with ESRD between 45 and 63 years old. DNA samples from collected blood were genotyped for three single-nucleotide polymorphisms of EDN1: K198N, 3A/4A, and T-1370G. Haplotype analysis was also done in 200 healthy individuals. We compared the frequencies of the different genotypes between the groups of slow and rapid progressors and the ages at the time of ESRD regarding the EDN1 genotypes. RESULTS: The EDN1 genotype distribution showed no differences among the groups of slow progressors, rapid progressors, the ADPKD group with ESRD between 45 and 63 years old, and the control group. Comparing the ages of ESRD of all patients, we did not find significant differences with regard to the different genotypes. Furthermore, we compared the combinations of the different haplotypes and the ages at the time of ESRD. We found no differences in ages at the time of ESRD in patients with different haplotypes in the endothelin promoter (T-1370G) in combination with 3A/4A or K198N polymorphisms. Comparing the ages at the time of ESRD in patients with different 3A/4A and K198N haplotypes, we found a significantly lower age at the time of ESRD (47.1 +/- 8.7 years) in the carriers of the 4A allele in combination with the 198N allele (4A/4A, 3A/4A + 198KN,NN) than in the carriers of the 4A allele homozygous for the K198 allele (52.9 +/- 10.9 years; 4A/4A, 3A/4A + 198KK; t test: p < 0.01) and in the carriers of the 198N allele homozygous for the 3A allele (53 +/- 11.2 years; 3A/3A + 198KN,NN; t test: p < 0.05). CONCLUSIONS: We excluded an effect of K198N, 3A/4A, and T-1370G polymorphisms of EDN1 on the progression of ADPKD. However, a deleterious effect of the combination of 4A and 198N alleles of EDN1 was observed in APKDK individuals.

Genetic basis of nephrotic syndrome--review.

Nephrotic syndrome (NS) is one of the most frequent syndromes characterized namely by heavy proteinuria. Majority of NS occurs as a sporadic form, the incidence of familial cases is from 3 to 5%. Seven genes have been recognized till present, which mutations are responsible for severe forms of NS: NPHS1, NPHS2, ACTN4, CD2AP and WT1, TRPC6, LAMB2. Proteins encoded by these genes (nephrin, podocin, alpha-actinin-4, an adapter protein anchoring CD2 and others) influence the function of the podocytes. In cases of mutation in NPHS1 gene, causing congenital nephrotic syndrome of the Finnish type (CNF), resistance to steroid therapy occurs regularly and recurrence of proteinuria after renal transplantation is about 20-25%. Mutations in NPHS2 gene lead to autosomal recessive steroid resistant nephrotic syndrome (histologically focal segmental glomerulosclerosis). It was concluded that patients with steroid resistant nephrotic syndrome (SRNS) with homozygous or compound heterozygous mutations in NPHS2 have reduced risk for recurrence of focal segmental glomerulosclerosis (FSGS) in renal transplant (only 8% in comparison with 35% in patients without mutation in NPHS2). A functional polymorphism of NPHS2 gene--R229Q was associated with a late-onset nephrotic syndrome and also with an increased risk of microalbuminuria in the general population. The R229Q variant encodes a protein with lower affinity for binding nephrin. This polymorphism appears to enhance susceptibility to FSGS in association with a second mutant NPHS2 allele. There are also 3 genetic loci connected with autosomal dominant forms of FSGS: ACTN4, TRPC6 and CD2AP (found only in the mice models). These forms of FSGS differ from the recessive form by later-onset and more slowly progressive course of the disease; these mutations seem to be responsible for only a fraction of the autosomal dominant pattern of FSGS.

The influence of the endothelin-converting enzyme-1 gene polymorphism on the progression of autosomal dominant polycystic kidney disease.

