Jana Reiterová

Long-Term Outcome of Patients with Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis with Renal Involvement

Background: Despite treatment, renal involvement in antineutrophil cytoplasmic autoantibody (ANCA)-positive vasculitis is still associated with significant long-term mortality and remains an important cause of end-stage renal failure. Methods: We retrospectively analyzed a series of 61 consecutive patients with newly diagnosed ANCA-associated renal vasculitis (54.1% Wegener’s granulomatosis, 23% renal-limited vasculitis, 16.4% microscopic polyangiitis, 4.9% Churg-Strauss syndrome) diagnosed between 1986 and 1997. Results: The median creatinine level at diagnosis was 221.5 (63–762) µmol/l, i.e. 2.5 (0.7–8.6) mg/dl, 32.8% were dialysis-dependent. All patients were treated with cyclophosphamide. Remission was achieved in 87% of patients. Relapses occurred in 44.7%. The median renal disease-free interval was 62.5 (0–138) months. The estimated patient survival at 5 and 10 years was 78.3 and 62.2%, respectively. Mortality was associated with age (p = 0.04 when age limit 50 years) and advanced renal failure (p = 0.038 when compared dialysis-dependent and independent patients). Estimated renal survival time at 5 and 10 years was 69.2 and 55.8%, respectively. At the end of follow-up, 50.8% of patients were in complete remission, 31% had died. The median serum creatinine level was 137.5 (77–469) µmol/l, i.e. 1.56 (0.87–5.3) mg/dl, 24.6% of patients were on regular dialysis treatment. Conclusion: Patient survival, relapse rate and mortality were comparable to similar reports. In view of the severity of the renal disease and the length of follow-up, renal survival was very good. Despite effective treatment, the long-term outcome of patients with ANCA-associated renal vasculitis remains unsatisfactory.

Silica and Asbestos Exposure in ANCA-Associated Vasculitis with Pulmonary Involvement

Silica and asbestos exposure are thought to belong to the triggering factors of antineutrophil cytoplasm antibodies (ANCA)-associated vasculitis. We carried out a study to find out whether patients with pulmonary involvement attributable to ANCA-associated vasculitis (AAV) have been exposed to silicon-containing materials. Thirty-one patients (12 women, 19 men, median age 51 years) were interviewed using a structured questionnaire. Occupational exposure to silicon-containing chemicals was reported by 22.6% of the patients (12.9% to SiO2, 9.7% to asbestos), compared with 0% of control subjects (p < 0.05). Our findings support the pathophysiologic role of silica in AAV.

Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. ADPKD is a systemic disorder with cysts and connective tissue abnormalities involving many organs. ADPKD caused by mutations in PKD1 gene is significantly more severe than the cases caused by PKD2 gene mutations. The large intra-familial variability of ADPKD highlights a role for genetic background.Case presentationHere we report a case of ADPKD family initially appearing unlinked to the PKD1 or PKD2 loci and the influence of mosaicism and hypomorphic allele on the variability of the clinical course of the disease. A grandmother with the PKD1 gene mutation in mosaicism (p.Val1105ArgfsX4) and with mild clinical course of ADPKD (end stage renal failure at the age of 77) seemed to have ADPKD because of PKD2 gene mutation. On the other hand, her grandson had a severe clinical course (end stage renal disease at the age of 45) in spite of the early treatment of mild hypertension. There was found by mutational analysis of PKD genes that the severe clinical course was caused by PKD1 gene frameshifting mutation inherited from his father and mildly affected grandmother in combination with inherited hypomorphic PKD1 allele with described missense mutation (p.Thr2250Met) from his clinically healthy mother. The sister with two cysts and with PKD1 hypomorphic allele became the kidney donor to her severely affected brother.ConclusionWe present the first case of ADPKD with the influence of mosaicism and hypomorphic allele of the PKD1 gene on clinical course of ADPKD in one family. Moreover, this report illustrates the role of molecular genetic testing in assessing young related kidney donors for patients with ADPKD.

Secondary membranous nephropathy--one center experience.

