Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1β/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1β/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1β–induced podocyte injury, potentially identifying new therapeutic targets.
Although spontaneous kidney transplant acceptance/tolerance occurs in mice and occasionally in humans, mechanisms remain unclear. Herein we test the hypothesis that EPO, a hormone predominantly produced by the adult kidney, has immunomodulating properties that are required for spontaneous kidney graft acceptance. , in a manner dependent on the EPO receptor and CD131 on antigen-presenting cells, EPO induced the secretion of active TGF by antigen-presenting cells, which in turn converted naïve CD4 T cells into functional Foxp3 regulatory T cells (Treg). In murine transplant models, pharmacologic downregulation of kidney-derived EPO prevented spontaneous Treg generation. In a controlled, prospective cohort clinical study, EPO administration at doses used to correct anemia augmented the frequency of peripheral CD4CD25CD127 T cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferation tyrosine phosphatase SHP-1-dependent uncoupling of IL-2R signaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2R signaling and maintaining constitutively quenched IL-2R signaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGF mRNA and abrogated kidney allograft acceptance. Together, our findings delineate the protolerogenic properties of EPO in inhibiting conventional T cells while simultaneously promoting Treg induction, and suggest that manipulating the EPO/EPO receptor signaling axis could be exploited to prevent and/or treat T cell-mediated pathologies, including transplant rejection.
With the aim to explore innovative tools for organ preservation, especially in marginal organs, we hereby describe a clinical trial of ex-vivo hypothermic oxygenated perfusion (HOPE) in the field of liver (Lt) and kidney transplantation (Kt) from extended criteria Donors (ecD) after brain death. A matched-case analysis of donor and recipient variables was developed: 10 HOPE-ECD livers and kidneys (HOPE-L and HOPE-K) were matched 1:3 with livers and kidneys preserved with static cold storage (ScS-L and ScS-K). Hope and ScS groups resulted with similar basal characteristics, both for recipients and donors. Cumulative liver and kidney graft dysfunction were 10% (HOPE L-K) vs. 31.7%, in ScS group (p = 0.05). Primary non-function was 3.3% for SCS-L vs. 0% for HOPE-L. No primary nonfunction was reported in HOPE-K and SCS-K. Median peak aspartate aminotransferase within 7-days post-LT was significantly higher in SCS-L when compared to HOPE-L (637 vs.344 U/L, p = 0.007). Graft survival at 1-year post-transplant was 93.3% for SCS-L vs. 100% of HOPE-L and 90% for SCS-K vs. 100% of HOPE-K. Clinical outcomes support our hypothesis of machine perfusion being a safe and effective system to reduce ischemic preservation injuries in Kt and in Lt.
Core tip: Mesenchymal stem cells (MSCs) may have an important therapeutic potential in acute kidney injury management. A body of evidence has demonstrated that MSCs act through a paracrine/endocrine secretion of soluble factors and microvesicles. We summarize preclinical studies and ongoing clinical trials that evaluate the role of MSCs in restoring kidney function. We critically explain the current concerns about the use of MSCs and microvesicles that limit their applications in clinical trials. Then, we propose the future directions that could lead to extend MSCs use in humans.Bianchi F, Sala E, Donadei C, Capelli I, La Manna G. reperfusion injury (IRI) is a major cause of AKI, and it is characterized by acute tubular injury and rapid renal dysfunction, generally caused by ischemic or toxic insults [1][2][3] . The kidney undergoing IRI presents an extensive and complex inflammatory/oxidative stress response, that may result in fibroblast proliferation and excessive deposition of extracellular matrix and has been recognized as a major contributor to end-stage kidney disease [4] . Although many efforts have been made to deal with this problem, such as new drugs and modern dialysis techniques, innovative interventions beyond supportive therapy are not available yet [5] ; therefore, a potent therapeutic intervention for ischemia AKI is imperative. In recent years, a promising approach to manage renal IRI is the use of mesenchymal stem cells (MSCs). Their use in treating different kind of diseases as immunological, vascular, cardiac and renal diseases has been extensively explored [6,7] . MSCs can be isolated from various sources, such as bone marrow or adipose tissue, but other organs have their own niches of MSC-like cells, such as the kidney. Besides their broad distribution in the body and an easy isolation, the interest in MSC was originally raised by their capacity to differentiate into other cell types, suggesting that they could be a source of healthy cells to repair/replace injured tissue [8] .There is evidence from both in vitro studies and animal models of AKI that MSCs can promote regenerative responses in the injured kidney, leading to tissue repair and improvement of renal function [9][10][11] . These beneficial effects have been initially ascribed to the trans-differentiation of MSCs into organ specific cells. However, at least in the kidney, this is a very rare event and the kidneyprotective effects of MSCs have been attributed mainly to paracrine mechanisms [12] . This review will focus on the application of cell therapy in AKI, and it will summarize the recent preclinical and clinical results about the use of MSCs in renal IRI (Figure 1). THERAPEUTIC POTENTIAL OF MESENCHYMAL STEM CELLSMesenchymal stem cells are undifferentiated adult stem cells derived from mesodermal embryonic layer that can differentiate into a broad range of different mesenchymal tissues, including cartilage, bone, muscle, stroma, fat, tendon, and other connective tissues [13] . These cells have been originally isolated f...
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Noninvasive diagnosis of kidney allograft inflammation in transplant recipients with stable graft function (subclinical rejection) could permit more effective therapy and prevent later development of de novo anti-donor HLA antibodies and/or graft dysfunction. Here we tested whether quantifying post-transplant donor-specific alloreactive T cells by IFN-γ ELISPOT assay noninvasively detects subclinical T-cell mediated rejection and/or predicts development of anti-donor HLA antibodies. Using an initial cross-sectional cohort of 60 kidney transplant patients with six-month surveillance biopsies, we found that negative ELISPOT assays accurately ruled out the presence of subclinical T cell mediated rejection. These results were validated using a distinct prospective cohort of 101 patients where donor specific IFN-γ ELISPOT results at both three- and six-months post-transplant significantly differentiated patients with subclinical T cell mediated rejection at six-month, independent of other clinical variables (odds ratio 0.072, 95% confidence interval 0.008-0.653). The post-transplant donor-specific IFN-γ ELISPOT results independently associated with subsequent development of significant anti-donor HLA antibodies (0.085, 0.008-0.862) and with significantly worse two-year function (estimated glomerular filtration rate) compared to patients with a negative test. Thus, post-transplant immune monitoring by donor-specific IFN-γ ELISPOT can assess risk for developing subclinical T cell mediated rejection and anti-donor HLA antibodies, potentially limiting the need for surveillance biopsies. Our study provides a guide for individualizing immunosuppression to improve post-transplant outcomes.
Introduction: Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited. Methods: We analyzed 68 different Band T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non-immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the ex vivo production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq). Results: After adjusting for multiple testing, plasma cells and regulatory B cells (B REG) were significantly higher (P < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels (P ¼ 0.042) and were associated with disease activity. Ex vivo-expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies (P < 0.001) in MN patients. Tumor necrosis factor-a (TNF-a) was the only significantly increased cytokine in MN patients (P < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire. Conclusion: This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.
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