Romana Rysava

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.

CYTOKINE PROFILE IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

To elucidate the pathogenetic mechanism of renal parenchymal injury in autosomal dominant polycystic kidney disease (ADPKD) patients, typically characterized by renal cystic changes paralleled by interstitial inflammation and gradual fibrotic changes, the role of selected inflammatory mediators was evaluated in a group of ADPKD patients with normal glomerular filtration rate. The plasma concentrations of IL‐6, IL‐8, ICAM‐1 and VCAM‐1 (which may reflect systemic response to inflammation/infection) were increased in the ADPKD patient group. Coupled with decreased urinary excretion of the IL‐1 receptor antagonist (which exerts an anti‐inflammatory role), these results suggest that even in overt infection free status, the proinflammatory system is more activated and anti‐inflammatory defence system weakened in ADPKD subjects. Our data support the current view that cytokines are candidate contributors to pathogenesis of ADPKD.

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.

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.

AL amyloidosis with renal involvement.

Primary (AL amyloidosis) is a systemic disease characterized by an amyloid deposition process in many organs, with unsatisfactory survival of patients. The monoclonal light chains form the fibrils that deposit and accumulate in tissues. Renal involvement is very frequent in AL amyloidosis and could lead to development of nephrotic syndrome followed by the renal failure in many cases. Classic therapeutic combination melphalan and prednisone has been supplemented with drugs with different mechanisms of action in this group of patients: high-dose dexamethasone, high-dose dexamethasone with melphalan, combination of vincristine, doxorubicin, and dexamethasone or newly high-dose melphalan supported by peripheral blood stem cell transplantation. This progressive therapy leads to the better survival and prognosis in the majority of patients. Alternative therapeutic approaches include thalidomide (alone or in combination with cyclophosphamide), lenalidomide, iododoxorubicin, etanercept and rituximab. The development of immunotherapy is expected in the near future.

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.

Can serum amyloid a or macrophage colony stimulating factor serve as marker of amyloid formation process

Amyloid formation depends on amyloid precursor production and is influenced by the activity of the underlying disorder and mediated by some proinflammatory cytokines. In this pilot study we tried to find some specific markers that could establish the activity of the disease. We investigated 45 samples of sera and 38 samples of urine from patients (pts) with secondary amyloidosis (AA), primary amyloidosis (AL), systemic autoimmune diseases with renal impairment (Vase) and healthy controls (Co). Pts with AA had increased plasma levels of TNFα (9.97±4.22 vs. 2.63±1.34 pg/mL, p<0.001) and SAA (43.14±16.0 vs. 3.42±0.7 ng/mL, p<0.05) in comparison with Co. Plasma levels of M‐CSF in the AA group were significantly increased in comparison with Co (1077.34±238.6 vs. 137.71±19.6, pg/mL, p<0.001) and also in comparison with Vase (482.24±86.7 pg/mL, p<0.05). Urinary excretions of TNFα (8.92±8.1 vs. 0.17±0.11 μg/mol creatinine, p<0.01), slL‐6R (1.39±1.14 vs. 0.07±0.05 g/mol creatinine, p<0.01) and M‐CSF (650.2±153.7 vs. 33.3±8.6 t.tg/mol creatinine, p<0.01) in AA were significantly increased in comparison with Co. Pts with AL had increased plasma levels of M‐CSF (819.83±264.2 vs. 137.71±19.6 pg/mL, p<0.05) and urinary excretion of M‐CSF (865.0±188.4 vs. 33.3±8.6μtg/mol creatinine, p<0.01) in comparison with Co. SAA has a low specificity for amyloidosis but is a sensitive acute phase reactant. TNFα, a proinflammatory cytokine, may reflect the activity of the underlying diseases in secondary amyloidosis. M‐CSF was increased both in plasma and urine in amyloidosis groups and seems to be the most promising (possibly specific) marker of amyloidosis.

Intracellular cytokine production in ANCA-associated vasculitis: low levels of interleukin-10 in remission are associated with a higher relapse rate in the long-term follow-up.

BACKGROUND AND AIMS Dysregulation of cell-mediated immune response likely plays a role in the pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), but it has not yet been fully established. The aim of this study was to assess the intracellular cytokine production in patients with AAV at different stages of the disease, in particular, in relation to the long-term prognosis. METHODS We included 69 patients with AAV and 24 healthy controls. Using flow cytometry, the following intracellular cytokines (IC) were measured in all patients: interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-2 and interleukin-4 in CD3+T cells and interleukin-10 (IL-10) and interleukin 12 (IL-12) in monocytes. Patients were then prospectively followed for a median of 43 months and cytokine production was related to the long-term prognosis. RESULTS When compared to healthy controls, increased IL-12 production was observed in AAV patients, both active (p<0.01) and in remission (p<0.05). In remission, increased IFN-gamma production was also found (p<0.01). IL-10 production was higher in active patients than in patients in remission (p<0.05) but did not differ from controls. Patients in remission who developed a relapse during follow-up had significantly lower IL-10 production than those without relapse (p<0.01). Results of this prospective study of IC production in AAV confirm findings of previous studies measuring circulating cytokine levels. CONCLUSIONS Activation of the immune system in AAV patients is noticeable even in remission. Patients with AAV display increased IL-12 production, which seems to be counterbalanced by IL-10. Low IL-10 levels in remission are associated with a higher relapse rate in the long-term follow-up.