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Coen A Stegeman

Publications and source records attributed to Coen A Stegeman.

At least 19 recordsLinked to original sources
PubMed2006

Induction of remission in active anti-neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide.

BACKGROUND: Active anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is commonly treated with cyclophosphamide, a drug with serious side effects, and with corticosteroids. OBJECTIVE: To determine the efficacy of a possible alternative drug for cyclophosphamide, oral mycophenolate mofetil (MMF) 1000 mg twice daily and oral prednisolone 1 mg/kg once daily as remission induction treatment. METHODS: 32 consecutive patients with 34 episodes of active vasculitis who could not be treated with cyclophosphamide were diagnosed for a median (range) of 6.0 (0.3-22) years and experienced 4 (0-14) relapses prior to the current episode. Treatment response and relapse-free survival were analysed. RESULTS: Complete remission (CR) was obtained in 25 (78%) patients, partial remission (PR) in 6 (19%), whereas 1 (3%) patient did not respond. 19 patients relapsed, 13 (52%) after CR, 14 (3-58) months after starting the treatment and 6 (100%) after PR, 6 (2-10) months after starting the treatment. The median relapse-free survival was 16 months, comparable with the interval between the previous relapse and the current MMF-treated relapse (17 (3-134) months). Relapse-free survival at 1, 3, and 5 years was 63%, 38% and 27%, respectively. Patients who had been treated successfully with cyclophosphamide before responded better (CR 84%, relapse 50%) than those who had not (CR 50%, relapse 100%). Minor gastrointestinal side effects and infections occurred frequently. MMF was prematurely discontinued due to adverse effects in two patients. CONCLUSION: MMF, in combination with prednisolone, can induce remission in patients with relapses of AAV intolerant to cyclophosphamide.

Adult↗
PubMed2006

Tubular kidney injury molecule-1 in protein-overload nephropathy.

Kim-1, a recently discovered membrane protein, is undetectable in normal kidneys but markedly induced in proximal tubules after ischemic and toxic injury. The function of Kim-1 is unclear, but it is implicated in damage/repair processes. The Kim-1 ectodomain is cleaved by metalloproteinases and detectable in urine. We studied Kim-1 in a nontoxic, nonischemic, model of tubulointerstitial damage caused by acute proteinuria. Uninephrectomized (NX) rats received daily (ip) injections of 2 g BSA (NX+BSA, n = 12) or saline (NX, n = 6) for 3 wk. Kidneys were stained for various damage markers by immunohistochemistry (IHC). Kim-1 mRNA (RT-PCR, in situ hybridization), protein (IHC, Western blotting), and urinary Kim-1 (Luminex) were determined. Spatial relations between Kim-1 and other damage markers were studied by double labeling IHC. NX+BSA rats developed massive proteinuria (1,217 +/- 313 vs. 18 +/- 2 mg/day in NX, P < 0.001) and significant renal damage. Kim-1 mRNA was upregulated eightfold in NX+BSA (ratio Kim-1/beta-actin, 4.08 +/- 2.56 vs. 0.52 +/- 0.64 in NX, P < 0.001) and localized to damaged tubules. Kim-1 protein expression was markedly induced in NX+BSA (2.46 +/- 1.19 vs. 0.39 +/- 0.10% staining/field in NX, P < 0.001). Urinary Kim-1 was significantly elevated in NX+BSA (921 +/- 592 vs. 87 +/- 164 pg/ml in NX, P < 0.001) and correlated with tissue Kim-1 expression (r = 0.66, P =0.02). Kim-1 protein was found at the apical membrane of dilated nephrons. Kim-1 expression was limited to areas with inflammation (MØ), fibrosis (alpha-smooth muscle actin), and tubular damage (osteopontin), and only occasionally with tubular dedifferentiation (vimentin). These results implicate involvement of Kim-1 in the pathogenesis of proteinuria-induced renal damage/repair. Urinary Kim-1 levels may serve as a marker of proteinuria-induced renal damage.

Animals↗
PubMed2006

Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides.

