tion than glomerulonephritis in relation to WG. This difference Renal histology in ANCA-associated vasculitis: Differences may be due to a delayed establishment of diagnosis in patients between diagnostic and serologic subgroups.with MPA compared to patients with WG. Both active and Background. Differences in renal histopathology between chronic lesions are more abundantly present in MPO-ANCAmicroscopic polyangiitis (MPA) and Wegener's granulomatopositive patients than in patients with PR3-ANCA-positivity, sis (WG), and between anti-neutrophil cytoplasm autoantibody which suggests that the pathogenesis of renal disease in these (ANCA) test results in patients with ANCA-associated vasculi-ANCA subsets could be different. Our results also suggest tis may provide insight into the differences in pathogenesis that ANCA test results may be useful in classifying ANCAand raise the opportunity of classifying the vasculitides more associated vasculitides. accurately. The possible differences in histopathology are investigated in this study.Methods. We report an analysis of 173 patients with renal disease in microscopic polyangiitis or Wegener's granulomato-Rapidly progressive deterioration of renal function sis. A total of 173 renal biopsies, performed at diagnosis, were is a frequent but clinically unfavorable feature of antiscored by two observers separately, using a previously stanneutrophil cytoplasm autoantibody (ANCA)-associated dardized protocol. Consensus on each biopsy was achieved during a central review.vasculitis, including microscopic polyangiitis, Wegener's Results. Normal glomeruli were more common in WG than granulomatosis, and renal limited vasculitis [1]. Usually, in MPA (P Ͻ 0.001). Glomerulosclerosis was more prominent this rapidly progressive deterioration of renal function in MPA than in WG (P ϭ 0.003). Interstitial fibrosis (P Ͻ is histopathologically accompanied by a pauci-immune 0.001), tubular atrophy (P Ͻ 0.001), and tubular casts (P ϭ crescentic necrotizing glomerulonephritis. However, the 0.005) were more frequently present and more severe in MPA than in WG. Presence of glomerulosclerosis was more extensive histopathological features vary among patients from mild in patients with myeloperoxidase (MPO)-ANCA than with focal segmental extracapillary proliferation to diffuse proteinase 3 (PR3)-ANCA (P ϭ 0.022). Interstitial fibrosis crescentic necrotizing glomerulonephritis with granulo-(P ϭ 0.008), tubular necrosis (P ϭ 0.030), tubular atrophy (P ϭ mas and tubular intra-epithelial infiltrates. In some cases, 0.013), and intra-epithelial infiltrates (P ϭ 0.006) were more extensive glomerulosclerosis is found [2]. frequently present and more severe in MPO-ANCA than in PR3-ANCA. The differences between microscopic polyangiitis and Conclusions. Glomerulonephritis in relation to MPA hasWegener's granulomatosis have been described as folmore characteristics of chronic injury at the time of presentalows [3,4]. Microscopic polyangiitis is characterized by a non-granulomatous systemic vasculitis that is as...

This study aimed to identify clinical and histologic prognostic indicators of renal outcome in patients with ANCA-associated vasculitis and severe renal involvement (serum creatinine >500 mol/L). One hundred patients who were enrolled in an international, randomized, clinical trial to compare plasma exchange with intravenous methylprednisolone as an additional initial treatment were analyzed prospectively. Diagnostic renal biopsies were performed upon entry into the study. Thirty-nine histologic and nine clinical parameters were determined as candidate predictors of renal outcome. The end points were renal function at the time of diagnosis (GFR 0 ) and 12 mo after diagnosis (GFR 12 ), dialysis at entry and 12 mo after diagnosis, and death. Multivariate analyses were performed. Predictive of GFR 0 were age (r ‫؍‬ ؊0.40, P ‫؍‬ 0.04), arteriosclerosis (r ‫؍‬ ؊0.53, P ‫؍‬ 0.01), segmental crescents (r ‫؍‬ 0.35, P ‫؍‬ 0.07), and eosinophilic infiltrate (r ‫؍‬ ؊0.41, P ‫؍‬ 0.04). Prognostic indicators for GFR 12 were age (r ‫؍‬ ؊0.32, P ‫؍‬ 0.01), normal glomeruli (r ‫؍‬ 0.24, P ‫؍‬ 0.04), tubular atrophy (r ‫؍‬ ؊0.28, P ‫؍‬ 0.02), intraepithelial infiltrate (r ‫؍‬ ؊0.26, P ‫؍‬ 0.03), and GFR 0 (r ‫؍‬ 0.29, P ‫؍‬ 0.01). Fibrous crescents (r ‫؍‬ 0.22, P ‫؍‬ 0.03) were predictive of dialysis at entry. Normal glomeruli (r ‫؍‬ ؊0.30, P ‫؍‬ 0.01) and treatment arm (r ‫؍‬ ؊0.28, P ‫؍‬ 0.02) were predictive of dialysis after 12 mo. No parameter predicted death. Both chronic and acute tubulointerstitial lesions predicted GFR 12 in severe ANCA-associated glomerulonephritis, whereas plasma exchange was a positive predictor of dialysis independence after 12 mo for the entire patient group. Plasma exchange remained a positive predictor when patients who were dialysis dependent at presentation were analyzed separately (r ‫؍‬ ؊0.36, P ‫؍‬ 0.01). Normal glomeruli were a positive predictor of dialysis independence and improved renal function after 12 mo, indicating that the unaffected part of the kidney is vital in determining renal outcome.

