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P>Background Several reports suggest an increased rate of adverse reactions to azathioprine in patients with Crohn's disease. Aim To compare the incidence of thiopurine-induced acute pancreatitis in patients with inflammatory bowel disease (IBD) with that in patients with vasculitis. Methods This retrospective analysis was performed using data collected in three databases by two university hospitals (241 patients with IBD and 108 patients with vasculitis) and one general district hospital (72 patients with IBD). Results The cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease equalled that of ulcerative colitis (UC) (2.6% vs. 3.7%) and this did not differ from vasculitis patients (2.6% vs.1.9%). In addition, the cumulative incidence of thiopurine-induced acute pancreatitis in UC patients was not different from that in vasculitis patients. In the IBD group, 100% of thiopurine-induced acute pancreatitis patients were women, whereas in the vasculitis group the two observed thiopurine-induced acute pancreatitis cases (n = 2 of 2) concerned were men (P = 0.012). Conclusions In this study, the alleged higher cumulative incidence of thiopurine-induced acute pancreatitis in Crohn's disease compared with vasculitis or UC patients was not confirmed. Female gender appears to be a risk factor for developing thiopurine-induced acute pancreatitis in IBD patients.

Objective. To analyze disease-free survival in patients with antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV) treated with cyclophosphamide only or switched to azathioprine after 3 months of full remission while taking cyclophosphamide. Methods. We analyzed disease-free survival in all consecutive patients diagnosed with AAV between 1990 and 2000 at our center. Patients were treated with cyclophosphamide only (1990-1996) or switched to azathioprine after 3 months of remission while taking cyclophosphamide (1997-2000). All patients received at least 12 months of followup. Results. Of the total 128 patients, 53 (41%) relapsed. Forty-four of the 128 patients (34%) had been switched to azathioprine therapy. Disease-free survival at 2 and 4 years was 76% and 65% in the cyclophosphamide group compared with 76% and 51% in the azathioprine group. In patients with proteinase 3 (PR3) classic ANCA (C-ANCA)-associated vasculitis who were switched to azathioprine (n = 33), a positive GANCA titer at the moment of treatment switch (n = 13) was significantly associated with relapse (RR 2.6, 95% confidence interval 1.1-8.0; P = 0.04). In patients with a negative ANCA titer at the time of switch to azathioprine, disease-free survival at 2 and 4 years was 80% and 62%, which was identical to that for patients treated with cyclophosphamide only. In patients who were ANCA-positive at the time of treatment switch, disease-free survival at 2 and 4 years was only 58% and 17%. Conclusion. Switching cyclophosphamide to azathioprine after induction of remission in patients with PR3-ANCA-associated vasculitis who are still ANCA-positive at the time of treatment switch is associated with a high risk of relapse.

Background. Severe renal disease is a feature of anti-neutrophil cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis. We evaluated patient and renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement at diagnosis during long-term follow-up. Methods. Eighty-five patients were diagnosed between 1982 and 1996 and followed until 2001 allowing greater than or equal to5 years of follow-up. All patients were treated with prednisolone and cyclophosphamide. Univariate and multivariate analyses with patient and renal survival as dependent variables were performed. Results. Of the 85 patients in this study, 17 (20%) died within one year after diagnosis. Of the 25 patients (29%) who were dialysis dependent at diagnosis, two remained dependent and two again became dialysis dependent after less than one year; nine died early without renal recovery. Risk factors for death occurring within one year in univariate analysis (RR, 95% CI) were age >65 years (6.5, 1.6-13.7) and dialysis dependency at diagnosis (3.6, 1.0-13). Twenty patients died beyond one year during the long-term follow-up. Male gender (4.7, 1.6-10) and developing dialysis dependency during follow-up (4.1, 1.4-12) were associated with poor outcome. Risk factor for renal failure within one year was dialysis dependency at diagnosis (29, 3.6-229). Of 64 patients dialysis independent one year after diagnosis, 12 patients became dialysis dependent during follow-up. A renal relapse was strongly associated with development of renal failure in long-term follow-up (17, 3.5-81). Conclusions.Early death and failure to recover renal function in P R3-ANCA associated vasculitis is associated with age >65 years and dialysis dependency at diagnosis. Long-term renal survival is determined by renal relapses during follow-up only. Slow, progressive renal failure without relapses is rarely observed in this group.

