Kidney regeneration and repair after transplantation

PURPOSE OF REVIEW: To briefly show which are the mechanisms and cell types involved in kidney regeneration and describe some of the therapies currently under study in regenerative medicine for kidney transplantation. RECENT FINDINGS: The kidney contains cell progenitors that under specific circumstances have the ability to regenerate specific structures. Apart from the knowledge gained in the self-regenerative properties of the kidney, new concepts in regenerative medicine such as organ engineering and the use of mesenchymal stem cell-based therapies are currently the focus of attention in the field. SUMMARY: Overall, kidney regeneration is a reality and the knowledge on how to control it will be one of the main scopes in the present and future

Datasets for the validation of the "in vivo" siRNA-silencing of CD40 and for the detection of new markers of atherosclerosis progression in ApoE-deficient mice

AbstractData presented in this Data in Brief article correspond to the article "in vivo" silencing of CD40 reduces progression of experimental atherogenesis through a NFκB/miR-125b axis and reveals new potential mediators in the pathogenesis of atherosclerosis" (M. Hueso, L. De Ramon, E. Navarro, E. Ripoll, J.M. Cruzado, J.M. Grinyo, J. Torras, 2016) [1]. Here, we describe the validation of the silencing of CD40 expression with a specific siRNA in ApoE−/− mouse aortas, and its systemic effects on splenic lymphocytic subpopulations as well as on the infiltration of aortic intima by F4/80+, galectin-3+ macrophages or by NF-κB+ cells. We also show the output of a Gene Ontology and TLDA analysis which allowed the detection of potential mediators of atherosclerosis progression. We provide the scientific community with a set of genes whose expression is increased during atherosclerosis progression but downregulated upon CD40 silencing

Decreased kidney graft survival in low immunological risk patients showing inflammation in normal protocol biopsies

Introduction The pros and cons for implementing protocol biopsies (PB) after kidney transplantation are still a matter of debate. We aimed to address the frequency of pathological findings in PB, to analyze their impact on long-term graft survival (GS) and to analyze the risk factors predicting an abnormal histology. Methods We analyzed 946 kidney PB obtained at a median time of 6.5 (±2.9) months after transplantation. Statistics included comparison between groups, Kaplan-Meier and multinomial logistic regression analysis. Results and Discussion PB diagnosis were: 53.4% normal; 46% IFTA; 12.3% borderline and 4.9% had subclinical acute rejection (SCAR). Inflammation had the strongest negative impact on GS. Therefore we split the cases into: "normal without inflammation", "normal with inflammation", "IFTA without inflammation", "IFTA with inflammation" and "rejection" (including SCAR and borderline). 15-year GS in PB diagnosed normal with inflammation was significantly decreased in a similar fashion as in rejection cases. Among normal biopsies, inflammation increased significantly the risk of 15-y graft loss (P = 0.01). Variables that predicted an abnormal biopsy were proteinuria, previous AR and DR-mismatch. Conclusion We conclude that inflammation in normal PB is associated with a significantly lower 15-y GS, comparable to rejection or IFTA with inflammation

Macrophage overexpressing NGAL ameliorated kidney fibrosis in the UUO mice model

Background/Aims: Alternatively activated macrophages (AAM) have regenerative and anti-inflammatory characteristics. Here, we sought to evaluate whether AAM cell therapy reduces renal inflammation and fibrosis in the unilateral ureteral obstruction (UUO) mice model. Methods: We stabilized macrophages by adenoviral vector NGAL (Neutrophil gelatinase-associated lipocalin-2) and infused them into UUO mice. To ascertain whether macrophages were capable of reaching the obstructed kidney, macrophages were stained and detected by in vivo cell tracking. Results: We demonstrated that some infused macrophages reached the obstructed kidney and that infusion of macrophages overexpressing NGAL was associated with reduced kidney interstitial fibrosis and inflammation. This therapeutic effect was mainly associated with the phenotype and function preservation of the transferred macrophages isolated from the obstructed kidney Conclusions: Macrophage plasticity is a major hurdle for achieving macrophage therapy success in chronic nephropathies and could be overcome by transferring lipocalin-2

CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms

Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100%intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitialCD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders

Regression of advanced diabetic nephropathy by hepatocyte growth factor gene therapy in rats

