Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN.

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1-3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.

[Genotoxic stress and the pathways of thymus cell death and lymph nodes of mice in conditions of immunocomplex pathology].

There were performed the studies of genotoxic stress and the ways of immunocompetent cells death (apoptosis and necrosis) in the modeling of immune system damage by immunization of CBA mice with the bovine serum albumin. Immunofluorescence studies of immunized mice were established the fixation of immune complexes in liver tissue, spleen, kidney and the aorta. Histological studies of these organs showed vascular system affection and, to a lesser extent, parenchyma. It has been shown that DNA comets index increases in 1,4 time in the lymph node cells and in 1,5 time in the thymus cells in the presence of BSA immunization. We also observed an increase in the number of cells with maximum damage DNA thymus preparations (3.4 fold) and lymph nodes (3.3-fold), respectively, indicating strong genotoxic stress. There were shown the reduce of live ICC number and their death increase, including the pro-inflammatory and immunogenic necrotic way. In that way, data which were obtained on the experimental model is evidenced that generalized immunecomplex pathologic process leads to DNA damage and ICC death both central and peripheral organs of the immune system. ICC genotoxic stress and their death amplification by the necrotic way may play a significant role in the immunecomplex deseases development. These factors of peripheral blood lymphocytes can serve as a prospective test system for assessing the severity of autoimmune and immune complex diseases and their treatment effectiveness.

Hematologic and immunological characteristics of Henoch-Schönlein purpura in rat and rabbit models induced with ovalbumin based on type III hypersensitivity.

Henoch-Schönlein purpura (HSP) is a common systemic vasculitis in children. Animal models of HSP are needed to better understand the mechanism of HSP. Here, we investigated hematologic and immunologic profiles in HSP rat and rabbit models. Models were established with ovalbumin (OVA) based on type III hypersensitivity. During the acute phase, the models exhibited varying degrees of cutaneous purpura, joint inflammatory response, gastrointestinal bleeding, glomerular capsule protein exudation, vascular dilatation, and increased IgA expression and immune complex deposition. Twenty four hours after antigen challenge, compared with the controls, the models showed a significantly increased white blood cell count and granulocytes count and percentage, decreased number and percentage of lymphocytes, no change in platelet concentration, significantly increased serum IL-4 and TNF-α levels, and decreased CD4(+) T cell, CD4/CD8 ratio, and C3 and C4 levels. Compared with the hematologic and immunologic profiles in pediatric HSP patients, the rat and rabbit HSP models can mimic pediatric HSP characteristics. Our studies provide two useful animal models for further investigations of the pathogenesis, diagnosis, drug screening and treatment of HSP.

Characterization, biomarkers, and reversibility of a monoclonal antibody-induced immune complex disease in cynomolgus monkeys (Macaca fascicularis).

Two 6-month repeat-dose toxicity studies in cynomolgus monkeys illustrated immune complex-mediated adverse findings in individual monkeys and identified parameters that potentially signal the onset of immune complex-mediated reactions following administration of RN6G, a monoclonal antibody (mAb). In the first study, 3 monkeys exhibited nondose-dependent severe clinical signs accompanied by decreased erythrocytes with increased reticulocytes, neutrophilia, monocytosis, thrombocytopenia, coagulopathy, decreased albumin, azotemia, and increased serum levels of activated complement products, prompting unscheduled euthanasia. Histologically, immunohistochemical localization of RN6G was associated with monkey immunoglobulin and complement components in glomeruli and other tissues, attributable to immune complex disease (ICD). All 3 animals also had anti-RN6G antibodies and decreased plasma levels of RN6G. Subsequently, an investigational study was designed and conducted with regulatory agency input to detect early onset of ICD and assess reversibility to support further clinical development. Dosing of individual animals ceased when biomarkers of ICD indicated adverse findings. Of the 12 monkeys, 1 developed anti-RN6G antibodies and decreased RN6G exposure that preceded elevations in complement products, interleukin-6, and coagulation parameters and decreases in albumin and fibrinogen. All findings in this monkey, except for antidrug antibody (ADA), reversed after cessation of dosing without progressing to adverse sequelae typically associated with ICD.