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2005

Addition of oleic acid to delipidated bovine serum albumin aggravates renal damage in experimental protein-overload nephrosis.

BACKGROUND: Non-esterified fatty acids (NEFA) carried on albumin may have a causal role in the development of chronic proteinuria-induced nephropathy. To investigate whether NEFA aggravate renal structural damage, we studied the effects of NEFA addition to delipidated bovine serum albumin (BSA) in protein-overload nephropathy. METHODS: Three groups of Wistar rats received daily intraperitoneal injections (3 weeks) of either 1 g NEFA-free BSA (BSA-0), or NEFA-free BSA with three (BSA-3) or six (BSA-6) molecules oleic acid added per BSA molecule. An additional group received saline injections only (SAL). Renal damage was evaluated by immunohistochemistry and RT-PCR. RESULTS: Interstitial and glomerular alpha-smooth muscle actin (alpha-SMA, marker of myofibroblast transformation) expression were higher in BSA-3/6 than in saline-injected controls (P < 0.001). Glomerular macrophage influx and desmin (marker of glomerular epithelial cell damage) expression were higher in all BSA-injected rats than SAL (P < 0.001). Interstitial macrophage influx was elevated in BSA-0/3 (P < 0.05) and BSA-6 (P < 0.001) compared to SAL. Addition of six molecules of oleic acid to BSA revealed higher interstitial and glomerular alpha-SMA expression (P < 0.001), increased interstitial macrophage numbers (P < 0.001) and enhanced glomerular desmin expression (P < 0.05) compared to BSA-0. RT-PCR revealed higher glomerular alpha-SMA mRNA expression in BSA-3/6 than SAL (P < 0.001 and 0.05, respectively), interstitial alpha-SMA mRNA was elevated in BSA-6 (P < 0.05). Interstitial TGF-beta1 mRNA expression was significantly higher in BSA-3 than SAL (P < 0.05). CONCLUSIONS: These data show that addition of oleic acid to NEFA-free BSA aggravates renal damage, suggesting a role for NEFA in the pathogenesis of proteinuric nephropathies.

Actins↗
PubMed2005

Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: A long-term followup study.

OBJECTIVE: To test whether antineutrophil cytoplasmic antibodies (ANCA) and ANCA-associated vasculitis (AAV) are not only induced during treatment with antithyroid drugs, but can also become evident when medication has been ceased, possibly after years. METHODS: Patients who visited our hospital for the treatment of hyperthyroidism were included (n = 207). Treatment consisted of antithyroid medications, radioactive iodide, thyroidectomy, or a combination of these treatment options. Patients were retested 3-6 years later to evaluate long-term effects of antithyroid drugs. Patients were tested for the presence of ANCA and, if positive, evaluated for the presence of AAV. RESULTS: Of 209 patients with hyperthyroidism, 12 patients (6%) were positive for myeloperoxidase- (MPO-), proteinase 3-, or human leukocyte elastase-ANCA. Seventy-seven of 209 patients were retested; 1 patient who had not been treated with antithyroid drugs had developed MPO-ANCA. In 3 of 6 patients previously positive, ANCA could still be detected. The presence of ANCA was highly associated with treatment with antithyroid drugs (odds ratio 11.8 [95% confidence interval 1.5-93.3]). Of 13 patients with a positive ANCA result on enzyme-linked immunosorbent assay, AAV with glomerulonephritis was diagnosed in 4 (31%). CONCLUSION: The presence of ANCA with or without vasculitis is associated with previous treatment with antithyroid drugs, possibly after years.

Adult↗
PubMed2005

Predictive performance of renal function equations in renal transplant recipients: an analysis of patient factors in bias.

