Plasma levels of atrial natriuretic peptide (ANP) were measured by radioimmunoassay in 43 non-dialyzed uremic patients at rest and during maximal exercise to assess the possible relationship between plasma ANP levels and cardiac function, as judged by M-mode echocardiography and exercise tolerance. Patients with poor exercise capacity (exercise time less than 6 min) on dynamic exercise test had decreased left ventricular ejection fraction, increased left atrial diameter, and increased left ventricular mass index (LVMI), compared with patients with better exercise capacity (exercise time greater than 6 min). Plasma ANP was significantly higher in patients with poor exercise capacity and impaired cardiac function (202 pg/ml [95% confidence interval 119 to 284] at rest and 227 pg/ml [149 to 304] during exercise), compared with patients with better exercise capacity (75 pg/ml [50 to 102], p less than 0.005, and 123 pg/ml [80 to 167], p less than 0.05, respectively). Plasma ANP increased significantly (p less than 0.005) during exercise only in patients with better cardiac function. The best correlation among the variables studied was found between LVMI and plasma ANP concentration at rest (r = 0.56, p less than 0.001) and during exercise (r = 0.51, p less than 0.005), whereas neither blood pressure nor renal function showed any significant correlation with ANP levels. We conclude that plasma ANP levels are elevated in uremic patients with impaired cardiac function, correlating with increased LVMI. Plasma ANP determinations are useful in identifying increased cardiac load and consequent cardiac hypertrophy and dysfunction with known associations with increased cardiovascular mortality in patients with chronic renal failure.
Idiopathic membranous glomerulonephritis (iMGN) has previously been shown to be associated with urinary excretion of terminal complement complexes while increased urinary levels of cytokines have been reported in mesangial proliferative glomerulonephritis. In the present cross-sectional study urinary excretion of IL-1β TNF-α, IL-6;, and soluble C5b-9 (SC5b-9) was examined for 23 patients with iMGN, 16 patients with diabetic nephropathy (DNP), and 17 healthy subjects. IL-1β excretion (pg/mg crea) was significantly higher in iMGN patients (375, range 162–11 000) than in DNP patients (39, range 22–59, P<0.001) or healthy controls (151, range 23–481, P<0.00l). TNF-α excretion rate (pg/mg crea) was clearly higher (38, range 21–700) in iMGN patients than in DNP patients (14, range 8–52, P< 0.001) or healthy subjects (11, range 7–26, P<0.001). Median IL-6 excretion (pg/mg crea) was only marginally higher in iMGN patients (73, range 0–850) than in healthy subjects (64, range 3–158, P=0.02) but significantly higher than in DNP patients (29, range 17–47, P<0.001). No significant correlation with corresponding serum values was observed for urinary IL-6 or TNF-α excretion. Urinary IL-1/β and TNF-α correlated with decreased renal function. Five of 23 patients showed progression of iMGN over a follow-up of 6 months. The excretion of all cytokines, TNF-α in particular, was significantly higher in patients with a progressive disease than in the other patients. High TNF-α excretion (>57 pg/mg crea) was detected in 4/5 patients with progression but in none of the stable patients (P<0.001). Seventy-seven per cent of the iMGN patients and 94% of DNP patients, but none of the healthy subjects had detectable SC5b-9 excretion. In DNP patients the urinary SC5b-9 levels correlated with proteinuria whereas in iMGN the SC5b-9 excretion could not be accounted for by proteinuria alone. Urinary excretion of SC5b-9 correlated with decreased renal function and had a relationship to urinary IL-1/β and TNF-α excretion in iMGN patients. Moreover the median excretion rate of SC5b-9 was higher in patients with than in those without progression of iMGN. The results suggest that increased urinary IL-1β, TNF-α, and SC5b-9 excretion are detected in patients having iMGN. They may be indicators of a progressive renal disease in iMGN.
Serum angiotensin-converting enzyme (ACE) activity was studied in healthy controls, in 57 untreated sarcoidosis patients, and in 164 patients with other chest or lymph node diseases. The serum ACE activity of healthy persons was independent of sex, intake of meals, and smoking habits. There were no diurnal variations. Healthy children had a significantly higher ACE mean value than adults, whose ACE activity was not affected by age. The sarcoidosis patients had the highest ACE mean values, but those of patients with silicosis and asbestosis were also significantly elevated. Pulmonary cancer patients had decreased serum ACE activity, which was probably due to antimitotic treatment. Serum lysozyme (LZM) concentrations did not correlate with normal ACE activity, but the correlation between elevated ACE and LZM was significant in sarcoidosis and silicosis, and the trend was clearly the same for asbestosis. This indicates separate sources for these enzymes when ACE activity is normal, and a common source, i.e. macrophages, when ACE activity is increased. ACE production in certain diseases involving macrophages may be due to the bradykinin inhibiting effect of this enzyme.