Transferrin-immune complex disease: a potentially overlooked gammopathy mediated by IgM and IgG.

The combination of marked hypersideremia, hypertransferrinemia, and monoclonal gammopathy of underdetermined significance (MGUS) should alert clinicians to the possible presence of an anti-transferrin immunoglobulin, an uncommon acquired disorder also defined as transferrin-immune complex disease (TICD). The authors have previously described a case of TICD with 100% transferrin saturation and liver iron overload. However, the findings in the few cases so far reported are heterogeneous, and the presence of high transferrin saturation and liver iron overload is not universal. In this article, the authors have described the identification of two additional patients with anti-transferrin monoclonal gammopathy, hypersideremia, and hypertransferrinemia, but with incomplete transferrin saturation and no hepatic iron overload. The autoantibodies were purified by using transferrin as affinity bait and characterized. One subject showed a high-titer monoclonal anti-transferrin IgM with a κ-type light chain. This finding is the first observation of IgM autoantibodies against transferrin. The other patient developed the disease after pregnancy. In this study, monoclonal antibody was an IgG mounting a κ-type light chain with altered molecular weight. These results highlight that transferrin might induce the development of a monoclonal immune response of different classes and specificity. The identification, in a single hematologic center, of three different subjects with anti-transferrin monoclonal gammopathy suggests that the disease probably represents a still underdiagnosed condition. From a clinical standpoint, these patients must be followed up both as MGUS and as hemochromatosis.

Schistosoma mansoni infection: an immune complex disease presenting with polyarthritis.

Schistosomiasis or bilharzia is a parasitic disease found in tropical countries. Most infections are subclinical but may progress to chronic form characterized most frequently by the presence of liver involvement and portal hypertension. We report a patient that presented chronic polyarthritis with positive rheumatoid factor. During investigation, increased liver enzymes, negative hepatitis serologies and signs of portal hypertension on an ultrasound examination raised suspicion of S. mansoni infection. We will discuss pathophysiology and clinical manifestations of S. mansoni infection with special attention to articular involvement.

A notable case report of May-Hegglin anomaly with immune complex-related nephropathy: a genetic and histological analysis.

May-Hegglin anomaly (MHA) is a rare autosomal dominant disease characterized by macrothrombocytopenia and leukocyte inclusions with microfilaments in the ribosomes. Mutations in the MYH9 gene, encoding non-muscle myosin heavy chain IIA (NMMHC-IIA) have been identified in patients with MHA and other MYH9-related diseases. Two young males (an older and younger brother) presented with macrothrombocytopenia and leukocyte inclusion bodies. Electron microscopy (EM) revealed parallel filaments in leukocyte inclusion bodies characteristic of MHA. Immunofluorescence microscopy (IF) showed NMMHC-IIA antibodies in 1 - 2 leukocyte inclusion bodies. These findings were consistent with MHA and they were identified to express the MYH9 mutation, D1424H. The older brother underwent a renal biopsy because of persistent proteinuria. Histology revealed mesangial proliferative glomerulonephritis with granular deposits of IgG and C1q. EM showed that the dense deposits were located in subendothelial cells, mesangial cells and Bowman's capsule. Immunocytochemistry revealed that NMMHC-IIA antibodies were localized in podocyte and endothelial cells in the glomerulus. Moreover, the expression of nephrin and podocin, slit diagram protein, was normal. An inflammatory mechanism may occur separately from MYH9-related disease. This report presents a case of MHA with immune complex-related nephropathy.

Abnormal immune complex processing and spontaneous glomerulonephritis in complement factor H-deficient mice with human complement receptor 1 on erythrocytes.

Complement receptor 1 (CR1) on human erythrocytes (Es) and complement factor H (CFH) on rodent platelets perform immune adherence, which is a function that allows the processing of immune complexes (ICs) bearing C3 by the mononuclear phagocyte system. Similar immune adherence occurs in the glomerular podocyte by CR1 in humans and CFH in rodents. As a model for human IC processing, we studied transgenic mice lacking CFH systemically but with human CR1 on Es. These CR1(hu)Tg/CFH(-/-) mice spontaneously developed proliferative glomerulonephritis, which was accelerated in a chronic serum sickness model by active immunization with heterologous apoferritin. ICs containing Ag, IgG and C3 bound to Es in CR1(hu)Tg/CFH(-/-) mice. In this setting, there was increased IC deposition in glomeruli, attributable to the presence of CR1 on Es, together with the absence of CFH on platelets and podocytes. In the absence of plasma CFH, the accumulated ICs activated complement, which led to spontaneous and chronic serum sickness-induced proliferative glomerulonephritis. These findings illustrate the complexities of complement-dependent IC processing by blood cells and in the glomerulus, and the importance of CFH as a plasma complement regulator.

Detection of plasma cells, C4d deposits and donor-specific antibodies on sequential graft biopsies of renal transplant recipients with chronic dysfunction.

BACKGROUND: In order to look for a relationship between humoral mechanisms of rejection and chronic allograft dysfunction, plasma cells, C4d deposits and donor-specific antibodies (DSA) were simultaneously sought on serial biopsies of kidney allograft recipients. PATIENTS AND METHODS: Ten recipients with chronic dysfunction (G1) and 8 recipients with long-term normal graft function (G2) were included. Biopsies and serums were sampled at early graft dysfunction (T1), between 8months and 2years (T2) and after the third year following transplantation (T3). RESULTS: In G1, plasma cells represented 12.3% (T1), 8.2% (T2) and 14.1% (T3) of mononuclear cells. The mean percentage of plasma cells was 11.6% in G1 versus 0.4% in G2 (p<0.05). A progressive rise in C4d deposits was seen in G1, from 25% at T1 to 80% at T3. Donor-specific antibodies were identified in at least one serum sample of 60% of the patients in G1 and 12.5% of the patients in G2 (p=0.012), whereas donor-specific antibodies were eluted from at least one biopsy of 50% of the patients in G1 and 12.5% of the patients in G2 (p=0.03). In G1, C4d deposits were significantly associated with plasma cells (p=0.0012) and anti-HLA Abs in serum samples and/or eluates (p=0.026). CONCLUSION: This study shows that plasma cells, DSA and C4d are associated in renal transplants developing chronic rejection.

The complement system in systemic autoimmune disease.

Complement is part of the innate immune system. Its major function is recognition and elimination of pathogens via direct killing and/or stimulation of phagocytosis. Activation of the complement system is, however, also involved in the pathogenesis of the systemic autoimmune diseases. Activation via the classical pathway has long been recognized in immune complex-mediated diseases such as cryoglobulinemic vasculitis and systemic lupus erythematosus (SLE). In SLE, the role of complement is somewhat paradoxical. It is involved in autoantibody-initiated tissue damage on the one hand, but, on the other hand, it appears to have protective features as hereditary deficiencies of classical pathway components are associated with an increased risk for SLE. There is increasing evidence that the alternative pathway of complement, even more than the classical pathway, is involved in many systemic autoimmune diseases. This is true for IgA-dominant Henoch Schönlein Purpura, in which additional activation of the lectin pathway contributes to more severe disease. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis the complement system was considered not to be involved since immunoglobulin deposition is generally absent in the lesions. However, recent studies, both in human and animal models, demonstrated complement activation via the alternative pathway as a major pathogenic mechanism. Insight into the role of the various pathways of complement in the systemic autoimmune diseases including the vasculitides opens up new ways of treatment by blocking effector pathways of complement. This has been demonstrated for monoclonal antibodies to C5 or C5a in experimental anti-phospholipid antibody syndrome and ANCA-associated vasculitis.

Activation of Fc gamma RI on monocytes triggers differentiation into immature dendritic cells that induce autoreactive T cell responses.

The formation of immune complexes results in activation of the innate immune system and subsequent induction of host inflammatory responses. In particular, the binding of IgG immune complexes to FcgammaR on monocytes triggers potent inflammatory responses leading to tissue injury in disease. We investigated whether activation of monocytes via FcgammaR induced cell differentiation, imparting specific inflammatory functions of the innate immune response. Human IgG alone induced monocytes to differentiate into cells with an immature dendritic cell (iDC) phenotype, including up-regulation of CD1b, CD80, CD86, and CD206. Differentiation into CD1b(+) iDC was dependent on activation via CD64 (FcgammaRI) and induction of GM-CSF. The human IgG-differentiated iDC were phenotypically different from GM-CSF-derived iDC at the same level of CD1b expression, with higher cell surface CD86, but lower MHC class II, CD32, CD206, and CD14. Finally, in comparison to GM-CSF-derived iDC, IgG-differentiated iDC were more efficient in activating T cells in both autologous and allogeneic mixed lymphocyte reactions but less efficient at presenting microbial Ag to T cells. Therefore, activation of FcgammaRI on monocytes triggers differentiation into specialized iDC with the capacity to expand autoreactive T cells that may contribute to the pathogenesis of immune complex-mediated tissue injury.

Warm autoimmune hemolytic anemia is an IgM-IgG immune complex disease.

Warm autoimmune hemolytic anemia (WAIHA) is characterized by polyclonal IgG autoantibodies binding to red blood cells (RBC). The characterization of the autoantigen in WAIHA has not yet led to definitive results, and the etiology of RBC autoantibodies remains unclear. An altered control of self-reactive IgG by autologous IgM has been proposed as the underlying mechanism of disease in WAIHA, suggesting that IgM-IgG immune complexes contribute to the pathophysiology of the disease. In the present study, we purified and characterized IgM from plasma of WAIHA patients and from healthy controls using FPLC-based protocols and optical biosensor technology, and investigated IgG present within the IgM fractions. We provide evidence that IgM-IgG immune complexes in plasma and associated with the RBC membrane are the characteristic feature of WAIHA, independent of the etiology of the disease. IgM-IgG immune complexes of WAIHA patients differ from IgM-IgG immune complexes of healthy individuals with regard to quantity and to structural composition. The data suggest that self-immunoglobulin is the original autoantigen underlying WAIHA. The molecular characterization of IgM-IgG immune complexes may define new targets for therapeutic intervention in WAIHA.

Blood and endothelium in immune complex-mediated tissue injury.

Antigen-antibody complexes can be formed both intravascularly and perivascularly and damage tissues by inducing inflammatory mechanisms. Recent studies have characterized a definite sequence of steps involved in these inflammatory mechanisms, and identified the predominance of particular chemical mediator(s) in each step. The lesions associated with this type of inflammation are characterized by the early development of plasma leakage, followed by the recruitment of polymorphonuclear leukocytes mediated by chemokines generated by FcgammaR-dependent mechanisms. The development of these lesions is modulated by endothelial cell-derived paracrine mediators, and activation of the coagulation system can ensue. The activation of platelets and coagulation, if not properly counterbalanced by fibrinolysis, might be a major factor for the late development of fibrotic changes and organ remodeling.

Role of IL-18 in acute lung inflammation.

We have examined the role of IL-18 after acute lung inflammation in rats caused by intrapulmonary deposition of IgG immune complexes. Constitutive IL-18 mRNA and protein expression (precursor form, 26 kDa) were found in normal rat lung, whereas in inflamed lungs, IL-18 mRNA was up-regulated; in bronchoalveolar (BAL) fluids, the 26-kDa protein form of IL-18 was increased at 2-4 h in inflamed lungs and remained elevated at 24 h, and the "mature" protein form of IL-18 (18 kDa) appeared in BAL fluids 1-8 h after onset of inflammation. ELISA studies confirmed induction of IL-18 in inflamed lungs (in lung homogenates and in BAL fluids). Prominent immunostaining for IL-18 was found in alveolar macrophages from inflamed lungs. When rat lung macrophages, fibroblasts, type II cells, and endothelial cells were cultured in vitro with LPS, only the first two produced IL-18. Intratracheal administration of rat recombinant IL-18 in the lung model caused significant increases in lung vascular permeability and in BAL content of neutrophils and in BAL content of TNF-alpha, IL-1beta, and cytokine-induced neutrophil chemoattractant, whereas intratracheal instillation of anti-IL-18 greatly reduced these changes and prevented increases in BAL content of IFN-gamma. Intratracheal administration of the natural antagonist of IL-18, IL-18 binding protein, resulted in suppressed lung vascular permeability and decreased BAL content of neutrophils, cytokines, and chemokines. These findings suggest that endogenous IL-18 functions as a proinflammatory cytokine in this model of acute lung inflammation, serving as an autocrine activator to bring about expression of other inflammatory mediators.