Wegener granulomatosis (WG) is strongly associated with the presence of antineutrophil cytoplasm autoantibodies (ANCA) with specificity for proteinase 3 (PR3). Relapses of WG are frequently preceded by a rise of autoantibody titer and PR3-ANCA are able to activate primed neutrophils in vitro . Except being stored intracellularly and translocated to the cell surface upon neutrophil stimulation, PR3 can also be detected on the surface of non-stimulated neutrophils (membrane PR3 or mPR3), with an interindividual variability in percentages of mPR3 − -positive cells and level of mPR3 expression. This study began with the hypothesis that the presence of PR3 on the surface of non-stimulated neutrophils enables interaction with PR3-ANCA and influences clinical manifestations of the disease. It analyzed mPR3 expression on neutrophils of 89 WG patients in complete remission and 72 healthy controls to evaluate whether the presence of PR3 on the surface of resting neutrophils is related to clinical manifestations of WG and/or to the susceptibility to develop relapses. The number of patients with a bimodal mPR3 expression on resting neutrophils did not differ between patients and controls. However, in WG patients, an increased percentage of mPR3 + neutrophils and an elevated level of mPR3 expression compared with healthy individuals ( P = 0.037) were found. Within the group of WG patients, an elevated level of mPR3 expression was significantly associated with an increased risk for relapse ( P = 0.021) and with an increased relapse rate ( P = 0.011), but not with the disease extent or particular manifestations at diagnosis or at relapse. These data support the hypothesis that PR3 expression on the membrane of neutrophils plays a role in the pathophysiology of PR3-ANCA associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a relapsing-remitting disease, which is treated with corticosteroids (CS) in combination with cyclophosphamide. One of the major side-effects of this treatment is osteoporosis, which may result in the increased occurrence of fractures. In the present study we measured the prevalence of reduced bone mineral density (BMD) in a cross-sectional cohort of patients and correlated BMD findings with cumulative doses of CS and/or cyclophosphamide. BMD was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, radius and proximal femur between January 1998 and December 1999. Cumulative doses of CS and cyclophosphamide were calculated by chart review. Ninety-nine consecutive patients (48 r en, 51 women) aged 55 +/- 16 years (mean +/- SD) were studied 50 months (median; range 0-400 months) after a diagnosis of ANCA-associated vasculitis had been made. Sixty-nine patients were treated with 10.7 g (median cumulative dose: range 0.4-67.2g) of CS, and 88 patients were treated with 34.1 g (median cumulative dose; range 0.8-324.3g) of cyclophosphamide. Fifty-seven percent of the patients had osteopenia (T-score: -1 to -2.5 SD), and 21 % had osteoporosis (T-score

The prevalence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) directed against myeloperoxidase (MPO) in pauci-immune necrotizing crescentic glomerulonephritis (NCGN) is dependent on the assay(s) used, We investigated the frequency of MPO-ANCA as detected by different assays for MPO-ANCA in a large cohort of patients with biopsy-proven pauci-immune NCGN. Sera from 121 consecutive untreated patients presenting with pauci-immune NCGN were tested for ANCA directed to proteinase-3 (PR3) at diagnosis. PR3-ANCA negative sera were tested by direct ELISA using recombinant or native MPO and by capture ELISA using two different specific monoclonal antibodies directed to MPO and three different antigenic sources. Sera from 80 relevant disease controls were tested to explore the specificity of the different assays. Thirty-eight out of 121 patients (31%) with pauci-immune NCGN did not have PR3-ANCA. Sufficient amounts of serum from 30 of these 38 PR3-ANCA negative patients were available for further testing, Recombinant and native MPO were recognized by similar numbers of sera in a direct ELISA (recombinant MPO: 93%. native MPO: 93%) and a capture ELISA (recombinant MPO: 77-87%. native MPO: 93%). Sera of patients with PR3-ANCA positive pauci-immune NCGN and disease controls were less frequently positive for MPO-ANCA in a capture ELISA (recombinant MPO: 3-7%, native MPO: 6-7%) than in a direct ELISA (recombinant MPO: 25%, native MPO: 13%). Both direct and capture ELISA assays using either native or recombinant MPO are sensitive techniques to detect MPO-ANCA in patients with pauci-immune NCGN. A capture ELISA performs better than a direct ELISA because it combines a higher specificity with a comparable sensitivity. Recombinant MPO is a good alternative for native MPO when used as antigen in a capture ELISA, but not when used in a direct ELISA because of lower specificity in this latter assay. (C) 2001 Elsevier Science B.V. All rights reserved.