Creatinine-based equations are available to estimate GFR. After renal transplantation body composition usually changes, thus specific validation is required for transplant recipients. Nine equations were compared with iothalamate glomerular filtration rate (GFR) at 1 year after transplantation in 798 recipients. Equations were analyzed for precision, bias and accuracy. Sources of bias were analyzed by univariate and multivariate analysis, with body mass index (BMI), age and sex as independent variables and bias as dependent variable. Four hundred and seventy-eight patients were studied to assess whether the equations can be used to monitor renal function over time. Predictive performance was modest for all equations. MDRD and Jelliffe 2 were the best predictors of GFR. Bias was significantly related to BMI, age and gender in most equations. Multivariate analysis confirmed their independent contribution to the bias of MDRD, Jelliffe 2 and most other equations. Over time, bias was relatively stable at group level, but predictive performance in individuals was modest. The predictive performance of renal function equations is modest in renal transplants, which hampers their use for accurate assessment of renal function in the individual. The role of patient factors in the systematic error suggests that development of better equations should be feasible by better incorporation of these factors.

Adult↗
PubMed2004

Immediate postoperative renal function deterioration in cardiac surgical patients predicts in-hospital mortality and long-term survival.

Postoperative renal function deterioration is a serious complication after cardiac surgery with cardiopulmonary bypass and is associated with increased in-hospital mortality. However, the long-term prognosis of patients with postoperative renal deterioration is not fully determined yet. Therefore, both in-hospital mortality and long-term survival were studied in patients with postoperative renal function deterioration. Included were 843 patients who underwent cardiac surgery with cardiopulmonary bypass in 1991. Postoperative renal function deterioration (increase in serum creatinine in the first postoperative week of at least 25%) occurred in 145 (17.2%) patients. In these patients, in-hospital mortality was 14.5%, versus 1.1% in patients without renal function deterioration (P < 0.001). Multivariate analysis significantly associated in-hospital mortality with postoperative renal function deterioration, re-exploration, postoperative cerebral stroke, duration of operation, age, and diabetes. In patients who were discharged alive, during long-term follow-up (100 mo), mortality was significantly increased in the patients with renal function deterioration (n = 124) as compared with those without renal function deterioration (hazard ratio 1.83; 95% confidence interval 1.38 to 3.20). Also after adjustment for other independently associated factors, the risk for mortality in patients with postoperative renal function deterioration remained elevated (hazard ratio 1.63; 95% confidence interval 1.15 to 2.32). The elevated risk for long-term mortality was independent of whether renal function had recovered at discharge from hospital. It is concluded that postoperative renal function deterioration in cardiac surgical patients not only results in increased in-hospital mortality but also adversely affects long-term survival.

Acute Kidney Injury↗
PubMed2004

Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis.

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 C-ANCA 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.

Adult↗
PubMed2004

Renal expression of matrix metalloproteinases in human ANCA-associated glomerulonephritis.

BACKGROUND: Expression of matrix metalloproteinases (MMPs) by infiltrating and intrinsic renal cells is increased in inflammatory conditions, and may correlate with disease activity of glomerulonephritis. We analysed renal expression of MMPs, tissue inhibitor of metalloproteinase-1 (TIMP-1) and markers of neutrophil and monocyte infiltration in renal biopsies of patients with active anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. METHODS: Immunohistochemical expression of MMP-2, -3, -9, TIMP-1, the neutrophil- and monocyte-derived MMP activators cathepsin G, neutrophil elastase and myeloperoxidase (MPO), and the monocyte marker CD14 was determined in renal biopsies of active proteinase 3 (PR3)-ANCA (n = 7) and MPO-ANCA (n = 6) associated glomerulonephritis, and in normal renal tissue (n = 4). Double labelling experiments of MMPs and TIMP-1 were performed with MPO and CD68, labelling neutrophils and macrophages. RESULTS: MMP-2-, MMP-3-, MMP-9- and TIMP-1-positive cells were detected in ANCA-associated glomerulonephritis in glomeruli with active inflammation (cellular crescents or fibrinoid necrosis), only occasionally in normal appearing glomeruli, and not in sclerotic glomeruli and positive cells were found in the tubulo-interstitium. MMPs and TIMP-1 were expressed predominantly by MPO-and CD68-positive cells. In normal renal tissue, no expression was detected, with the exception of weak mesangial staining for MMP-2. In ANCA-associated glomerulonephritis, glomerular MMP-2, -9 and TIMP-1 correlated with glomerular cathepsin G expression, while the number of MMP-9-expressing cells per glomerulus correlated with the percentage of crescentic glomeruli. Tubulo-interstitial expression of MMPs correlated with all markers of neutrophil and monocyte infiltration, and interstitial MMP-9 and TIMP-1 expression correlated with renal function at the time of renal biopsy. CONCLUSIONS: Expression of glomerular and interstitial MMP-2, -3, -9 and TIMP-1 is increased in active ANCA-associated glomerulonephritis and correlates with inflammatory activity.