Introduction. Secondary membranous nephropathy (MN) is most commonly seen in the setting of autoimmune disease, infection, and neoplasia, and with certain therapeutic agents. The aim of our study was to analyze the presenting features and outcome of the patients with secondary MN. Patients and Methods. We retrospectively studied patients with secondary MN diagnosed between the years 1991–2002. In this period, we performed a total of 1874 renal biopsies. MN was diagnosed in 129 cases. Results. In 40 patients (31%), an underlying primary cause was verified (70% women, 30% men, median age 49.5 years). In 18 patients (45%), the disease was drug induced, 11 patients (27.5%) had autoimmune disease, seven patients (17.5%) solid tumors, three patients (7.5%) hepatitis B, and one patient was diagnosed with both hepatitis B and prostate carcinoma. At presentation, median proteinuria was 4.09 g/24 h; 60% were nephrotic. Most of the patients had normal renal function with a median serum creatinine 79 µmol/L and a median GFR 1.285 ml/s. The patients were treated according to the underlying disease. At the end of the follow-up, the patients with drug-induced MN were in complete remission after the discontinuation of the drug. The patients with autoimmune disease were treated with immunosuppression, most of them with very good results. The outcome of the patients with neoplasia was much worse. Conclusion. A thorough and repeated exclusion of secondary forms of MN has significant prognostic and therapeutic implications, especially in drug-induced and autoimmune MN.

The retrospective analysis of 343 Czech patients with IgA nephropathy--one centre experience.

BACKGROUND The aim of our study was to retrospectively analyse the clinical data and the histological findings of 343 patients (pts) followed up with IgA nephropathy (IgAN) in our department of nephrology. We have assessed the main demographic, clinical and histological data, and the medical treatment of IgAN pts. METHODS Multivariate analysis was used to evaluate the effect of different variables on ≥50% increase of plasma creatinine level from baseline during a median follow-up of 4 years. RESULTS In our group of IgAN pts, the male gender (68%) predominated over female gender (32%). At the time of renal biopsy, the median age of IgAN pts was 32.3 (18-90) years, the median level of serum creatinine was 119 μmol/L and the median level of proteinuria was 1.8 g/day. Most of the pts were found to have arterial hypertension (56.7%). The majority of the pts with arterial hypertension were treated with inhibitors of angiotensin-converting enzyme (80.4%) and the remaining pts (42.6%) were treated with angiotensin II receptor blockers. Fifty per cent of the pts (170 pts) were treated of corticosteroids, 21% of the pts (71 pts) used a combined immunosuppressive treatment of corticosteroids and cyclophosphamide, 8% of the pts (27 pts) took azathioprine, 1.5% of the pts (5 pts) took cyclosporine and 1.5% of the pts (5 pts) were given mycophenolate mofetil. Hypertension at presentation, fibrointimal proliferation of arterial vessels, interstitial fibrosis and interstitial inflammation were shown to be associated with ≥50% increase of plasma creatinine level from baseline in univariate analysis (P<0.05 for hypertension and fibrointimal proliferation; P<0.01 for interstitial fibrosis and inflammation). Using stepwise logistic regression presenting proteinuria>2 g/day [odds ratio (OR)=2.24, P<0.01], tubular atrophy (OR=4.97, P<0.01) and damage of tubular epithelium (OR=1.78, P<0.05) were found as risk factors for ≥50% increase of plasma creatinine level from baseline. CONCLUSION Our retrospective analysis found valuable information not only about the clinical, laboratory and histological findings in IgAN pts but also information about the risk factors influencing the progression of renal insufficiency.

Influence of the Alpha-Adducin and ACE Gene Polymorphism on the Progression of Autosomal-Dominant Polycystic Kidney Disease

Background: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability can not be fully explained by the genetic heterogenity of the disease. We examined the influence of the ACE I/D polymorphism, adducin Trp460Gly polymorphism and the association of both polymorphisms on the progression of ADPKD towards end-stage renal failure (ESRF). Methods: 320 ADPKD patients (pts) were analyzed, 220 pts (113 males, 107 females) with ESRF before 63 years of age, with a subgroup (rapid progressors) of 20 pts (12 males, 8 females) with ESRF before 40 years of age, 52 pts (23 males, 29 females) with ESRF later than 63 years of age (slow progressors), 48 ADPKD pts (18 males, 30 females) with mean age ±50 years with serum creatinine <110 µmol/l (slow progressors) and 200 genetically unrelated healthy Czech subjects. DNA samples from collected blood were genotyped for the ACE I/D polymorphism and the Trp460Gly of α-adducin gene polymorphism. Results: The α-adducin genotypes showed no differences among the groups of slow progressors (74% Gly/Gly, 22.9% Gly/Trp and 3.1% Trp/Trp), pts with ESRF before 63 years of age (67.7% Gly/Gly, 30.5% Gly/Trp and 1.8% Trp/Trp) and rapid progressors (75% Gly/Gly, 25% Gly/Trp). The ACE genotypes did not differ among the groups of slow progressors (27.1% I/I, 44.8% I/D and 28.1% D/D), pts with ESRF before 63 years of age (23.6% I/I, 51.4% I/D and 25% D/D) and rapid progressors (20% I/I, 55% I/D and 25% D/D). The distribution did not differ from the control group. The ages of ESRF according to different genotypes did not significantly differ. We observed a significant tendency to better prognosis in Trp allele carriers for I/I genotype in comparison with Gly/Gly homozygous subjects. Conclusion: The ACE and α-adducin polymorphisms do not play a significant role in the progression of ADPKD to ESRF.