Diabetic nephropathy is the main cause of end-stage renal disease requiring dialysis in developed countries. In this study, we demonstrated the therapeutic effect of hepatocyte growth factor (HGF) on advanced rather than early diabetic nephropathy using a rat model of streptozotocin-induced diabetes. Early diabetic nephropathy (16 weeks after induction of diabetes) was characterized by albuminuria, hyperfiltration, and glomerular hypertrophy, whereas advanced diabetic nephropathy showed prominent transforming growth factor (TGF)-beta1 upregulation, mesangial expansion, and glomerulosclerosis. An SP1017-formulated human HGF (hHGF) plasmid was administered by intramuscular injection combined with electroporation over a 30-day follow-up in rats with early and advanced diabetic nephropathy. hHGF gene therapy upregulated endogenous rat HGF in the diabetic kidney (rat HGF by RT-PCR was threefold higher than in diabetic rats without therapy). hHGF gene therapy did not improve functional or morphologic abnormalities in early diabetic nephropathy. hHGF gene therapy reduced albuminuria and induced strong regression of mesangial expansion and glomerulosclerosis in advanced diabetic nephropathy. These findings were associated with suppression of renal TGF-beta1 and mesangial connective tissue growth factor (CTGF) upregulation, inhibition of renal tissue inhibitor of metalloproteinase (TIMP)-1 expression, and reduction of renal interstitial myofibroblasts. In conclusion, our results suggest that hHGF gene therapy may be considered as an innovative therapeutic strategy to treat advanced diabetic nephropathy

Artificial intelligence for the artificial kidney: Pointers to the future of a personalized hemodialysis therapy

Current dialysis devices are not able to react when unexpected changes occur during dialysis treatment, or to learn about experience for therapy personalization. Furthermore, great efforts are dedicated to develop miniaturized artificial kidneys to achieve a continuous and personalized dialysis therapy, in order to improve patient’s quality of life. These innovative dialysis devices will require a real-time monitoring of equipment alarms, dialysis parameters and patient-related data to ensure patient safety and to allow instantaneous changes of the dialysis prescription for assessment of their adequacy. The analysis and evaluation of the resulting large-scale data sets enters the realm of Big Data and will require real-time predictive models. These may come from the fields of Machine Learning and Computational Intelligence, both included in Artificial Intelligence, a branch of engineering involved with the creation of devices that simulate intelligent behavior. The incorporation of Artificial Intelligence should provide a fully new approach to data analysis, enabling future advances in personalized dialysis therapies. With the purpose to learn about the present and potential future impact on medicine from experts in Artificial Intelligence and Machine Learning, a scientific meeting was organized in the Hospital of Bellvitge (Barcelona, Spain). As an outcome of that meeting, the aim of this review is to investigate Artificial Intelligence experiences on dialysis, with a focus on potential barriers, challenges and prospects for future applications of these technologies.Postprint (author's final draft

JAK3-STAT pathway blocking benefits in experimental lupus nephritis

Es va publicar un erratum de l'article a: Arthritis Research & Therapy, 2016, vol. 18 , num. 1, p. 152Background: Lupus nephritis (LN) is a complex chronic autoimmune disease of unknown etiology characterized by loss of tolerance against several self-antigens. Cytokines are known to be central players in LN pathogenesis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is one important pathway that mediates signal transduction of several cytokines. In this study, we examined the pathogenic role of this pathway and how CP-690,550 treatment influences LN outcome. Methods: Six-month-old NZB/NZWF1 mice were divided into two different treatment groups: (1) control animals given vehicle treatment, cyclophosphamide, and mycophenolate mofetil treatment as positive controls of the therapy and (2) mice treated with CP-690,550, a JAK3 inhibitor. Mice were treated for 12 weeks. We evaluated renal function, anti-double-stranded DNA (anti-dsDNA) antibody, renal histology changes, kidney complement and immunoglobulin G (IgG) deposits, T-cell and macrophage infiltration, kidney inflammatory gene expression, and circulating cytokine changes. Results: CP-690,550 treatment significantly reduced proteinuria and improved renal function and histological lesions of the kidney. Compared with vehicle-treated animals, those undergoing CP-690,550 treatment showed significantly diminished anti-dsDNA antibody and complement component C3 and IgG deposition in glomeruli. We also observed a significant reduction of T-cell and macrophage infiltration. Kidney gene expression revealed a reduction in inflammatory cytokines and complement and related macrophage-attracting genes. Circulating inflammatory cytokines were also reduced with treatment. Conclusions: On the basis of our results, we conclude that the JAK-STAT pathway is implicated in the progression of renal inflammation in NZB/WF1 mice and that targeting JAK3 with CP-690,550 is effective in slowing down the course of experimental LN. Thus, CP-690,550 could become a new therapeutic tool in LN and other autoimmune diseases

Pre-transplant donor-specific T-cell alloreactivity is strongly associated with early acute cellular rejection in kidney transplant recipients not receiving T-cell depleting induction therapy

Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rap- idly recognize alloantigens and activate the effector immune response, which leads to allo- graft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by denovo activated na ï ve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell re- sponses were evaluated using the IFN- γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cel- lular sensitization and its predominant time-frame impact on allograft outcome, and was fur- ther validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year inci- dence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular re- jection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosup- pression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensiti- zation before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy