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C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival ( p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Purpose of Review: This review discusses recent findings that are changing and expanding the spectrum of pathologic changes associated with antibodies directed against renal allografts., Recent Findings: This review focuses on four lesions: subclinical antibody-mediated rejection (AMR), C4d-negative AMR, intimal arteritis, and arterial intimal fibrosis. A number of studies have identified morphologic lesions of AMR in protocol biopsies of normally functioning renal allografts, particularly in sensitized recipients, that correlate with subsequent development of chronic changes in the graft, including transplant glomerulopathy. These same studies as well as molecular studies of indication biopsies of conventional renal allografts have noted evidence of microvascular injury, which, in the presence of donor-specific antibodies (DSAs) but the absence of C4d deposition in peritubular capillaries, is associated with development of transplant glomerulopathy and graft loss. Finally, recent studies suggest that intimal arteritis, previously felt to represent a lesion of cell-mediated rejection, and bland arterial intimal fibrosis, resembling arteriosclerosis, may in some cases be manifestations of DSA-induced graft injury., Summary: Incorporation of these newly recognized lesions of AMR into a working diagnostic schema with sufficient sensitivity and specificity to minimize undertreatment and overtreatment of patients is an important challenge currently faced by renal pathologists and transplant clinicians.

Background and Objectives: Modern imaging techniques have increased the incidental detection of renal atherosclerotic disease (RAD). Because immune activation may hasten RAD progression, identifying cellular immune markers might provide clues to clinical activity. In this study, cellular immune markers were assessed in early RAD., Design, Setting, Participants, & Measurements: Immune cell markers in peripheral blood of two groups of hypertensive patients with normal carotid and coronary arteries were evaluated: 28 patients had incidental RAD and 22 patients had normal renal arteries; 21 renal arteries obtained at necropsy from individuals with history of hypertension and tissue evidence of RAD were examined and matched with 21 individuals with normal renal arteries. Cell subpopulations were measured by flow cytometry in peripheral blood and direct cell count, respectively, using T and dendritic cells monoclonal antibodies., Results: Peripheral blood of RAD patients showed increased numbers of cells expressing CD3, CD4, CD83, and CD86. CD4 to CD8 ratio was 8.3 ± 1.4 (RAD) to 3.4 ± 0.9 (normal; P<0.001). No differences were found in CD25, CD8, and S100 among groups. Postmortem samples from RAD showed increased CD3+, CD4+, CD86+, and S100+ cells, whereas CD25+ and CD8+ were unmodified between groups. CD4+ to CD8+ ratio was higher in the RAD(PM) group., Conclusions: These results are consistent with an increased expression of immune cell markers in early RAD. Additional studies will explore if they may potentially turn into treatment targets to prevent disease progression.

Objectives: Various genetic variants of inhibitory immune signals have been suspected as feasible causes of Kawasaki disease (KD). We investigated the associative role of programmed death-1 (PD-1) gene in the pathogenesis of KD by injecting bacilli Calmette Guérin (BCG) to PD-1 gene knockout (PD-1KO) mice., Methods: In order to induce KD-like clinical manifestations in young PD-1KO mice, intradermal injection of the bacilli Calmette Guérin (BCG) was performed twice on the abdominal skin with a 4-week interval. For defining the role of BCG, heat shock protein (HSP) 65 was challenged. In addition, Staphylococcus aureus was adopted as a microorganism that does not contain HSP65 structure. One month after the second injection, heart, liver, and kidneys were removed and examined., Results: PD-1KO mice showed KD-like features including prolonged fever for more than 5 days, erythematous swelling on soles, tail skin desquamation, and gallbladder (GB) hydrops. Inflammatory cell aggregation and intimal proliferation in at least more than one coronary artery was found in all PD-1KO mice whereas scanty coronary lesion was found in wild type (WT) mice. When the PD-1KO mice were injected twice with HSP65, coronary arterial lesions similar to those seen after BCG injection were observed. Inflammatory reactions in other organs including hepatic arteries, renal arteries, and biliary arteries were also observed in PD-1KO mice., Conclusions: Our data suggest that PD-1 gene may be one of the genetic predispositions of KD and antigens containing HSP65 structure could be a triggering factor of KD by our animal model of KD.

Purpose of Review: Terminology for posttransplant renal arterial lesions is confusing, with multiple terms being applied, the more common among them being the comprehensive terms, transplant arteriosclerosis and transplant atherosclerosis; endarteritis, for intimal lesions with an inflammatory component; and finally for advanced lesions with or without intimal inflammation, transplant arteriopathy. However, these latter lesions may present the appearance of banal arteriosclerosis, albeit more advanced expected on the basis of donor age. This review explores the distinctions to be drawn among these various descriptive terms., Recent Findings: Cell-mediated arterial lesions due to T-cell cell-endothelial interactions and antibody-mediated lesions, due to antiendothelial cell antibodies, show many common features: myofibroblasts, some of recipient origin, laying down extracellular matrix. However, they differ in that cell-mediated intimal lesions initially have a prominent leukocytic component, usually absent in antibody-mediated lesions. The antibodies most frequently implicated are antihuman leukocyte antigen class I and class 2 antibodies. With the exception of a sometimes more cellular intima and initial absence of dense collagen and elastic fibers, these latter lesions resemble those of arteriosclerosis of aging., Summary: Many instances of lesions designated as transplant arteriopathy are morphologically similar or identical to typical renal arteriosclerosis and could equally be regarded as accelerated arteriosclerosis.

Objective: The objective of the study was to evaluate the fetal renal artery impedance in the context of inflammation-associated preterm birth., Study Design: We conducted a prospective Doppler assessment of the fetal renal artery impedance in 70 singleton fetuses. The study group consisted of 56 premature fetuses (median, 28.1 [interquartile range, 25.3-30.6] weeks at enrollment). Gestational age (GA) reference ranges were generated based on fetuses with uncomplicated pregnancies (n = 14). Doppler studies included renal artery pulsatility index (PI), resistance index (RI), systolic/diastolic (S/D) ratio, and presence or absence of end-diastolic blood flow. Proteomic profiling (surface-enhanced laser desorption ionization time-of-flight) was used for assessment of intraamniotic inflammation and biomarker peak corresponding to beta2-microglubin. Data were interpreted in relationship to amniotic fluid index (AFI), cord blood interleukin (IL)-6 and erythropoietin (EPO) levels. The cardiovascular and metabolic profiles of the neonates were investigated in the first 24 hours of life., Results: Fetuses delivered by mothers with intraamniotic inflammation had higher cord blood IL-6 but not EPO levels. Fetal inflammation did not affect either renal artery PI, RI, S/D ratio, or end-diastolic blood flow. Neonates delivered in the context of intraamniotic inflammation had higher serum blood urea nitrogen levels, which correlated significantly with AF IL-6 levels. The renal artery RI and SD ratio were inversely correlated with the AFI independent of GA, cord blood IL-6, and status of the membranes., Conclusion: The fetus is capable of sustaining normal renal artery impedance despite inflammation. Resistance in the renal vascular bed affects urine output independent of inflammation.

This study was performed to clarify the relationship between changes in contractile proteins in renal vascular walls and the prognosis of hypertension during pregnancy. Twenty preeclamptic patients underwent renal biopsies after delivery and were divided into the following three groups: group I, patients with persistent hypertension after delivery (n = 7; mean age, 34.8 +/- 1.4 years [SE]); group II, patients who became normotensive after delivery and hypertensive again during follow-up (n = 5; mean age, 34.8 +/- 1.6 years), and group III, patients who became normotensive after delivery (n = 8; mean age, 28.0 +/- 1.0 years). We also examined age-matched healthy controls (group IV; n = 7; mean age, 34.9 +/- 1.5 years). Renal biopsy specimens were immunohistochemically stained by the avidin-biotinylated peroxidase complex method using antimonoclonal smooth muscle cell myosin heavy chain isoform antibodies (SM-1, SM-2) and antimonoclonal alpha-smooth muscle cell actin antibody (actin). We estimated and semiquantitatively scored the degree of staining in each section. In interlobular arteries, SM-1, SM-2, and actin staining in group I were significantly reduced compared with group IV (SM-1, SM-2, P: < 0.05; actin, P: < 0.01). In afferent arterioles (Afs), SM-1, SM-2, and actin staining were reduced in group I. SM-2 staining in group I was significantly reduced compared with the other three groups (versus group II, P: < 0.05; versus groups III and IV, P: < 0.01). These findings suggest that phenotypic changes in vascular smooth muscle cells (especially the disappearance of SM-2 in Afs) reflect the stage of underlying essential hypertension and can predict from the change in hypertension during pregnancy whether it will persist after delivery.