Since t he elevated concentration of serum C-reactive protein (CRP) is a sensitive indicator of underlying inflammation, we investigated the association between serum CRP during the initial 6 post-transplantation months and histopathological changes in the 6-month protocol biopsies in 79 patients. We stained the biopsies for CRP and C3 to elucidate a possible role of CRP in renal injuries.Forty patients showed no or minimal (Grade 0-1) tubular atrophy or interstitial fibrosis and 39 patients mild to moderate (Grade > or = 2) chronic histopathological changes. The latter group had had higher concentration of CRP during the first 6 post-transplant months. Because the histopathological changes predict poor long-term prognosis, we followed--from 6th month onwards--40 patients who had no or minimal histopathologic changes, and analyzed the association between CRP elevation and development of chronic allograft dysfunction. During this follow-up period (mean 51, range 14-72 months), 23 of 40 patients retained normal CRP level (Group A, mean CRP 1.12 mg/l), and 17 patients had elevated CRP concentrations (Group B, mean CRP 4.16 mg/l); 24-hour creatinine clearance improved or remained the same in all Group A patients, whereas it decreased in 7 of 17 (41%) of Group B patients (p < 0.001). In Group B patients, the annual change of creatinine clearance correlated inversely with the mean CRP concentration (r = -0.682, p < 0.01).Our results show that histological changes in 6-month biopsies were more prominent in patients with more transplantation-associated complications, infections and frequently higher CRP levels during the initial 6 post-transplant months than in those with lower CRP levels. During post-biopsy follow-up, we found low-grade systemic inflammation--measured as elevated CRP--to associate with impairment of graft function in patients with no or minimal histological findings in 6-month biopsies, and permanently low CRP to rule out chronic allograft dysfunction.
72 adult patients with idiopathic membranous glomerulonephritis (iMGN), 92% having proteinuria 3 g/24 h or more, were studied for the clinical evolution of the disease and factors which might be involved in the development of chronic renal insufficiency (CRI). At 10 years, 46% were in complete or partial remission, 4% had the nephrotic syndrome (NS), 26% had some degree of CRI, and 24% were dead or started on dialysis. The actuarial patient and kidney survival rates were 80% and 64%, respectively at 10 years. Patient survival rate was not affected by gender, age (after adjustment for age- and sex-matched population) or the severity of NS at diagnosis. 20 patients showed CRI and apart from the more frequent (p < 0.05) presence of CRI at diagnosis, no clinical features discriminated them from those having intact renal function. Furthermore, no clinical factors at diagnosis predicted the final renal function among the 72 patients. However, it appeared that the evolution of clinical status of iMGN was rapid CRI appearing 1.4 (median, range from 0 to 15.1) years after the diagnosis. At one and two years, renal function correlated significantly (r = 0.54, p < 0.0001 at two years) with the final renal function. What is more, the type of the evolution of proteinuria over the first two years gave valuable information on the eventual deterioration of renal function. Patients having stable non-nephrotic grade proteinuria and those in whom NS disappeared, had excellent renal outcome while those in particular showing an increased severity of NS had poor prognosis in terms of renal survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Serum angiotensin-converting enzyme (ACE) activity was related to clinical markers of disease activity, mainly chest X-rays, pulmonary function tests and serum lysozyme (LZM) in 41 sarcoidosis patients, who received corticosteroid treatment. Increased ACE activity before treatment predicted improvement of diffusion capacity during treatment, whereas chest X-rays improved regardless of the initial ACE value. ACE decreased after initiation of treatment both in sarcoidosis patients and in healthy volunteers. In sarcoidosis most decreases were parallelled by similar LZM changes, which did not occur in volunteers. When an apparently stable state had been achieved, ACE was no longer a reliable monitor of disease activity. It often fluctuated within normal limits without accompanying clinical or LZM changes. It was not dose-dependent during daily medication but increased during alternate day administration. This may reflect decreased suppression of ACE by steroids but may also indicate reactivation of the disease process. Elevated ACE values after cessation of treatment preceded or parallelled a relapse. LZM values did not add to the information provided by ACE measurements before, during or after treatment.
In previous phases of this project, proteinase 3 (PR3) and myeloperoxidase (MPO), the main antigenic target molecules of antineutrophil cytopiasmic antibodies, were isolated and applied in standardized ELISAs. In this study, standardized ELISAs with three PR3 preparations (from Copenhagen (CO), Raisdorf (RS) and Leiden (LF)) and one MPO preparation (from Copenhagen), were evaluated in a large retro-and prospective clitiical study. New patients (n=174) with primary systemic vasculitis (Wegener's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive glomerulonephritis, classical PAN and Churg-Strauss Syndrome) were included. Retrospectively, another 190 patients were evaluated. Furthermore control sera were obtained from patients with other forms of vasculitis, glomerulonephritis or granulomatous diseases (disease controls, n = 184) and healthy donors (healthy controls, n = 728). All patients were categorized by a system based on clinical and histoiogical data. Patients were followed up for at least 1 year after diagnosis in order to evaluate a possible correlation between ANCA levels and disease activity. The sensitivity of the anti-PR3 assays for histologically proven WG was between 59% and 69% in new patients, with a sensitivity of 22% for the anti-MPO assay. Similar figures were found for patients with clinically suspected WG. This was comparable with the results of the IIF test. In MPA and IRPGN a larger percentage of patients had antiMPO antibodies than in WG. Only a few patients with PAN and CSS were investigated, and most of these were negative in the ELISAs. The specificity ofthe assays for disease controls was 89-91% for the anti-PR3 assays and 95% for the anti-MPO assay. In the healthy controls the specificity was 98-99%. The specificity of the IIF test was 97% for a cANCA pattern and 81 % for a pANCA pattern in disease controls. The combination of cANCA with anti-PR3 and pANCA with anti-MPO both had a specificity of 99%. Further details will be presented during the meeting, in addition to the results of a follow-up study with correlation ofdisease activity and ANCA level. From this study we can conclude that ELISAs using purified PR3 or MPO are not more sensitive than the IIF test. However, the anti-MPO assay is more specific for systemic vascuitis as compared to disease controls with related diseases. Furthermore, the combination of the IIF test with antigen-specific ELISAs is very specific for the diagnosis Wegetier's granulomatosis, microscopic polyangiitis and idiopathic rapidly progressive gtomerulonephritis.