Adult↗
PubMed2004

Early identification of risk factors for refractory secondary hyperparathyroidism in patients with long-term renal replacement therapy.

BACKGROUND: Secondary hyperparathyroidism can complicate renal replacement therapy (RRT) in patients with end-stage renal disease. Current medical therapies often result in hypercalcaemia and fail to correct hyperparathyroidism, but might be more effective at an early stage of disease. The aim of this study was to identify prognostic factors at the start and during the first year of RRT for refractory secondary hyperparathyroidism needing parathyroidectomy (PTx) during long-term follow-up. METHODS: A total of 202 consecutive patients starting RRT between August 1988 and August 1996 at our centre with at least 1 year of follow-up were included. Biochemical and treatment data at the start and during the first year of RRT were collected. Univariate and multivariate analyses were used to identify risk factors for PTx during follow-up. RESULTS: Thirty-three patients (16%) needed PTx after 52+/-23 months of RRT. Need for PTx was not different between patients undergoing haemodialysis and peritoneal dialysis, but was associated with parameters reflecting calcium and phosphate control at start and after 1 year of RRT. In a Cox multivariate model, serum parathyroid hormone [relative risk (RR): 1.02 per pmol/l; P<0.001], phosphate (RR: 1.107 per 0.1 mmol/l; P = 0.002) and alkaline phosphatase (RR: 1.004 per U/l; P = 0.049) after 1 year of RRT were independently associated with increased risk for PTx. CONCLUSIONS: Failure of control of calcium-phosphate metabolism at the start of and early during RRT is strongly associated with PTx during long-term follow-up. Given the high prevalence of insufficient phosphate control, patients may benefit from aggressive correction of serum phosphate in the pre-dialysis and early dialysis period.

Child↗
PubMed2004

Effect of prescribing a high protein diet and increasing the dose of dialysis on nutrition in stable chronic haemodialysis patients: a randomized, controlled trial.

BACKGROUND: Protein requirements in stable, adequately dialysed haemodialysis patients are not known and recommendations vary. It is not known whether increasing the dialysis dose above the accepted adequate level has a favourable effect on nutrition. The aim of this study was to determine whether prescribing a high protein diet and increasing the dose of dialysis would have a favourable effect on dietary protein intake and nutritional status in stable, adequately dialysed haemodialysis patients. Effects on hyperphosphataemia and acidosis were also studied. METHODS: Patients were randomized to a high dialysis dose (HDD) group (target Kt/V(eq) of 1.4) or a regular dialysis dose (RDD) group (target Kt/V(eq) of 1.0). All patients were prescribed a high protein (HP) diet [1.3 g/kg of ideal body weight (IBW)/day] and a regular protein (RP) diet (0.9 g/kg/day), each during 40 weeks in a crossover design. In 50 patients, 23 in the HDD and 27 in the RDD group follow-up was > or =10 weeks. These patients, aged 56+/-15 years, were included in the analysis. Nutritional status was assessed by anthropometry, plasma albumin and a nutritional index. RESULTS: Delivered Kt/V(eq) in the HDD group (1.26+/-0.14) was significantly higher than in the RDD group (1.02+/-0.08). Protein intake estimated from total nitrogen appearance (PNA) measurements and food records (DPI) was significantly higher during the HP diet (PNA(IBW), 1.01+/-0.18 g/kg/day; DPI(IBW), 1.15+/-0.18 g/kg/day) than during the RP diet (PNA(IBW), 0.90+/-0.14 g/kg/day; DPI(IBW), 0.94+/-0.11 g/kg/day). Increasing the dialysis dose did not increase protein intake either during the HP or RP diet. Plasma albumin (41.9+/-3.0 g/l) lean body mass (107+/-15% of normal values) and the nutritional index did not differ between the dialysis dose groups or protein diets and remained stable overtime. Dry body weight (97+/-14%) and total fat mass increased over time in the HDD group, but remained stable in the RDD group suggesting an effect of dialysis dose on energy balance. There was no effect of the protein diets on dry body weight or total fat mass. Plasma phosphate levels and oral bicarbonate supplements were lower in the HDD group, but were comparable between the protein diets. CONCLUSIONS: Prescribing a HP diet resulted in a modest increase in actual protein intake, but increasing dialysis dose did not have a contributing effect. A HP diet or increasing the dialysis dose did not have a favourable effect on the nutritional status. A dietary protein intake of at least 0.9 g/kg IBW/day appears to be sufficient for adequately dialysed haemodialysis patients without overt malnutrition.