Hepatitis C virus (HCV) infection has been associated with de novo or recurrent membranoproliferative glomerulonephritis and acute transplant glomerulopathy in transplanted kidneys. Recently, anticardiolipin antibodies (ACA) have been linked with chronic HCV infection. A few reports have suggested an association between ACA and renal allograft thrombosis. This study examines the clinical and pathologic features of HCV-positive renal allograft recipients at our institution. From 1990 to 1996, 379 kidney transplants were performed. We identified 18 recipients (4.8%) with HCV-positive serology pretransplant. Determination of IgG and IgM ACA was performed by enzyme-linked immunosorbent assay, using pretransplant sera. Among the 18 patients, five patients presented with biopsy-proven de novo renal thrombotic microangiopathy (RTMA), occurring 5 to 120 d (median, 14 d) after transplant. No differences in pretransplant characteristics were observed between patients with (n = 5) or without (n = 13) RTMA. All five patients had a positive ACA test (either IgG or IgM titer > 2 SD above normal), compared with only one of 13 patients without RTMA. The mean value for IgG ACA was significantly higher in the RTMA patients than in patients without RTMA (22.9 +/- 14.1 versus 6.9 +/- 4.9 IgG phospholipid units, P = 0.02); however, there were no significant differences in IgM ACA titers. Rheumatoid factor and complement C4 levels were normal in pretransplant sera of patients with RTMA. Patients with RTMA had their cyclosporine withdrawn (four of five) or the dose was decreased (one of five), and one of five underwent plasmapheresis. Four of five patients died within 5 yr after transplant, compared with no deaths in the other 13 patients. Finally, as a control group, seven HCV-negative renal allograft recipients who presented with RTMA/hemolytic uremic syndrome during the same time period were found to have normal ACA values (IgG or IgM). RTMA associated with ACA in HCV-positive renal allograft recipients may represent a new clinical entity. The occurrence of this syndrome may have deleterious consequences for patient and graft survival.

We examined the infiltration of acutely rejecting renal allografts (DA-->LEW) by ED1+ and ED2+ macrophages and T lymphocytes at intervals of 24 h after transplantation. Donor and recipient macrophages were differentiated by MHC class II antigen expression in double-staining experiments with ED1. Proliferation was assayed after pulse-labelling with BrdU. We subdivided allograft infiltration into three consecutive phases: 1) During phase I on days 1 to 2 after allogeneic kidney transplantation, perivascular infiltrates developed that contained numerous donor and recipient macrophages. Allograft rejection could already be diagnosed 24 h after transplantation by perivascular infiltration of T lymphocytes, whereas T cells were rarely found in isografts. 2) Phase II of allograft rejection from day 3 to 4 was characterized by massive propagation of the infiltrate. About equal numbers of interstitial donor and recipient macrophages were counted. Both macrophages and T lymphocytes proliferated in situ and macrophages outnumbered T cells until complete rejection. 3) During phase III the allograft was destroyed. Large intravascular monocytes surprisingly expressed the ED2 antigen. In the interstitium of viable graft regions, the population of recipient macrophages grew, whereas the population of donor macrophages and of T lymphocytes decreased.

