Pathologic features of antibody-mediated rejection in renal allografts: an expanding spectrum.

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.

Bacille Calmette Guérin (BCG) can induce Kawasaki disease-like features in programmed death-1 (PD-1) gene knockout mice.

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.

Accelerated arteriosclerosis: a form of transplant arteriopathy.

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.

Fetal renal artery impedance as assessed by Doppler ultrasound in pregnancies complicated by intraamniotic inflammation and preterm birth.

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.

C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection.

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.

Renal vascular walls in patients with preeclampsia superimposed on essential hypertension.

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.

Immunohistochemical findings in the renal vascular lesions of progressive systemic sclerosis.

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.

Massive uncomplicated vascular immune complex deposits in the kidney of a patient with systemic lupus erythematosus.

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.

Fluorescent studies on the potential existence of vascular metallic immune complexes.

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.

[Phenotypic difference of lymphocytes circulating in tumorous renal artery and renal vein in patients with renal cell carcinoma].

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.

Local and systemic cellular immunity in early renal artery atherosclerosis.

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.

Antigen specificities and clinical distribution of ANCA in kidney diseases.

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.