UNLABELLED: BACKGROUND; A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD), the most common renal hereditary disease. Endothelin-1 (ET-1) has been suggested to be an important disease-promoting factor of the kidney. Endothelin-converting enzyme-1 (ECE-1) is the main protease responsible for ET-1 generation by cleavage of its functionally inactive precursor. We examined the influence of the ECE-1b C-338A polymorphism on the progression of ADPKD toward end-stage renal disease (ESRD). The A allele was suggested to be associated with higher plasma level of ET-1. METHODS: 200 ADPKD patients (107 males, 93 females) who had reached ESRD were analyzed. Patients were divided into three groups: (1) 47 patients (23 males, 24 females) with ESRD later than in 63 yr (slow progressors); (2) 71 patients (38 males, 33 females) with ESRD before 45 yr (rapid progressors); and (3) 82 patients (46 males, 36 females) with ESRD between 45-63 yr. Moreover, we analyzed 160 genetically unrelated healthy Czech subjects as the control group (82 males, 78 females, mean age 51.4 +/- 8.2 yr). DNA samples from collected blood were genotyped for ECE-1b C-338A polymorphism using described polymerase chain reaction (PCR) followed by restriction enzyme digestion. We compared the frequencies of different genotypes between the groups of slow and rapid progressors and the ages of ESRD with regard to different genotypes. RESULTS: The ECE-1b C-338A genotype distribution showed no differences among the groups of slow progressors, rapid progressors, ADPKD group with ESRD between 45-63 yr and control group. Comparing the ages of ESRD of all patients, we did not find significant differences in the ages with regard to different genotypes: CC (51.5 +/- 10.1 yr), AC (51.6 +/- 11.4 yr), AA (48.2 +/- 5.9 yr). There was a tendency to lower age of ESRD in AA homozygotes in comparison with other genotypes (t-test, p = 0.12). We found no influence of gender. CONCLUSION: We excluded the effect of ECE-1b C-338A polymorphism on the progression of ADPKD. We could observe a mild tendency toward faster decline of renal function in AA homozygous individuals.

Does electron microscopy change the view of the diagnosis of IgA nephropathy?

Our study is aimed to reveal the frequency and clinical significance of the coincidence of two widely spread entities, e.g. minimal change disease (MCD) and IgA nephropathy (IgAN), claimed to be found in an overwhelming number in some Asian regions. We retrospectively analyzed clinical and histological data from 627 renal biopsies, performed in our department from January 2002 to January 2005 and completed electron microscopy in 112 specimens diagnosed as IgAN. The coincidence of IgAN and MCD was found in 8 patients (7.1%). The coincidence of IgAN and minimal change nephrotic syndrome (MCNS) clinically--especially presence of nephrotic syndrome and the response to drug therapy (with corticosteroids)--behaves as "pure" MCN. Our data from Czech Republic seem to suggest that the combination of IgAN with MCNS can be found relatively frequently not only in Asian patients (as stressed by some authors of Asian origin) but also in European inhabitants. The pathogenesis of the coincidence of IgAN and MCD needs to be elucidated by further studies.

Focal segmental glomerulosclerosis in solitary kidney in WAGR syndrome.

WAGR syndrome consists of Wilms' tumour, aniridia, genitourinary malformations and mental retardation, and is associated with chromosomal microdeletion of 11p13. We report a case of young male, exhibiting several typical features of WAGR syndrome (e.g. WT, aniridia and genitourinary abnormalities), but missing some other (mental retardation and chromosomal abnormality absent). Renal biopsy performed in our patient for unexplained proteinuria showed focal segmental glomerulosclerosis, presumably of secondary origin; the decrease of proteinuria was achieved by the firm control of BP in conjunction with the reduction of body weight.

The influence of G-protein beta3-subunit gene and endothelial nitric oxide synthase gene in exon 7 polymorphisms on progression of autosomal dominant polycystic kidney disease.