The current study tests whether hypercholesterolemia influences the distribution of endothelial cell microfilaments during the initiation and growth of fatty streak-type lesions. We classified the lesions occurring over a 20-week period into four types based on the location and extent of macrophage infiltration observed microscopically. The earliest lesion was characterized by leukocytes adherent to the endothelial surface. Minimal lesions were characterized by a few cells in the subendothelium. Intermediate lesions consisted of numerous subendothelial leukocytes in a minimally raised lesion. Advanced fatty streak lesions were elevated, with several layers of leukocytes. The organization of peripheral junctional actin (the dense peripheral band) and of central endothelial cell actin microfilament bundles was studied in each of these lesions by using fluorescent microscopy. We found that in the aorta away from branch sites and in areas away from lesions, the central microfilament distribution was unaffected by hypercholesterolemia. The macrophages entered the wall without any identifiable reorganization in the microfilaments. During the accumulation of subendothelial macrophages in minimal and intermediate lesions, stress fibers were initially increased in comparison to lesion-free areas. In raised advanced lesions, the central microfilaments became thinner and disappeared. However, at flow dividers, where central stress fibers are normally prominent, endothelial cells on the surface of intermediate lesions showed a reduction in central fibers, and peripheral bands became prominent. This finding was associated with changes in cell shape from elongated to cobblestone type. Thus, actin microfilament bundles in endothelial cells underwent substantial changes in distribution during the accumulation of subendothelial macrophages, forming hypercholesterolemia-induced fatty streak-type lesions. These changes may influence endothelial substrate adhesion, permeability, or repair after injury.

The case of a patient with systemic lupus erythematosus (SLE) is reported which was accompanied by renal dysfunction and massive vascular immune deposits in the kidney without active glomerular lesions. The renal biopsy showed arterioles and small arteries with circumferential periodic acid-Schiff (PAS) and Masson trichrome-positive homogenous material in the subendothelial area in the absence of thrombotic, necrotizing or inflammatory lesions. Immunofluorescence and electron microscopy examination demonstrated immune deposits in the vascular walls. Glomeruli showed only minor abnormalities with a trend to collapse. There was no improvement in renal dysfunction over a 4-year period until the patient's death, despite steroid therapy producing a decrease in disease activity. The autopsy showed similar vascular changes to those seen in the biopsy, however; glomeruli were either sclerotic or showed a trend to collapse. Massive uncomplicated vascular immune complex deposition without active glomerular lesions is rare. The present case indicates that this type of lupus vasculopathy may be a prognostic factor for the loss of renal function in SLE mediated by hemodynamic glomerular injury.

Phenotypic difference of lymphocytes circulating in tumorous renal artery and renal vein in patients with renal cell carcinoma was studied. Fifteen patients with no prior treatment were studied, from whom blood samples were taken at the time of radical nephrectomy. Mononuclear cells separated from tumorous renal arterial and venous blood were analyzed for cell surface markers. CD3, CD4, CD8, CD11b, CD16, CD25, CD57, Leu8 HLA-DR were compared. CD25 positive cells were significantly increased in venous blood than in arterial blood in the kidneys with tumor. No significant difference was found regarding the other surface markers.

Antineutrophil cytoplasmic autoantibodies (ANCA) specific for constituents of neutrophil primary granules and monocyte lysosomes have been demonstrated in various vasculitic disorders. The staining pattern in indirect immunofluorescence microscopy using alcohol-fixed neutrophils as substrate allows distinction among 3 types of ANCA: 1) classic anti-neutrophil cytoplasmic antibody (cANCA, formerly known as ACPA); 2) a type with a perinuclear/nuclear staining pattern produced when alcohol-fixed neutrophils are used as substrate (pANCA); and 3) a mixture of both of the above types (xANCA, also described recently as pANCA). Most cANCA are directed against proteinase 3 ("Wegener's autoantigen"). Some pANCA have specificity for myeloperoxidase and are associated with idiopathic crescentic glomerulonephritis ("renal vasculitis") and other systemic vasculitides exhibiting a paucity of immune deposits in blood vessels. In addition to being a useful serological marker, ANCA appear to be directly involved in the pathogenesis of systemic vasculitis. ANCA can activate cytokine-primed granulocytes and monocytes to undergo a respiratory burst and degranulation. This effect leads to vasculitis through the attachment of these cells to the vascular endothelium primed by cytokine-induced expression of adhesion molecules (E-LAM 1) on the endothelium. Thus, the release of toxic oxygen radicals and lytic enzymes is capable of causing vascular damage. In the present paper we report on the main target antigens and on the history, nomenclature, laboratory methods, and etiopathological implication of ANCA. Additional pathophysiological aspects of ANCA and/or autoreactive T cells and immunoregulatory events are also discussed.