Comparative study of circulating immune complexes quantity detection by three assays--CIF-ELISA, C1q-ELISA and anti-C3 ELISA.

The assessment of the soluble immune complexes (IC) in human sera is traditionally performed by the C1q binding assay. In the present study, a novel method for the quantity of immune complexes was reported. The methodology was based on measuring their deposition on solid-phase C3 binding glycoprotein (CIF), using an enzyme-linked immunosorbent assay. We also used ELISA that employed anti-C3 antibodies to determined the quantity of immune complexes. The three assays were evaluated for their performance characteristics on the same specially prepared samples: 55 normal sera, 99 sera from RA, 88 sera from SLE, and 27 sera from PSS. The results were compared by reference to a common standard-heat aggregated IgG that possesses many activities of immune complexes. Three of the tests used displayed almost the same specificity (over 95%), while their relative sensitivity varied depending on the disease sera tested. The sensitivity of the assays used was recorded highest for C1q ELISA-28.97% of positive sera, followed by CIF-ELISA-19.63% and lowest for anti-C3 ELISA-17.29%. A well-expressed correlation was found between CIF-ELISA and anti-C3 ELISA data (r=0.42), and a week correlation was noted when comparing CIF-ELISA and C1q ELISA IC levels detected (r=0.28). When the correlation coefficients were calculated individually for each disease category, they were clearly different, and that reflected indirectly in different sensitivities of the test for various disease categories. We also found that the results from the simultaneous performance of the tests demonstrated low percentage positive results when three or two assays were used. This is most probably due to the different assay abilities to detect IC with different sizes and composition, which shows that a small part of IC in the tested sera can be detected simultaneously by more than one assay. On the basis of the results obtained, we concluded that optimal screening for IC could be achieved by parallel application of several different methods.

Ceftizoxime-induced hemolysis due to immune complexes: case report and determination of the epitope responsible for immune complex-mediated hemolysis.

BACKGROUND: Several occurrences of immune complex-mediated, cephalosporin-induced intravascular hemolysis have been reported. This report describes the first case of hemolytic anemia caused by an immune-complex mechanism associated with ceftizoxime and delineates the epitope responsible for hemolysis. CASE REPORT: The patient's serum was tested for antibody that reacted with five penicillins and 30 cephems (all types of cephalosporins) by using protocols to detect drug-adsorption and immune-complex mechanisms. The patient's antibody that formed immune complexes with ceftizoxime reacted with 10 of 30 cephems. These 10 drugs were classified as oxime-type cephalosporins, which have a common structural formula consisting of [(Z)-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetoamido] at the C7 position on 7-aminocephalosporinic acid with or without substitution at the C3 position. CONCLUSION: The patient's antibody recognized a common structure in 10 oxime-type cephalosporins, and immune complexes formed by the antibody specifically or nonspecifically bound to red cell membranes. Therefore, when intermittent antibiotic therapy is required, as in this case, care should be taken in antibiotic selection to avoid drug-induced hemolytic anemia. In addition, when this type of hemolysis is observed, tests for antibody that reacts by adsorption and immune-complex mechanisms should be performed against penicillins and cephems to select antibiotics not showing a cross-reaction.

Enzyme immunoassays for measuring complement-dependent prevention of immune precipitation (PIP) and solubilization of preformed antigen-antibody complexes (SOL).

