Reduced glomerular endothelial thrombomodulin is associated with glomerular macrophage infiltration in diabetic nephropathy

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin.Immunopathology of vascular and renal diseases and of organ and celltransplantationIP1

Early systemic microvascular damage in pigs with atherogenic diabetes mellitus coincides with renal angiopoietin dysbalance

Background: Diabetes mellitus (DM) is associated with a range of microvascular complications including diabetic nephropathy (DN). Microvascular abnormalities in the kidneys are common histopathologic findings in DN, which represent one manifestation of ongoing systemic microvascular damage. Recently, sidestream dark-field (SDF) imaging has emerged as a noninvasive tool that enables one to visualize the microcirculation. In this study, we investigated whether changes in the systemic microvasculature induced by DM and an atherogenic diet correlated spatiotemporally with renal damage. Methods: Atherosclerotic lesion development was triggered in streptozotocin-induced DM pigs (140 mg/kg body weight) by administering an atherogenic diet for approximately 11 months. Fifteen months following induction of DM, microvascular morphology was visualized in control pigs (n = 7), non-diabetic pigs fed an atherogenic diet (ATH, n = 5), and DM pigs fed an atherogenic diet (DM+ATH, n = 5) using SDF imaging of oral mucosal tissue. Subsequently, kidneys were harvested from anethesized pigs and the expression levels of well-established markers for microvascular integrity, such as Angiopoietin-1 (Angpt1) and Angiopoietin-2 (Angpt2) were determined immunohistochemically, while endothelial cell (EC) abundance was determined by immunostaining for von Willebrand factor (vWF). Results: Our study revealed an increase in the capillary tortuosity index in DM+ATH pigs (2.31±0.17) as compared to the control groups (Controls 0.89±0.08 and ATH 1.55±0.11; p<0.05). Kidney biopsies showed marked glomerular lesions consisting of mesangial expansion and podocyte lesions. Furthermore, we observed a disturbed Angpt2/ Angpt1balance in the cortex of the kidney, as evidenced by increased expression of Angpt2 in DM+ATH pigs as compared to Control pigs (p<0.05). Conclusion: In the setting of DM, atherogenesis leads to the augmentation of mucosal capillary tortuosity, indicative of systemic microvascular damage. Concomitantly, a dysbalance in renal angiopoietins was correlated with the development of diabetic nephropathy. As such, our studies strongly suggest that defects in the systemic microvasculature mirror the accumulation of microvascular damage in the kidney

The NET-effect of combining rituximab with belimumab in severe systemic lupus erythematosus

Afdeling Klinische Chemie en Laboratoriumgeneeskunde (AKCL

Human leukocyte antigen selected allogeneic mesenchymal stromal cell therapy in renal transplantation: the Neptune study, a phase I single-center study

Mesenchymal stromal cells (MSC) hold promise as a novel immune-modulatory therapy in organ transplantation. First clinical studies have used autologous MSCs; however, the use of allogeneic "off-the-shelf" MSCs is more sustainable for broad clinical implementation, although with the risk of causing sensitization. We investigated safety and feasibility of allogeneic MSCs in renal transplantation, using a matching strategy that prevented repeated mismatches. Ten patients received two doses of 1.5 x 10(6)/kg allogeneic MSCs 6 months after transplantation in a single-center nonrandomized phase Ib trial, followed by lowering of tacrolimus (trough level 3 ng/mL) in combination with everolimus and prednisone. Primary end point was safety, measured by biopsy proven acute rejection (BPAR) and graft loss 12 months after transplantation. Immune monitoring was performed before and after infusion. No BPAR or graft loss occurred and renal function remained stable. One patient retrospectively had DSAs against MSCs, formed before infusion. No major alterations in T and B cell populations or plasma cytokines were observed upon MSC infusion. Administration of HLA selected allogeneic MSCs combined with low-dose tacrolimus 6 months after transplantation is safe at least in the first year after renal transplantation. This sets the stage to further explore the efficacy of third-party MSCs in renal transplantation.Nephrolog

Complement Component C1q as Serum Biomarker to Detect Active Tuberculosis

Transplantation and autoimmunit

"In my beginning is my end": usefulness of repeat kidney biopsies in lupus nephritis

Malvar et al. report the results of a study on protocolized repeat renal biopsies in 76 patients with class III or IV (+/- class V) lupus nephritis. They show that managing maintenance therapy in patients with lupus nephritis through protocolized repeat kidney biopsies results in a lower flare rate. Provided that these results can be replicated in other studies, there is an argument for protocolized repeat kidney biopsies to become the standard of care. Copyright (C) 2019, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.Immunopathology of vascular and renal diseases and of organ and celltransplantationIP1

Histological manifestations of rhabdomyolysis in the kidney

Nephrolog

Investigations in systemic vasculitis - The role of renal pathology

ANCA-associated vasculitis (AAV) describes a group of small-vessel vasculitides with frequent renal involvement. The first description of these conditions can be traced back to the 19th-century paper on necrotizing vasculitis by Kussmaul and Maier. Since then, our understanding of the pathogenesis has improved and the histopathological lesions have been described in detail. Characteristic histologic lesions in ANCA-associated glomerulonephritis (AAGN) are fibrinoid necrosis and crescents, often accompanied by tubulointerstitial inflammation. The discovery of ANCAs has not rendered renal biopsies obsolete in the diagnostic process. Currently, renal biopsies remain the gold standard for the diagnosis of AAV in conjunction with ANCA serology. In addition to diagnosis, renal biopsies are useful for patient prognosis. The evaluation of renal histological samples from patients with new-onset AAV who participated in clinical trials led to the proposal of the histopathological classification for AAGN. The prognostic value of this classification continues to be validated and an update is expected soon. (C) 2018 Elsevier Ltd. All rights reserved.Immunopathology of vascular and renal diseases and of organ and celltransplantationIP1

The role of complement in antineutrophil cytoplasmic antibody-associated vasculitis

Purpose of review To provide a comprehensive overview of the current insight into the role of complement activation in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). In addition, the therapeutic options targeting the complement system in AAV are discussed. Recent findings It has become increasingly clear that complement, and more specifically signalling through the C5a receptor, contributes to the immunopathology of AAV. This has led to the design of clinical trials with a C5a receptor blocker. The first results show a reduction in tissue damage and a favourable safety profile, as other parts of the complement defence system are left intact. Summary Although AAV was initially regarded as a pauci-immune disease, it is now well established that, in addition to autoantibodies, complement plays an essential role in the disease process. Animal models delivered the first insight, but the effective therapeutic interventions using complement inhibitors provided the proof that indeed complement activation contributes to disease activity and tissue damage in human AAV.Immunopathology of vascular and renal diseases and of organ and celltransplantationIP1

Histopathological classification of antineutrophil cytoplasmic antibody-associated glomerulonephritis: an update

IP1AImmunopathology of vascular and renal diseases and of organ and celltransplantatio