The antigenic specificity and clinical distribution of the antineutrophil cytoplasmic antibodies (ANCA) in kidney diseases have recently been extensively studied. In patients with systemic vasculitis, the great predominance of two major ANCA antigens, proteinase 3 (PR3) and myeloperoxidase (MPO), is now established. PR3 and MPO are colocalized in the azurophilic granules of neutrophils and translocated to the cell surface during activation, and thus are able to interact with autoantibodies after neutrophil preactivation. Furthermore, by comparison of amino acid and DNA sequences, it has been shown that PR3 is identical to myeloblastin, which has been described independently and is involved in the control of growth and differentiation of leukemic cells. Aside from the two major ANCA antigens, a number of neutrophil cytoplasmic antigens recognized by ANCA have been identified, including human leukocyte elastase, lactoferrin, CAP57, and cathepsin G. These rare ANCA specificities occur in a limited number of patients. The variety of ANCA antigen specificities contrasts, however, with the fact that the vast majority of ANCA-positive sera are monospecific for one single ANCA antigen. With regard to clinical distribution, ANCA have major diagnostic significance in the four conditions in which they are frequently detected: Wegener's granulomatosis (WG), Churg and Strauss Syndrome (CSS), microscopic periarteritis (MPA), and necrotic and crescentic glomerulonephritis (NCGN). However, the initial dichotomy between MPO-associated vasculitis (NCGN, MPA) and that associated with anti-PR3 antibodies (WG) appears far from absolute.

After a long period during which few new data on the vasculitides emerged, the past decade has seen a real explosion of data on the subject. This began with basic clinical descriptions and the delineation of long term outcome as survival improved to a major extent under the influence of improved treatment regimes. In parallel, better understanding of the immunopathology has emerged. Of particular interest have been descriptions of autoantibody systems in vasculitis which seem to be specific to vasculitis and therefore diagnostically useful: the antineutrophil cytoplasmic antibodies (ANCA). Whether or not these are pathogenetically significant as well as useful remains a matter for debate. In parallel, anti endothelial cell antibodies have been described, but their role (if any), in pathogenesis remains equally obscure. There are some suggestions that vasculitis is becoming more common, but increased awareness and the availability of ANCA have undoubtedly increased awareness of the subject.

Kidney, ureter, kidney artery, and kidney vein tissue were obtained from a single human transplant specimen. The donors erythrocyte blood group phenotype was A1Le(a-b+). Total non-acid glycolipid fractions were isolated and individual glycolipid components were identified by immunostaining thin layer plates with a panel of monoclonal antibodies and by mass spectrometry of the permethylated and permethylated-reduced total glycolipid fractions. The dominating glycolipids in all tissues were mono- to tetraglycosylceramides. In the kidney, ureter, and artery tissue less than 1% of the glycolipids were of blood group type, having more than 4 sugar residues. In contrast, 14% of the vein glycolipids were of blood group type, and the dominating components were type 1 chain blood group H pentaglycosylceramides and A hexaglycosylceramides. Trace amounts of structurally different blood group A glycolipids (type 1 to 4 core saccharide chains) with up to 10 sugar residues were found in the kidney, ureter, and vein tissues, including evidence for a novel blood group A heptaglycosylceramide based on the type 3 chain in the vein. The only detected A glycolipid antigen in the artery tissue was the blood group A difucosyl type 1 chain heptaglycosylceramide (ALeb) structure. Blood group Lewis and related antigens (Lea, Leb, and ALeb) were expressed in the kidney, ureter, and artery, but were completely lacking in the vein, indicating that the Le gene-coded alpha 1-4-fucosyltransferase was not expressed in this tissue. The X and Y antigens (type 2 chain isomers of the Lea and Leb antigens) were detected only in the kidney tissue.

Ninety-one renal biopsies were examined by immunofluorescent staining for the presence of C3 and immunoglobulins in the walls of renal arteries (RAW), tubules and glomeruli. The diseases studied were non-systemic renal immune complex diseases, systemic diseases with kidney involvement, renal diseases with minimal pathological changes and histological normal kidneys. In a high percentage of cases C3 and, to a lesser degree, deposits of immunoglobulins were found in the RAW, the deposits being found both in immunological and non-immunological diseases. Deposits of C3 but not of C4, C1q, fibrinogen, and immunoglobulins were found in the RAW of 11 normal kidneys examined.