Background. Protein intake in hemodialysis patients can be estimated indirectly from the protein equivalent of total nitrogen appearance (PNA) during the interdialytic period. A reliable estimate of the patient's urea distribution volume (UDV) is required to assess protein intake from PNA values. UDV values are derived frequently from simple anthropometric equations. Methods. UDV values based on anthropometric methods were compared with UDV values determined by direct dialysate quantitation (DDQ) in 54 stable chronic hemodialysis patients. The anthropometric methods included the following: the Watson equations (WAT), a fixed proportion of postdialysis body weight, 58% for males and 55% for females (% body wt), and skinfold thickness measurements (SFT). Postdialysis blood samples were drawn at 15-minutes postdialysis. Results. UDVWAT and UDVSFT overestimated UDVDDQ by about 8 L [limits of agreement (LOA): 2.6 to 14.2 L] in males and about 6 L (LOA: -0.8 to 12.4 L) in females. The overestimation by UDV%BW was even larger: 10.5 L (LOA: 2.0 to 19.0 L) in males and 11.1 L (LOA: 2.1 to 20.1 L) in females. The difference between UDV%BW and UDVDDQ correlated with the percentage of body fat (r = 0.57) and body mass index (r = 0.48). In a subgroup of seven patients, UDV was also determined by dilution (DIL) of the stable isotope [C-13]urea. UDVWAT and UDV%BW overestimated UDVDIL significantly. In contrast, UDVDDQ was significantly smaller than UDVDIL, even after correction for incomplete postdialysis equilibration. PNA values calculated using the various UDV estimates were compared with dietary protein intake (DPI) assessed from food records. PNA(DDQ) (61 +/- 10 g/day) did not differ significantly from DPI (63 +/- 13 g/day), but the agreement in individual patients varied considerably (LOA, -24 to 20 g/day). Anthropometric-based PNA values overestimated DPI by 8 to 16 g/day. Conclusions. Anthropometry-based equations overestimate UDV values in hemodialysis patients, leading to an overestimation of PNA values. Although PNA measurements by DDQ appear to be more reliable for assessing protein intake, PNA(DDQ) values should be interpreted with caution in individual hemodialysis patients.

Background Nitric oxide (NO) is produced by nitric oxide synthases (NOS), which are either constitutively expressed in the kidney or inducible, in resident and infiltrating cells during inflammation and allograft rejection. NO is rapidly degraded to the stable end products nitrite and nitrate, which can be measured in serum and urine, and may serve as noninvasive markers of kidney allograft rejection. Methods. Total nitrite and nitrate levels (NOx) were measured in serum and urine thrice meekly after an overnight fast in 18 consecutive patients following renal cadaveric transplantation. Inducible NOS (iNOS) and endothelial NOS (eNOS) expression was immunochemically determined in renal biopsy specimens with or without acute rejection (AR). Results. Serum NOx levels increased days before AR and were significantly higher at the moment of AR (27 +/- 12.4 mu mol/L) compared with recipients with an uncomplicated course (13 +/- 7.6 mu mol/L), but not compared with recipients with cyclosporine (CsA) toxicity (20 +/- 13.0 mu mol/L), Urinary NOx levels were significantly lower during AR (20 +/- 13.6 mu mol/mmol creatinine) compared with an uncomplicated course (64 +/- 25.2 mu mol/mmol creatinine) or CsA toxicity (53.8 +/- 28.3 mu mol/mmol creatinine). Interstitial and glomerular iNOS expression was significantly increased in biopsy specimens showing AR. Unexpectedly glomerular eNOS expression was significantly decreased in patients with AR. Conclusions. This study reports differences in NOx levels in serum and urine, which may help discriminate AR episodes from an uncomplicated course or CsA toxicity. As expected, renal iNOS expression is increased in acute allograft rejection, The decrease in glomerular eNOS expression suggests an intriguing link between acute and chronic rejection.