Cross-Over Studies↗
PubMed2004

ANCA-GBM dot-blot: evaluation of an assay in the differential diagnosis of patients presenting with rapidly progressive glomerulonephritis.

Rapidly progressive glomerulonephritis (RPGN) is characterized by rapid and progressive loss of renal function and the presence of crescentic glomerulonephritis (CGN). Early diagnosis and appropriate treatment is mandatory to prevent death and/or renal failure. We have evaluated an ANCA-GBM dot-blot diagnostic test in terms of sensitivity, specificity, and inter-observer effect in consecutive patients with RPGN ( n = 82). Control sera ( n = 34) included healthy and relevant disease controls. Dot-blots were independently evaluated by nine observers. Proteinase 3 (PR3)-ANCA, myeloperoxidase (MPO)-ANCA, and both were detected by ELISA in 36, 32, and 3 samples of 71 patients with pauci-immune CGN, respectively. Two additional samples were ANCA negative. The dot-blot revealed a sensitivity of 92-95% for PR3-ANCA and 80-86% for MPO-ANCA. The specificity of the dot-blot for PR3- and MPO-ANCA was 100%. In the patients with anti-GBM nephritis ( n = 9) anti-GBM was detected by both ELISA and dot-blot (sensitivity: 100%). The specificity of the anti-GBM dot-blot was 91-94%. However, the inter-observer effect was relatively high for detection of anti-GBM antibodies (24%). In conclusion, the ANCA-GBM dot-blot is a useful screening tool in situations where conventional ANCA testing is not readily available with excellent performance for PR3-ANCA detection, but less optimal sensitivity for MPO-ANCA and specificity for anti-GBM detection. Therefore, it is recommended to include the following advises in the report to the physicians: 1) patients with a high clinical suspicion for MPO-ANCA-associated RPGN and negative dot-blot must have conventional analysis for MPO-ANCA, and 2) negative anti-GBM dot-blot makes anti-GBM disease very unlikely, but positive samples should be confirmed by conventional anti-GBM tests.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2004

Trends in the incidence of treated end-stage renal failure in The Netherlands: hope for the future?

This study shows that in The Netherlands there is a changing pattern in incidence of renal replacement therapy over time when adjusted for age and sex. There has been an almost linear increase in crude incidence rates during four decades. However, unlike the situation elsewhere in the Western world, a flattening of the curve has been observed during the last six years. The growing incidence of end-stage renal disease (ESRD) due to especially hypertensive renovascular disease and diabetes mellitus type 2 has been neutralized by a decrease in ESRD due to glomerulonephritis, urologic interstitial nephritis, and diabetes mellitus type 1. The latter observations suggest that renoprotective interventions can be successful on a population level, and thus, provide hope for the future. To battle the increase in ESRD due to atherosclerosis and diabetes mellitus type 2-related renal disease, it is important that screening programs are being developed that enable us to identify in an early phase patients at risk for development of ESRD who may benefit from preventive strategies. Population screening for albuminuria will be helpful in this respect.