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.

Influence of the endothelial nitric oxide synthase polymorphism on the progression of autosomal dominant polycystic kidney disease and IgA nephropathy.

Background: The reason of variability of clinical course and progression to end-stage renal failure (ESRF) of two widespread chronic nephropathies–-autosomal dominant polycystic kidney disease (ADPKD) and IgA nephropathy (IGAN) is not clear. The endothelial dysfunction is considered in the number of factors possibly influencing the prognosis of these nephropathies. Our study tried to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphisms in intron 4 could have some relevance to the progression of ADPKD and/or IgA nephropathy. Methods: We examined 128 Czech patients with ADPKD (62 males, 66 females) and 93 patients with IGAN (51 males, 42 females). As a control group we used 100 genetically unrelated healthy subjects (50 men, 50 women, mean age 51.2 ± 8.2). The genomic DNA was amplified by polymerase chain reaction (PCR) and the products were separated on 1.5% agarose gel and visualized by ultraviolet transillumination. We compared homozygous subjects for ecNOSb allele with homozygous and heterozygous subjects for ecNOSa allele. Results: The frequencies of ecNOSa/b + a/a and ecNOSb/b genotypes were 19% (19/100) and 81% (81/100) in the control group. The frequencies of ecNOSa/b + a/a and ecNOSb/b genotypes in ADPKD patients were: 26.6% (8/30) and 73.4% (22/30) in ADPKD patients with normal renal function, 30% (9/30) and 70% (21/30) in ADPKD with ESRF, 35.2% (18/51) and 64.8% (33/51) in young ADPKD patients, 60% (12/20) and 40% (8/20) in ADPKD patients with ESRF later than in 62 years. In IGAN the frequencies of ecNOSa/b + a/a and ecNOSb/b genotypes were 24% (12/50) and 76% (38/50) in IgA with normal renal function and 20.9 % (9/43) and 79.1% (38/43) in IgA with ESRF. Conclusion: Both in ADPKD and IGAN groups there was no significant difference in the frequencies of ecNOS genotypes between patients with normal renal function and age matched patients with ESRF and between patients with normal renal function and control group. The frequency of ecNOS a allele was significantly higher in a number limited group ADPKD patients with ESRF later than in 62 years (Chi-square test p < 0.05). This higher frequency of a allele among ADPKD patients with later onset of ESRF could suggest the trend of positive influence of a allele in ADPKD patients.

Endothelial Nitric Oxide Synthase Affects the Progression of Autosomal Dominant Polycystic Kidney Disease

Background/Aim: The phenotypic variability of autosomal dominant polycystic kidney disease (ADPKD) cannot be explained only by various mutations of two known genes (PKD1 and PKD2), but the influence of other unknown factors should also be considered. Impairment of endothelial function has been observed in ADPKD patients. Our study tried to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphisms in intron 4 could have some relevance to the progression of ADPKD. Methods: We examined 155 Czech patients with ADPKD (80 males, 75 females; mean age 43.4 ± 14.7 years) and 100 genetically unrelated healthy subjects (50 men, 50 women; mean age 51.2 ± 8.2 years). The genomic DNA was amplified by polymerase chain reaction and the products were separated on 1.5% agarose gel and visualised by ultraviolet transillumination. We compared subjects homozygous for the ecNOSb allele with subjects homozygous and heterozygous for the ecNOSa allele. Results: The frequencies of ecNOSb/b, ecNOSa/b and ecNOSa/a were 81% (81/100), 17% (17/100) and 2% (2/100), respectively, in the control group, 60% (30/50), 32% (16/50) and 8% (4/50), respectively, in ADPKD patients with end-stage renal failure (ESRF), and 68.5% (72/105), 28.6% (30/105) and 2.9% (3/105), respectively, in ADPKD patients with normal renal function. The two-tailed t test revealed that the frequency of the ecNOSa allele (ecNOSa/b and ecNOSa/a) in dialysed patients was significantly higher than in ADPKD patients with normal renal function (p < 0.05). Conclusion: The a allele of the ecNOS gene polymorphism showed a significantly higher incidence among patients with ESRF caused by ADPKD. The a allele might have a negative influence on the progression of ADPKD.

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.