Objective. Prediction of relapses in Wegener's granulomatosis (WG) by measuring levels of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) remains a controversial issue. To assess the value of serial quantification of ANCA by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for monitoring disease activity in patients with WG, a prospective observational study was conducted in patients with WG attending an outpatient clinic in the Netherlands. Methods. One hundred patients with WG (85 with PR3-ANCA, 15 with MPO-ANCA) were studied prospectively from 1996 to 1998. Serum samples were obtained and analyzed every 2 months for ANCA levels. Disease activity was prospectively assessed without knowledge of the ANCA levels. Results. Relapses occurred in 37 of 100 patients (37%). Thirty-four (92%) of the 37 patients showed a rise in the level of ANCA preceding their relapse, as detected by ELISA or IIF. The predictive value of an increase in ANCA titers for relapse was 57% (17 of 30) for cytoplasmic/classic ANCA (cANCA; by IIF), 71% (27 of 38) for PR3-ANCA (by ELISA), and 100% (3 of 3) for MPO-ANCA (by ELISA). The predictive value of a rise in ANCA as measured by ELISA or IIF did not substantially improve following concomitant measurement of the IgG3 subclass of PR3-ANCA. Forty-three percent of patients who showed a rise in cANCA (by IIF) and 29% with a rise in PR3-ANCA (by ELISA) did not subsequently experience a relapse. Conclusion. Serial measurement of ANCA levels is valuable for the early prediction of relapses in patients with WG.

Background. Progressive renal function loss is common after lung transplantation. To facilitate the design of renoprotective strategies, identification of early predictors for long-term renal function loss would be useful. Methods. We prospectively analyzed renal function [glomerular filtration rate (GFR); I-125-iothalamate clearance] in a closely monitored cohort (minimum 24-month follow-up) of 57 patients who received lung transplants between November 1990 and September 1996 in our center. The analyzed end points were the slope of the GFR from 6 months posttransplant onward and the GFR at 24 months after transplantation. Results. Before transplantation, the GFR was 100 ml/min (median, range 59-163). It decreased to 67 ml/ min (29-123) at 6 months, 53 ml/min (17-116) at 24 months, and 51 ml/min (20-87) at 36 months after transplantation. The magnitude of the loss of GFR 1 month post-transplantation was the only factor significantly correlated with absolute GFR at 24 months after transplantation. Pulmonary diagnosis was significantly associated with long-term rate of renal function loss. Median loss of GFR was greatest in patients with cystic fibrosis (-10 ml/min/year, range -14 to -6 ml/min/year), preserved in pulmonary hypertension (-1 ml/min/year, range -6 to +7 ml/min/year), and in between in emphysema (-6 mi/min/year, range -27 to +12 ml/min/year). No other factors could be identified. Conclusions. In lung transplant recipients, the 1-month postoperative loss of GFR is an early marker for long term renal prognosis. Pulmonary diagnosis appears to be a relevant predictor as well. These factors may guide further research and the development of preventive strategies.

Background: Progressive renal function loss during long-term follow up is common after lung transplantation and close monitoring is warranted, Since changes in creatinine generation and excretion may occur after lung transplantation, the reliability of creatinine-based methods of renal function assessment to serial measurements of glomerular filtration rate (GFR) were compared in this population. Methods: Renal function with serial measurements of GFR by iothalamate clearance every 6 months after transplantation was studied in a cohort of 40 lung transplant recipients with at least 24 months of follow up, transplanted between November 1990 and October 1995 in this center. The correlation between the rate of renal function loss calculated from the slope of GFR and the following creatinine-based indices: 1/S-creatinine, Cockcroft clearance and Levey estimation were analyzed, The absolute difference between GFR and Cockcroft clearance and Levey estimation pre- post-transplantation at several points was also studied. Results: The slopes of 1/S-creatinine (r = 0.85), Cockcroft clearance (r = 0.86), and the Levey estimation (r = 0.84) correlated significantly with the slope of GFR as measured by iothalamate clearance. However, all creatinine-based slopes underestimate the rate of GFR loss. Cockcroft clearance and the reciprocal value of serum creatinine do not detect small GFR losses. During long-term follow up a time-dependent discrepancy between Cockcroft clearance, Levey estimation and GFR was observed which may partially explain the observations for this population. Conclusion: Creatinine-based slopes correlate with GFR slopes after lung transplantation, but consistently underestimate the rate of GFR decline. The Levey estimation is the most sensitive method used to detect small GFR losses and may be preferable when no GFR measurement is available. In special conditions when an accurate renal function assessment is needed true GFR may be necessary.

