pANCA-vasculitis associated with rectal adenocarcinoma.

We report the case of a 69-year-old male patient who was admitted for fever, dry cough, recurrent sinusitis with epistaxis, anorexia with weight loss of 20 kg over a 3-month period, myalgia, and mononeuritis multiplex. He was diagnosed with pANCA/anti-MPO associated vasculitis and rectal adenocarcinoma. The tumor was treated by surgical resection. Recurrence of vasculitis occurred during steroid tapering which prompted us to add Mycophenolate mofetyl. A complete remission was achieved. We conclude that in the present case the vasculitis was an independent disease, not a paraneoplastic phenomenon. We discuss the value of different ANCA serologies for diagnostics and follow-up, the epidemiology of vasculitis associated with malignancy, and the concept of vasculitis as a paraneoplastic syndrome.

T cells in the pathogenesis of ANCA-associated vasculitis: current knowledge.

AAV are a group of systemic immune-mediated diseases with a strong and highly specific association with ANCA. In recent years, there has been increasing evidence that ANCA might play a direct pathogenic role in triggering AAV. Nevertheless, effectors of cell-mediated immunity prevail in the inflammation sites in patients with AAV. Numerous studies found increased markers of T-cell activation in AAV. Moreover, this activation persisted even in remission and despite treatment. Finally, successful therapeutic attempts using T cell-directed treatment were also reported. There has therefore been substantial evidence that T cells are involved in the pathogenesis of AAV, even though the exact mechanisms are yet to be elucidated. In this review, recent findings on the contribution of T cells to the pathogenic processes in AAV will be briefly summarized. Special emphasis will be placed on the Th1/Th2 concept, the role of T-regulatory cells, and the role of effector memory T cells in the pathogenesis of AAV.

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.

Optimizing the therapeutic strategies in ANCA-associated vasculitis--single centre experience with international randomized trials.

ANCA-associated vasculitides, including Wegener's granulomatosis and microscopic polyangiitis, are systemic autoimmune diseases with poor prognosis in untreated patients, which can be dramatically improved by current therapeutic modalities. The aim of multi-centre randomized trials of the European Vasculitis Study Group is to optimise and standardise treatment of these diseases. From 1995-2001 our department contributed a total of 40 patients to the trials CYCAZAREM (cyclophosphamide versus azathioprine during remission for generalised vasculitis), MEPEX (plasma exchange versus methylprednisolone for severe renal vasculitis) and CYCLOPS (daily oral versus pulse cyclophosphamide during induction phase for generalised vasculitis). In this paper, we report on the preliminary results of long-term follow up of our patients included in international trials. The mean time of follow-up of the patients was 55.7 months with the patient survival rate of 72% and renal survival rate of 65%. Remission was achieved in 82% of patients, out of which 42% suffered a relapse. In generalised forms of vasculitides, treatment with cyclophosphamide is nowadays established as the standard therapy. The aim, however, is to further minimise its toxic effects by choosing the optimal therapeutic strategies. Complete results of all trials have not yet been published; nevertheless, the preliminary available data have already revealed new potential therapeutic approaches.

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 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.

Daily oral versus pulse intravenous cyclophosphamide in the therapy of ANCA-associated vasculitis--preliminary single center experience.

The aim of the multicentric randomized trial CYCLOPS is to optimize the treatment of induction of remission in patients with generalized, but not immediately life-threatening ANCA (antineutrophil cytoplasmic antibodies) -associated vasculitis. This will be achieved by reducing the dose of cyclophosphamide by administering it as intermittent pulses. The lower cumulative dose will be very probably accompanied with lower toxicity, whereas the effectivity should be comparable. We have enrolled 28 patients to the study. At present, 18 of them are suitable for evaluation. Our preliminary results show that pulse intermittent administration of cyclophosphamide is safer from the point of morbidity and mortality due to infectious complications. In our hands, this treatment modality does not seem to be less effective than the conventional daily oral cyclophosphamide. However, unambiguous results and treatment recommendations will not be available until the final evaluation of all patients enrolled in the trial.

[An unusual cause of acute anuric renal failure]. / Neobvyklá prícina akutního anurického renálního selhání.

We present a case of a 79-years old woman with acute anuric renal failure due to biopsy confirmed immunotactoid glomerulonephritis. Despite biclonal gammopathy IgG lambda, no hematologic or any other underlying malignancy was found. A possible association with viral hepatitis, cryoglobulinemia or autoimmune disease was also excluded. The patient was treated with pulse i.v. dexamethasone with very good results. Diuresis resumed and renal function gradually normalized. Our patient is one of the oldest patients with immunotactoid glomerulonephritis described. The presentation by acute renal failure with an improvement of renal function after therapy has not been previously published.

ANCA-associated renal vasculitis--epidemiology, diagnostics and treatment.

The pauciimmune small-vessel vasculitides are multisystem diseases with frequent renal involvement. They are strongly associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). In this review we have focused on the ethiopathogenesis and the role of ANCA, clinical presentation and histopathologic findings of different ANCA - associated vasculitides (AAV). Current treatment strategies and the overall and renal outcome of patients with AAV are also discussed.

[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.

Current treatment strategies in ANCA-positive renal vasculitis-lessons from European randomized trials.