We have developed simple and sensitive enzyme-based methods for evaluating the ability of serum complement to prevent immune complex precipitation (PIP) or to solubilize preformed immune complexes (SOL). Alkaline phosphatase, serving both as antigen and label, is added to goat IgG anti-alkaline phosphatase antibodies, with serum present throughout the assay (PIP), or added after immune complex formation (SOL). After incubation at 37 degrees C for 1 h followed by centrifugation, the enzyme activity of the supernatant, reflecting the amount of immune complexes in solution, is measured by colorimetry. Results are expressed with reference to a standard serum pool assigned 100 arbitrary units (AU). Intra- and inter-assay variabilities are within 10%. The normal ranges were 67-133 AU for PIP and 72-129 AU for SOL. These methods have been standardized for clinical use in relation to impaired complement function and immune complex disease, and adapted for measuring complement mediated binding of immune complexes to erythrocytes. They are sensitive, easy to perform and do not require expensive facilities. By measuring the interaction of complement with immune complexes, these methods may highlight aspects of the classical and the alternative pathway that are different from those detected using haemolysis as an endpoint.

C2 deficiency in blood donors and lupus patients: prevalence, clinical characteristics and HLA-associations in the Brazilian population.

The objective of the present study was to investigate the prevalence, clinical characteristics, and HLA association of C2 deficiency in the Brazilian population. The frequency of C2 deficiency profile (C2Q degree profile) was 2.2% among 1503 blood donors and 6.6% among 166 patients with systemic lupus erythematosus (SLE). A higher incidence of clinical manifestations possibly related to immune complex disease was observed among blood donors with C2Q degree profile and their relatives with C2Q degree profile when compared to the normal C2 relatives. The comparison of clinical and laboratory features between SLE patients with C2Q degree profile and those with normal C2 revealed earlier disease onset, higher frequency of oral ulcerations and lower frequency of anti-native DNA antibodies in the first group. The HLA study conducted on 18 individuals with C2Q degree profile (11 blood donors and 7 SLE patients) confirmed the previously reported association with the antigens HLA-A25, B18 and DR2, supporting the concept that probably most C2 deficiency cases, throughout the world, are due to a single mutation in the C2 gene in linkage disequilibrium with the A25B18DR2 haplotype.

[Correction of immune disorders in surgery of duodenal ulcer]. / Korrektsiia immunologicheskikh narushenii v khirurgii iazvennoi bolezni dvenadtsatiperstnoi kishki.

The dynamics of immune status in 124 patients operated on for duodenal ulcer are analysed. The patients were divided into two groups: in the study group (60 patients) regional lymphoimmune stimulation with T-activin was used, in patients of the control group T-activin was not used. The depression of immune system in short term period after surgical intervention was detected. The injection of T-activin into the round ligamentum of the liver influences favourably the course of the disease and promotes correction of immune disorders, thus preventing short-term postoperative complications.

Does truly 'idiopathic' crescentic glomerulonephritis exist?

Crescentic glomerulonephritis is usually classified into antiglomerular basement membrane (GBM) disease, immune-complex disease, or pauci-immune crescentic nephritis. The last category includes patients with systemic vasculitis as well as 'idiopathic' isolated crescentic nephritis. The presence of anti-neutrophil cytoplasmic antibodies (ANCA) in many patients with apparently isolated crescentic nephritis suggests that this represents a renal-limited form of vasculitis, and that truly 'idiopathic' crescentic nephritis is a very rare entity. We reviewed all renal biopsies with extracapillary proliferation seen at our centre since the availability of an ANCA assay (4-year period). There were 89 such biopsies of a total of 1240, of which 82 had sufficient details for further analysis. Of these, 10 had anti-GBM disease, 35 had epithelial proliferation associated with a variety of other diseases, and 36 had ANCA-associated disease. Nine of this last group had no extrarenal features and would previously have been classified as 'idiopathic' crescentic glomerulonephritis. The single remaining patient had an inactive glomerulonephritis with a scarred crescent; the predominant lesion was an interstitial nephritis. We therefore conclude that truly 'idiopathic' crescentic nephritis is very rare, if it exists at all. The ability to provide a practically complete classification of crescentic nephritis has important prognostic and therapeutic consequences.