Background. The protein equivalent of total nitrogen appearance (PNA) is assumed to be a reliable estimate of dietary protein intake in haemodialysis patients. Protein requirements are related to body size. In order to standardize PNA to individual differences in body size, PNA is normalized to various terms related to the patient's body weight. It is not clear which is the most appropriate method to normalize PNA. Methods. We calculated five commonly used variants of normalized PNA and related them to indices of nutritional status in 57 stable chronic haemodialysis patients, 57 +/- 15 (mean +/- SD) years of age. PNA, determined by direct dialysate quantification, was normalized to actual post-dialysis dry body weight (DBW), normal body weight (DBW(normal)), lean body mass (LBM), normal lean body mass (LBM(normal)), and 'normalized' body weight (N). Nutritional status was assessed using an index of nutrition composed of anthropometry derived parameters and plasma albumin concentration. Results. PNA(DBW) (0.85 +/- 0.14 g/kg/d) tended to be higher than PNA(DBWnormal) (0.81 +/- 0.14 g/kg/d). PNA(LBM) (1.17 +/- 0.19 g/kg/d) did not differ from PNA(LBMnormal) (1.19 +/- 0.21 g/kg/d). PNA(N) (1.06 +/- 0.14 g/kg/d) was significantly higher than PNA(DBW) and PNA(LBMnormal). but lower than PNA(LBM) and PNA(LBMnormal). Actual PNA (61 +/- 13 g/d) correlated significantly with DBW (r = 0.52) and LBM (r = 0.63) indicating that large patients eat more protein. Interestingly, actual PNA correlated with plasma albumin (r = 0.33) and with the overall index of nutrition (r = 0.27) as well. PNA(DBW) correlated negatively with relative DBW (r = -0.32), expressed as a percentage of normal values, indicating that PNA(DBW) is relatively high in underweight patients. In contrast, PNA(DBWnormal) correlated positively with all nutritional parameters as well as with the overall index of nutrition (r = 0.33). PNA(N) and PNA(LBM) did not correlate with the nutritional status, but PNA(LBMnormal) correlated positively with relative DBW (r = 0.50) and with overall nutritional status (r = 0.34). PNA(DBWnormal) and PNA(LBMnormal) in well-nourished patients showed overlap with the values in patients with evident malnutrition, despite the positive correlation of the normalized PNA values with nutritional status. Conclusions. Normalizing PNA by DBW(normal) and LBM(normal) appeared to be the most appropriate method to standardize protein intake in haemodialysis patients. Since actual PNA is the purest estimate of protein intake that correlated with nutritional status, we recommend to evaluate actual PNA as well in studies that relate protein intake to patient outcome.

Objective. Several studies have recently identified polymorphisms of receptors for the Fc fragment of IgG (Fc gamma R) as genetic factors influencing susceptibility to multiple autoimmune and infectious diseases. This genetic predisposition could also influence the expression of Wegener's granulomatosis (WG), a systemic autoimmune disease with chronic nasal carriage of Staphylococcus aureus as an important risk factor for disease relapses. Therefore, we analyzed 3 functional Fc gamma R polymorphisms from 91 patients with WG and 154 controls for a possible relationship with disease expression and occurrence of relapses. Methods. Fc gamma R phenotypes were determined using amplification of Fc gamma R-genomic regions in allotype-specific polymerase chain reactions. Of particular interest in the analysis were 2 allotypic forms of Fc gamma RIIa (R131 or H131) and 2 allotypic forms of Fc gamma RIIIa (V158 or F158), all of which are functionally different. Results. Analysis of Fc gamma R phenotypes demonstrated that patients with WG were more prone to disease relapse in the first 5 years after diagnosis if they were homozygous for both the R131 form of Fc gamma RIIa and the F158 form of Fc gamma RIIIa (relative risk 3,3, 95% confidence interval 1.6-6.8). These polymorphisms are both associated with decreased FcR-mediated clearance, which may be relevant to the chronic nasal carriage of S aureus. Conclusion. Both the R/H131 polymorphism of Fc gamma RIIa and the V/F158 polymorphism of Fc gamma RIIIa represent heritable risk factors for the development of disease relapses in WG.