Antineutrophil cytoplasmic antibody (ANCA)-positive renal vasculitis is the most common cause of rapidly progressive (crescentic) glomerulonephritis. Its life-threatening natural course may be modified substantially by current treatment modalities. The European Vasculitis Study Group (EUVAS) developed a subclassification of ANCA-positive vasculitides based on the disease severity at presentation, and have organized (so far) two waves of clinical trials. The first wave of randomized clinical trials had the aim of optimizing the existing therapeutic regimens; the second wave concentrated on testing some newer therapeutic approaches. Here, the design and available results of the first wave and the design of some second wave trials are reviewed briefly. The potential of the new targeted approaches (e.g. anti-tumour necrosis factor therapy) is also briefly mentioned.

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 heterogeneity 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 micromol/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 alpha-adducin gene polymorphism. RESULTS: The alpha-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 alpha-adducin polymorphisms do not play a significant role in the progression of ADPKD to ESRF.

[Bartter syndrome or renal tubular acidosis?]. / Bartteruv syndrom ci renální tubulární acidóza?

In normotensive patients (pts) with apparently inherited electrolyte disorder characterized by hypokalemia and with metabolic alkalosis the suspicion is usually pronounced on the diagnosis of Bartter syndrome or Gitelman syndrome. During the last two years three pts were admitted to our nephrologic unit of the 1st Internal Department of the 1st Medical School who presented with hypokalemia, metabolic alkalosis and alkalic urine and were followed previously under working diagnosis of (incomplete) renal tubular acidosis. In the article we give the description of the clinical picture in the three pts diagnosed as Bartter/Gitelman syndrome. In conclusion--the problems of differential diagnosis in pts with such a complex disorder of acidobase balance are discussed and new diagnostic approach with mutational studies is suggested.

[Leptin in patients wit nephrotic syndrome]. / Leptin u pacientu s nefrotickým syndromem.

Nephrotic syndrome (NS) remains a serious clinical setting characterized by marked proteinuria, hypoproteinemia and hypercholesterolemia, usually accompanied by the presence of oedemas. It could be presumed, that the newly discovered hormone leptin plays an important role in the complex metabolic processes occurring in patients with NS, in which apart from the changes in the hydratation, and the protein and lipid spectre profile changes, the alteration of the metabolism of glycides elicited by the treatment with corticosteroids (CS) is often observed. The aim of the study was to investigate the plasma levels of leptin and its plasma soluble receptor (sLe-R) before and after the treatment with CS and to evaluate their relationship with albuminemia and/or proteinuria. The study group consisted of 15 men and 15 women (mean age 49 +/- 13.7 years) with newly diagnosed NS, verified by renal biopsy, in which subsequently CS treatment was started. Before the treatment (period 1) and further one month (period 2) and six months (period 3) after the start of the treatment the following parameters were measured: body mass index (BMI), serum levels of creatinine, albumin, cholesterol, triglyceride, cholinesterase, proteinuria/24 hour and plasma levels of leptin and sLe-R. In comparison to the relatively high values of BMI in the period 1 a decrease of BMI towards the physiologic range was observed during the treatment periods. Statistically significant changes were also observed in proteinuria (decrease) and in serum cholesterol and albumin levels of whereas in other biochemical parameters, including plasma leptin and sLe-R levels, statistically significant changes were not found. A trend to negative correlation with borderline statistical significance could be observed between leptin and sLe-R. The results of our relatively unique study on leptin--dealing with long-term follow-up of the patients with NS suggest that regardless prominent metabolic alterations present in NS the plasma levels of leptin and sLe-R remain relatively stable, and that of regulation of leptin in this setting is probably complex and multifactorial.

[Multiple extrarenal complications in Wegener granulomatosis]. / Mnohocetné extrarenální komplikace Wegenerovy granulomatózy.

This is a case report of a patient with Wegener's granulomatosis (WG), who initially presented with a corneal perforation. In addition to the eye involvement, the pauciimmune necrotizing glomerulonephritis with crescent formation, E.N.T. and pulmonary involvement were diagnosed. The patient also suffered from the acute myocardial infarction, most likely due to coronal arteritis. In addition to the coronal ischaemia she also had vasculitis of the aortic valve due to the WG. Another rare complication was the massive intestinal bleeding. The patient had also a skin vasculitis and non-specific symptoms such as artralgias and fever. The correct diagnosis was supported by positive cANCA. A clinical and laboratory remission of the disease was achieved by combined immunosuppressive therapy. Subsequently, she developed a subglotic stenosis possibly due to reparative changes.

[Methods used in the detection of apoptosis]. / Soucasné metody pouzívané k detekci apoptózy.

Apoptosis is a physiological form of cell death, whose dysregulation may lead to cancer or to autoimmune and degenerative diseases. In this review article, distinctive biochemical, molecular and morphological features of apoptosis are being discussed, as well as the principles of the elementary detection methods. Apoptosis is characterized by nuclear, plasma membrane, and mitochondrial changes. For reliable detection of apoptosis, it is generally recommended to employ at least two different methods together with microscopic verification of the distinctive morphological alterations.

[Less common causes of thrombocytopenia (case reports)]. / Nekteré vzácnejsí príciny trombocytopenie (kazuistiky).

We report three case reports of different, less frequent causes of thrombocytopenia--autoimmune thrombocytopenic purpura (AITP), thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT). Pathophysiology of these conditions is also discussed. AITP is an autoimmune disorder characterized by destruction of thrombocytes by autoantibodies targeted to platelet antigens. The cause of thrombocytopenia in TTP is an endothelial disorder with subsequent formation of platelet aggregates. HIT type I is a frequent, mild form of thrombocytopenia caused by reversible aggregation of thrombocytes following to heparin administration. HIT type II is a late, more severe form of thrombocytopenia caused by immunologic mechanisms.