These data suggest that in ANCA-associated glomerulonephritis, GFR0 and predominantly chronic renal lesions are potent predictors of GFR18. Active lesions are associated with renal function recovery and may be reversible. The formula for the estimation of GFR18 shows that a combination of GFR0 and renal histology is a better predictor for GFR18 than GFR0 only.

Considerable evidence suggests that the concentration of free thyroxine, circulating unbound to serum proteins, is more closely relattd to a subject's thyroidal status than is the concentration of total thyroxine (1). Because of the intense binding of thyroxine by the serum proteins, the concentration of free thyroxine is very small and not measurable by conventional chemical methods. Robbins and Rall (2), on the basis of electrophoretic data and the binding characteristics of bovine serum albumin, estimated that the concentration of free thyroxine in normal subjects was in the order of 6 x 10-1" M. By equilibrium dialysis of whole serum, Sterling and Hegedus (3) arrived at a figure approximately twice this. Other techniques for assessing the relative concentrations of free thyroxine in various clinical and physiological states include measurement of the fractional rate of dialysis of I'1"-labeled thyroxine (T4-I131 ) across a semipermeable membrane from one serum compartment to another (4, 5), and simultaneous determination of red-cell uptake of I131-labeled triiodothyronine (T3-"131) and serum protein-bound iodine (PBI) (6).In the present study, we used two independent methods to provide a relative measure of the fraction of thyroxine bound to serum proteins and the concentration of free thyroxine in serum. One method is based on the principle of equilibrium dialysis of diluted serum in an aqueous buffer at pH1 7.4; the other involves determination of critical ratios by filter-paper electrophoresis of whole serum in a glycine-acetate buffer at pH 8.6. Such an electrophoretic system reveals three species of protein-binding sites: thyroxine-binding globulin (TBG), albumin, and thyroxine-binding prealbumin (TBPA). Applied to the study of sera of normal and pregnant subjects and patients with hypothyroidism and hyperthyroidism, these methods gave results that were consistent internally and also with the current view that concentrations of free thyroxine are elevated in hyperthyroidism, depressed in hypothyroidism, and normal in pregnancy. The investigation was thereupon extended to a more intensive study of thyroxine-binding by the serum proteins of patients with nonthyroidal disease. Ingbar and Freinkel (7) have noted that in patients with a variety of diseases, a reduced quantity of thyroxine was associated with TBPA, and this finding suggested to us the possibility that such alterations could influence the level of free thyroxine in serum. METHODS Equilibrium dialysisThe method of these studies is partly based on the dialysis procedures used by Sterling and Tabachnick in their investigation of thyroxine-binding by serum albumin (8). Analogous techniques have been used to study the interaction of certain drugs with thyroxine-binding proteins (9-11). T4-IP`,I tested for chromatographic purity as previously described (9), was added to the serum sample in quantities sufficient to increase the endogenous concentration of thyroxine by 1 ,ug per 100 ml. The mixture was allowed to equilibrate for 30 minutes at room tem...

In patients who have anti-neutrophil cytoplasm autoantibody (ANCA)-associated glomerulonephritis and are on dialysis at time of diagnosis, renal function is sometimes insufficiently restored by immunosuppressive treatment, which often coincides with potentially lethal adverse effects. This study investigated the clinical and histologic variables that determine the chances of dialysis independence, dialysis dependence, or death after 12 mo in these patients. Sixty-nine patients who had ANCA-associated glomerulonephritis and were dialysis dependent at diagnosis received uniform, standard immunosuppressive therapy plus either intravenous methylprednisolone or plasma exchange. Eleven clinical and histologic variables were assessed. Univariate and binary logistic regression analyses were performed. Predictive parameters were entered into a two-step binary logistic regression analysis to differentiate among the outcomes of dialysis independence, dialysis dependence, or death. The point at which the chance of therapy-related death exceeded the chance of dialysis independence was determined. The chance of recovery exceeded the chance of dying in most cases. Intravenous methylprednisolone as adjunctive therapy plus Ͻ18% normal glomeruli and severe tubular atrophy increased the chance of therapy-related death over the chance of dialysis independence. Plasma exchange treatment plus severe tubular atrophy and Ͻ2% normal glomeruli increased the chance of therapy-related death over that of dialysis independence. Even with ominous histologic findings, the chance of renal recovery exceeds the chance of therapy-related death when these patients are treated with plasma exchange as adjunctive therapy.