Dita Maixnerova

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.

Treatment of lupus nephritis with cyclosporine - an outcome analysis.

Background: The optimal therapy for lupus nephritis (LN), including the role of cyclosporine (CsA), still lacks scientifically valid clinical experience. We evaluated the efficacy of CsA in the induction and maintenance treatment of patients with biopsy-proven LN. Patients and Methods: A total of 31 patients (25 women, 6 men, mean age 29.5 years) were enrolled in the study. The majority had proliferative LN. The mean follow-up was 85.6 ± 24.7 months. Results: CsA was used as first-line treatment in 38.7% of patients and as second-line treatment in 61.3% of patients. Complete remission was achieved in 93.5% of patients. The relapse rate was 45.2%. The mean disease-free interval was 33 months. At the end of follow-up, a total of 67.9% of the patients were in remission. The treatment led to significant improvement in proteinuria (p = 0.001) and stabilization of renal function. Conclusion: CsA might be an appropriate and a less toxic alternative drug for LN both as a first-choice and rescue therapy.

Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy

Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.

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 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 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.

The coincidence of IgA nephropathy and Fabry disease

BackgroundIgA nephropathy (IgAN) is the most common glomerulonephritis, which may also coexist with other diseases. We present two patients with an unusual coincidence of IgAN and Fabry disease (FD).Case presentationA 26 year-old man underwent a renal biopsy in February 2001. Histopathology showed very advanced IgAN and vascular changes as a result of hypertension. Because of his progressive renal insufficiency the patient began hemodialysis in August 2001. By means of the blood spot test screening method the diagnosis of FD was suspected. Low activity of alpha-galactosidase A in the patient’s plasma and leukocytes and DNA analysis confirmed the diagnosis of FD. Enzyme replacement therapy started in July 2004. Then the patient underwent kidney transplantation in November 2005. Currently, his actual serum creatinine level is 250 μmol/l. Other organ damages included hypertrophic cardiomyopathy, neuropathic pain and febrile crisis. After enzyme replacement therapy, myocardial hypertrophy has stabilized and other symptoms have disappeared. No further progression of the disease has been noted.The other patient, a 30 year-old woman, suffered from long-term hematuria with a good renal function. Recently, proteinuria (2.6 g/day) appeared and a renal biopsy was performed. Histopathology showed IgAN with remarkably enlarged podocytes. A combination of IgAN and a high suspicion of FD was diagnosed. Electron microscopy revealed dense deposits in paramesangial areas typical for IgAN and podocytes with inclusive zebra bodies and myelin figures characteristic of FD. FD was confirmed by the decreased alpha-galactosidase A activity in plasma and leukocytes and by DNA and RNA analysis. Enzyme replacement therapy and family screening were initiated.ConclusionsOur results emphasize the role of complexity in the process of diagnostic evaluation of kidney biopsy samples. Electron microscopy represents an integral part of histopathology, and genetic analysis plays a more and more important role in the final diagnosis, which is followed by causal treatment.

Toward Noninvasive Diagnosis of IgA Nephropathy: A Pilot Urinary Metabolomic and Proteomic Study

IgA nephropathy is diagnosed by renal biopsy, an invasive procedure with a risk of significant complications. Noninvasive approaches are needed for possible diagnostic purposes and especially for monitoring disease activity or responses to treatment. In this pilot project, we assessed the utility of urine samples as source of biomarkers of IgA nephropathy. We used spot urine specimens from 19 healthy controls, 11 patients with IgA nephropathy, and 8 renal-disease controls collected on day of renal biopsy. Urine samples were analyzed using untargeted metabolomic and targeted proteomic analyses by several experimental techniques: liquid chromatography coupled with mass spectrometry, immunomagnetic isolation of target proteins coupled with quantitation by mass spectrometry, and protein arrays. No single individual biomarker completely differentiated the three groups. Therefore, we tested the utility of several markers combined in a panel. Discriminant analysis revealed that combination of seven markers, three metabolites (dodecanal, 8-hydroxyguanosine, and leukotriene C4), three proteins (α1-antitrypsin, IgA-uromodulin complex, and galactose-deficient IgA1), and heparan sulfate, differentiated patients with IgA nephropathy from patients with other renal diseases and healthy controls. Future studies are needed to validate these preliminary findings and to determine the power of these urinary markers for assessment of responses to therapy.

IgA Nephropathy in Czech Patients - Are We Able Reliably Predict the Outcome?

Background/Aims: The aim of our study was to retrospectively analyse data of 520 Czech patients with IgA nephropathy (IgAN) and to specify the risk factors affecting renal survival of IgAN patients. Methods: Cox proportional hazards regression model was used to evaluate the effects of different variables on renal survival during a median follow up of six years. McNemar´s test was used to analyse the progression of renal function according to Bartosik´s formula. Results: In our retrospective analysis of 520 Czech IgAN patients Cox proportional hazards regression model with five variables [hypertension, sex, GFR, proteinuria, age] was used. Significant regression coefficient was found for GFR, hypertension and proteinuria. Using stepwise algorithm GFR (OR = 3.09), hypertension (OR = 2.09) and proteinuria (OR = 1.97) were found as the most important factors for renal survival in our group of IgAN patients. Among patients with CKD 3 we found significantly better renal survival in patients with proteinuria < 1g/day compared to patients with higher proteinuria. We did not find the significant difference between predicted progression of renal function due to Bartosik´s formula and real progression of renal parametres assessed by GFR at the end of the follow up in our group of IgAN patients. Conclusion: Our retrospective study of 520 Czech IgAN patients confirmed GFR, hypertension and proteinuria as the most important factors affecting the prognosis of IgAN patients. We validated Toronto Bartosik´s formula to predict prognosis of IgAN patients.

Erratum to: Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort

Rosanna Coppo & Danilo Lofaro & Roberta R. Camilla & Shubha Bellur & Daniel Cattran & H. Terence Cook & Ian S. D. Roberts & Licia Peruzzi & Alessandro Amore & Francesco Emma & Laura Fuiano & Ulla Berg & Rezan Topaloglu & Yelda Bilginer & Loreto Gesualdo & Rosaria Polci & Malgorzata Mizerska-Wasiak & Yasar Caliskan & Sigrid Lundberg & Giovanni Cancarini & Colin Geddes & Jack Wetzels & Andrzej Wiecek & Magdalena Durlik & Stefano Cusinato & Cristiana Rollino & Milena Maggio & Manuel Praga & Hilde K. Smerud & Vladimir Tesar & Dita Maixnerova & Jonathan Barratt & Teresa Papalia & Renzo Bonofiglio & Gianna Mazzucco & Costantinos Giannakakis & Magnus Soderberg & Diclehan Orhan & Anna Maria Di Palma & JadwigaMaldyk &YaseminOzluk &Birgitta Sudelin &Regina Tardanico &DavidKipgen & Eric Steenbergen & Henryk Karkoszka & Agnieszka Perkowska-Ptasinska & Franco Ferrario & Eduardo Gutierrez & Eva Honsova