Inherited differences in the quantity and site of renal deposition of antigen were studied in two inbred strains of healthy rats, one of which, Lewis, is susceptible to Heymann's nephritis and the other (DA) is resistant. Deposition of human cationic immunoglobulin G (IgG) was significantly less in the liver, spleen and kidneys of Lewis rats compared with DA rats, which suggests that the density of the negatively charged molecules in the capillary walls of Lewis rats is less than in DA rats. Immunofluorescent studies of the kidneys 15 min after administration of cationic IgG showed that it could be detected only on the glomerular basement membrane (GBM) and that the intensity of the deposits was less in Lewis rats. The mesangial uptake of aggregated IgG was greater in DA rats at all times studied. There was remarkable similarity in the glomerular processing of cationic IgG and aggregated IgG in both strains. These differences in glomerular properties, capillary charge and mesangial uptake may lead to differences in the deposition of antigen within the glomerulus and in the response to the subsequent inflammatory reactions. This provides a new hypothesis for genetic predisposition of individuals to particular glomerulopathies.

Renal arteriolar thickening, which occurs in response to the presence of cadmium ions, was investigated by fluorescent microscopy. In an acridine orange-stained preparation of the rat kidney, positive fluorescence was observed in the media of renal arterioles following long-term implantation of cadmium wire into the cortex, but was absent in animals similarly treated with copper wire or plastic. The presence of lymphocytic foci around the thickened vessels in cadmium-containing kidneys, together with recent evidence pointing to an association of RNA with immune complex formation, would suggest that the vascular thickening in the presence of cadmium ions is attributable, at least in part, to the mural location of a metallic-originated immune complex.

Four selected patients with progressive systemic sclerosis showed deposition of immunoglobulins and complement in diseased renal arteries and arterioles. Although three patients had hypertension, in two of these malignant, the third patient did not have hypertension over a four year period. These findings suggest that immune complexes may be involved in the pathogenesis of some cases of progressive systemic sclerosis, the primary target being the vascular system.

Mice immunized with laminin isolated from mouse EHS sarcoma developed immune-mediated pathological changes in the basement membranes of the kidneys and lungs, and in the subendothelial basement membranes of arteries in the kidney. Subendothelial and mesangial dense deposits were seen in the renal glomerulus. Thickening and splitting of both the glomerular basement membrane and the alveolar basement membrane occurred in mice immunized with laminin. Granular dense structures were present in the lamina densa of subendothelial basement membranes of renal arteries. Staining for in vivo-bound mouse IgG was observed primarily along the glomerular basement membrane and in the mesangium by the indirect peroxidase technique. Mouse IgG was also detected in the adventitial connective tissue of renal arteries and was present focally along tubular basement membranes. No circulating antibody was detectable using either Western immunoblotting or microELISA techniques.

Although the glomerulonephritis (GN) and renal vasculitis in polyarteritis nodosa (PAN) are generally considered to be immune-mediated, the pathogenesis of the renal injury and the role of immune complex (IC) deposition are unclear. To better define the nature of the glomerular and vascular injury in PAN, we performed a detailed ultrastructural study of 27 renal biopsies from 20 patients with histologically confirmed PAN of the microscopic or overlap (microscopic/macroscopic) type. A total of 48 arteries and arterioles were studied ultrastructurally, including 20 vessels with recognizable vasculitis in 1 micron-thick survey sections. By immunofluorescence, glomerular and vascular immunoglobulin deposits were generally scanty, primarily located in areas of necrosis or sclerosis. Fibrinogen, C3 and C1 were more commonly detected, often in the absence of demonstrable immunoglobulin. By electron microscopy, discrete electron-dense deposits of probable immune-type were found in the glomeruli of five initial biopsies. No electron-dense deposits were identified in any of the arteries or arterioles studied. In both glomeruli and vessels, endothelial injury and subendothelial fibrin deposition were the earliest detectable ultrastructural changes. The pathogenetic implications of these findings are discussed.