Previously, it was found that patients with necrotizing crescentic glomerulonephritis (NCGN) and anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against proteinase 3 (anti-PR3) had a faster deterioration of renal function and more active renal vasculitic lesions than patients with ANCA directed against myeloperoxidase (anti-MPO). Because ANCA-mediated neutrophil activation is thought to play an important role in the pathophysiology of this form of glomerulonephritis, this study was conducted to determine whether anti-PR3 are capable of inducing a more pronounced activation of neutrophils in vitro than anti-MPO. To test this hypothesis, the release of reactive oxygen radicals, as assessed by ferricytochrome c reduction and by dihydrorhodamine 123 oxidation, and the release of granule constituents from healthy donor neutrophils upon stimulation with IgG fractions were measured from 17 anti-PR3- and 14 anti-MPO-positive patients with active NCGN. Patients with anti-PR3 had a higher renal activity index (P

The toxicity and pharmacokinetic properties of a drug determine whether hemodialysis and/or hemoperfusion are indicated in acute intoxications. Valproic acid is considered unremovable by hemodialysis because of the high protein binding of 90%-95%. A 27-year-old male with a history of seizures was admitted to the emergency room because of coma, hypernatriemia, and respiratory failure caused by an intoxication with a large dose of valproic acid. At admission; the plasma valproic acid level was 1414 mg/L (9.9 mmol/L) (therapeutic range: 50-100 mg/L (350-700 umol/L). The anion gap was 26 mmol/L (normal

Patients with anti-myeloperoxidase (MPO)-associated necrotizing crescentic glomerulonephritis (NCGN) may develop chronic renal failure (CRF) leading to end-stage renal disease despite an initially favorable response to treatment. The aim of this study was to determine the prognostic value of clinical, laboratory, and histopathologic features at the time of presentation and during follow-up for the development of CRF in 21 consecutive anti-MPO-positive patients with NCGN, Renal function did not recover in two of five patients who were dialysis-dependent at presentation. The remaining 19 patients all went into remission and were off dialysis at 3 mo after diagnosis. At long-term follow-up, nine of these patients had stable renal function and did not relapse (group A), five patients developed CRF without signs of relapse (group B), and five patients relapsed (group C). At diagnosis, serum creatinine, C-reactive protein, and anti-MPO levels did not differ between groups A, B, and C, Microscopic erythrocyturia resolved in all patients within 4 mo of treatment, BP at presentation and during follow-up did not differ between groups A, B, and C. Proteinuria at diagnosis and in the first 6 mo after diagnosis was higher in patients who developed CRF than in patients with a stable renal function. Anti-MPO levels at 3 mo had decreased compared with anti-MPO levels at diagnosis in groups A and C, whereas anti-MPO levels did not fall significantly in patients who developed CRF. The predictive value of a renal biopsy at diagnosis on long-term renal outcome was limited. In conclusion, a higher degree of proteinuria at diagnosis and during follow-upas well as persistently elevated anti-MPO levels after induction of remission are associated with the development of CRF and are predictive of poor renal outcome in anti-MPO-associated NCGN.

We questioned the superiority of angiotensin converting enzyme (ACE) inhibitors to beta blocking drugs with regard to renal function outcome in patients with mild to moderate renal insufficiency and normal to moderately elevated blood pressure (BP). We therefore studied 89 patients in a prospective double-blind randomized trial comparing the effect of enalapril and atenolol on the slope of glomerular filtration rate (GFR). Mean baseline GFR was 53 +/- 20 ml/min, untreated BP 152 +/- 20 mm Hg systolic and 90 +/- 11 mm Hg diastolic and median proteinuria 0.6 g/24 hr (interquartile range 0.0 to 2.5). After a run-in period without antihypertensives, the test drug was titrated to lower diastolic BP to a predefined goal of 10 mm Hg below baseline and/or below 95 mm Hg. The median follow up was 3.9 years. Antihypertensive therapy resulted in a comparable decrease of BP in both study groups. Filtration fraction and proteinuria decreased in both groups. The slept of GFR over time was not different between both groups (-1.39 +/- 2.82 and -1.97 +/- 3.38 ml/min/year on atenolol and enalapril, respectively). In multiple regression analysis a higher baseline GFR, a greater decrease in GFR and in proteinuria during titration and a lower proteinuria during follow up were independently related to a better GFR slope. We conclude that the use of ACE inhibitors is not imperative in all patients with non-diabetic nephropathy.