BACKGROUND: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. We examined the influence of G-protein beta3-subunit C825T polymorphism and endothelial nitric oxide synthase Glu298Asp polymorphism on the progression of ADPKD towards end stage renal failure (ESRF). METHODS: 306 ADPKD patients (pts) were analyzed; 261 pts (136 males, 125 females) with ESRF, with subgroup of 73 pts (44 males, 29 females) with ESRF before 45 years (rapid progressors), 46 pts (20 males, 26 females) with ESRF later than in 63 years (slow progressors) and 45 ADPKD pts (17 males, 28 females) in mean age 51 years with serum creatinine under 110 micromol/L (slow progressors) and 100 genetically unrelated healthy Czech subjects. DNA samples from collected blood were genotyped for G-protein beta3-subunit C825T genotype in exon 10 and for endothelial nitric oxide synthase Glu298Asp genotype in exon 7. RESULTS: The G-protein beta3-subunit C825T genotype exhibited no significant differences among the groups of slow progressors (6.6% (6/91) TT, 54.9% (50/91) CT, 38.8% (35/91) CC), rapid progressors (9.6% (7/73) TT, 46.6% (34/73) CT, 43.8% (32/73) CC), ADPKD group with ESRF between 40-63 years (9.2% (13/142) TT, 50% (71/142) CT, 40.8% (58/142) CC) and control group (12% TT, 44% CT, 44% CC). When comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages: males TT--51.7+/-8.8 years, CT--51.9+/-10.3 years, CC--49.7+/-10.2 years and females TT--56+/-9.9 years, CT--53.2+/-8.5 years, CC--53.9+/-8.7 years. The endothelial nitric oxide synthase Glu298Asp and Asp29Asp genotypes were significantly more frequent in rapid progressors (9.6% (7/73) Asp/Asp, 39.7% (29/73) Asp/Glu, 50.7% (37/73) Glu/Glu) and in ADPKD group with ESRF between 40-63 years (11.3% (16/142) Asp/Asp, 41.5% (59/142) Asp/Glu, 47.2% (67/142) Glu/Glu) in comparison with slow progressors (8.8% (8/91) Asp/Asp, 24.2% (22/91) Asp/Glu, 67.0% (61/91) Glu/Glu) and with control group (8% Asp/Asp, 32% Asp/Glu, 60% Glu/Glu) (Chi-square test, p<0.05). Comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages in males with Asp/Asp--54.9+/-10.4 years, Asp/Glu--50.2+/-9.4 years, Glu/Glu--51.0+/-10.4 years. We found out in homozygous Asp/Asp females significantly earlier onset of ESRF (49.2+/-5.6 years) in comparison with heterozygous females (53.3+/-7.2 years) and with Glu/Glu homozygous females (54.8+/-9.7 years) (t-test, p<0.05). CONCLUSION: We excluded the significance of G-protein beta3-subunit C825T polymorphism on the progression of ADPKD. We established the negative prognostic value of the carriers of Asp variant of eNOS polymorphism. Finding of new modifiers could have in future clinical consequences for ADPKD patients.

[Fibrillary glomerulonephritis]. / Fibrilární glomerulonefritis.

An overview of fibrillary glomerulonephritis (GN) is given as well as the description of clinical course in four patients diagnosed and treated in our department. Fibrillary GN and immunotactoid glomerulopathy are entities, characterized by fibrillar and microtubular deposits in mesangium and the glomerular capillary loops. Decisive for diagnosis of fibrillary GN (resp. immunotactoid GN) remains the electron microscopy (EM) of the renal biopsy (RB) specimen. At the nephrologic division of 1st Internal Department of 1st Medical School of Charles University four cases of patients with fibrillary GN were diagnosed from the mid seventies (when both entities were newly described) by the end of the year 2001. In all patients the diagnosis was proven by EM. RB was indicated mainly for proteinuria, hematuria and decrease of renal function. On conclusion: though fibrillary GN/immunotactoid GN are relatively rare disorders, they represent entities, which should not be omitted in the differential diagnosis of nephrotic syndrome/renal insufficiency and which deserve further study.