Humans↗
PubMed2003

High expression of TIAF-1 in chronic kidney and liver allograft rejection and in activated T-helper cells.

BACKGROUND: T helper cells are important modulators of the allograft immune response. A small number of genes are already known to be differentially expressed in T helper 1 (Th1) and T helper 2 (Th2) cells, but it is likely that many other genes are functionally important. To study gene expression in Th1 and Th2 cells, we used serial analysis of gene expression. One of the differentially expressed genes was TIAF-1, which is a TGF-beta 1-induced antiapoptotic factor, known to inhibit the cytotoxic effects of tumor necrosis factor-alpha on mouse fibroblasts. We hypothesized that TIAF-1 plays a protective role against apoptosis during allograft rejection. METHODS: We examined TIAF-1 mRNA and protein expression in kidney and liver allograft biopsy specimens from patients with chronic or acute rejection by reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: TIAF-1 mRNA and protein were not detectable in normal kidney and liver; however, the expression of TIAF-1 was up-regulated in most biopsy specimens with chronic and a few with acute allograft rejection. Immunohistochemistry for TIAF-1 revealed expression in the inflammatory infiltrate and in tubular epithelial cells. CONCLUSIONS: TIAF-1 mRNA and protein are predominantly up-regulated in kidney and liver allografts with chronic rejection. This does not seem to be related to the cyclosporine A therapy. Expression of TIAF-1 in the lymphocytes during chronic allograft rejection may be related to the predominance of a Th2 response in this condition. The expression in the transplanted tissue may protect these cells from apoptosis.

Apoptosis Regulatory Proteins↗
PubMed2003

Image analysis: a novel approach for the quantification of antineutrophil cytoplasmic antibody levels in patients with Wegener's granulomatosis.

Rises in antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) have predictive potential for a relapse of Wegener's granulomatosis (WG). To assess the value of image analysis for monitoring ANCA levels, we measured PR3-ANCA in a cohort of PR3-ANCA positive patients with WG that were prospectively followed in our clinic and compared findings with other techniques. ANCA levels were measured serially by quantitative image analysis, titration in indirect immunofluorescence (IIF), two different directly coated antigen-specific enzyme-linked immunosorbent assays (ELISA), and a capture ELISA using a PR3-specific monoclonal antibody in 16 consecutive WG patients prior to a renal relapse, and in 16 age- and sex-matched patients with inactive WG. The positive predictive value (PPV) of an increase in ANCA titers by image analysis for relapse was 69% (11 of 16). The PPV of an increase in ANCA was 61% (11 of 18) by IIF, 71% (12 of 17) by a commercial direct ELISA, 63% (12 of 19) by in-house direct ELISA, and 75% (12 of 16) by capture ELISA. The negative predictive value (NPV) of the absence of an increase in ANCA titers by image analysis for relapse was 69% (11 of 16). The NPV of the absence of an increase in ANCA was 64% (9 of 14) by IIF, 73% (11 of 15) by a commercial direct ELISA, 63% (9 of 13) by in-house direct ELISA, and 75% (12 of 16) by capture ELISA. In conclusions, quantitative image analysis is a novel technique based on the principle of IIF to quantify ANCA levels in a single dilution in a patient sample. No major differences were observed between image analysis and the other techniques in their capacity to predict relapses of disease activity.

Adult↗
PubMed2003

Protective role of endothelial nitric oxide synthase.

Nitric oxide is a versatile molecule, with its actions ranging from haemodynamic regulation to anti-proliferative effects on vascular smooth muscle cells. Nitric oxide is produced by the nitric oxide synthases, endothelial NOS (eNOS), neural NOS (nNOS), and inducible NOS (iNOS). Constitutively expressed eNOS produces low concentrations of NO, which is necessary for a good endothelial function and integrity. Endothelial derived NO is often seen as a protective agent in a variety of diseases. This review will focus on the potential protective role of eNOS. We will discuss recent data derived from studies in eNOS knockout mice and other experimental models. Furthermore, the role of eNOS in human diseases is described and possible therapeutic intervention strategies will be discussed.

Animals↗