Background Respiratory tract infections may trigger relapses in patients with Wegener's granulomatosis in remission. Uncontrolled data have suggested that treatment with trimethoprim-sulfamethoxazole (co-trimoxazole) may be beneficial. Methods We conducted a prospective, randomized, placebo-controlled study of the efficacy of cotrimoxazole (800 mg of sulfamethoxazole and 160 mg of trimethoprim) given twice daily for 24 months in preventing relapses in patients with Wegener's granulomatosis in remission during or after treatment with cyclophosphamide and prednisolone. Relapses and infections were assessed with predefined criteria based on clinical, laboratory, and histopathological findings. Patients were evaluated at least once every three months for signs of disease activity, compliance with the treatment regimen, side effects of the therapy, and evidence of infections. Titers of serum antineutrophil cytoplasmic antibodies were measured serially. Results Forty-one patients were assigned to receive co-trimoxazole, and 40 to receive placebo. In 8 of the 41 patients in the co-trimoxazole group (20 percent), the drug had to be stopped because of side effects. According to life-table analysis, 82 percent of the patients in the co-trimoxazole group remained in remission at 24 months, as compared with 60 per cent of those in the placebo group (relative risk of relapse, 0.40; 95 percent confidence interval, 0.17 to 0.98). There were fewer respiratory tract infections (P = 0.005) and non-respiratory tract infections (P = 0.05) in the co-trimoxazole group than in the placebo group. There were no significant differences in antineutrophil cytoplasmic antibody titers at any time. Proportional-hazards regression analysis identified treatment with co-trimoxazole as an independent factor associated with prolonged disease-free survival and a positive antineutrophil cytoplasmic antibody test at the sta rt of treatment as a risk factor for relapse. Conclusions Treatment with co-trimoxazole reduces the incidence of relapses in patients with Wegener's granulomatosis in remission. (C)1996, Massachusetts Medical Society.

T cell-mediated immunity is hypothesized to play an important role in the pathogenesis of granulomatous inflammation and vasculitis as found in patients with WG. The antigenic specificities of those T cells remain, however, unknown. Anti-neutrophil cytoplasmic antibodies (ANCA) present in patients with WG are directed to proteinase 3 (PR3) and myeloperoxidase (MPO). In the present study we investigated the proliferative capacity of peripheral blood mononuclear cells (PBMC) from patients with WG and age- and sex-matched controls in response to the WG autoantigens PR3 and MPO. Possible mitogenic effects of active PR3 and toxic effects of active MPO were excluded by using heat-inactivated PR3 and MPO. Antigen-specific stimulation induced by these autoantigens was studied by using processed PR3 and MPO in the lymphocyte stimulation test (LST). Proliferation induced by processed antigen correlated with that by heat-inactivated free antigen. The general capacity to proliferate in response to mitogens and recall antigens did not differ between patients and controls. However, patients with WG who were or had been positive for PR3-ANCA (n = 17) responded more strongly to PR3 than to MPO and showed higher responses to PR3 compared with controls (n = 13). Within the PR3-ANCA group T cell proliferation did not correlate with ANCA titre. In a small group of patients with MPO-ANCA (n = 5) no differences were observed compared with controls for MPG-specific proliferation. The data presented demonstrate that autoreactive PR3-specific T cells are present in patients with WG. Their fine specificity and possible role in the pathogenesis of WG have to be defined in further studies.

Recurrent Wegener's granulomatosis (WG) was diagnosed in a 40 year old man presenting with a solitary mass in the right lung apex and with possible lymph node enlargement in the anterior mediastinum, resembling malignancy. Eight years previously, a first episode of WG involving the upper airways and kidneys, but not the lungs, had been successfully treated with prednisolone and cyclophosphamide, which could be stopped after 2 yrs. The antineutrophil cytoplasmic antibody titres (anti-protease 3), which had been very high during the first disease episode, failed to predict the recurrence.