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BACKGROUND AND AIMS The long-term use of peritoneal dialysis is limited due to changes of the peritoneum. Those can be attributed to both, uremia and the effect of the peritoneal dialysis solution on the peritoneum. Although the effect of peritoneal dialysis on the peritoneal histology has been investigated for more than 40 years, most studies fail to report intraindividual changes of the peritoneum but report cross-sectional data from different patients at different timepoints of their dialysis career. The aim of our study was to investigate the intraindividual changes over time associated with peritoneal dialysis as part of the GRiP (German Registry in PD). METHOD Among patients documented by the GRiP study group 37 patients were identified in which two peritoneal samples were collected at least 2 months apart. The median [IQR] patient age was 63.6 [52.8–70.5] years with a median [IQR] BMI of 27.8 [22.4–31.8] kg/m2. The time between the two biopsies was 20.0 [7.2–27.6] months. Removal or change of the PD catheter was due to infection in 20 of the 37 patients (54%). Samples from the parietal peritoneum were collected at prespecified locations. Routine histology using hematoxylin–eosin was performed. The thickness of the submesothelial compacta was analysed with AxioVision SE64 Rel.4.9. software. GraphPad Prism 9 (San Diego, CA, USA) was used for statistical analysis. Comparison between histological parameters at implantation and explantation was done by using a paired t-test using a significance level of P RESULTS Comparing the intraindividual thickness of the compacta at the time of implantation and explantation of the peritoneal dialysis catheter we saw a significant increase of the median [IQR] ‘minimum thickness’ from 50.0 [20.5–89.5] µm to 130.0 [42.5–195.5] µm, the ‘average thickness’ from 102.0 [77.75–162.5.5] µm to 181.5 [123.3–265.5] as well as the ‘maximum thickness’ from 148.0 [107.0–208.0] µm to 240 [182.0–381.0] (Fig. 1). Further, the degree of peritoneal fibrosis increased significantly (Fig. 2). CONCLUSION The longitudinal, intraindividual assessment of peritoneal biopsies in a sizeable cohort of patients confirms previous cross-sectional data showing an increase in the thickness of the sumesothelial compacta over time.

BackgroundThe small number of organ donors forces transplant centres to consider potentially suboptimal kidneys for transplantation. Eurotransplant established an algorithm for rescue allocation (RA) of kidneys repeatedly declined or not allocated within 5 h after procurement. Data on the outcomes and benefits of RA are scarce to date.MethodsWe conducted a retrospective 8-year analysis of transplant outcomes of RA offers based on our in-house criteria catalogue for acceptance and decline of organs and potential recipients.ResultsRA donors and recipients were both older compared with standard allocation (SA). RA donors more frequently had a history of hypertension, diabetes or fulfilled expanded criteria donor key parameters. RA recipients had poorer human leucocyte antigen (HLA) matches and longer cold ischaemia times (CITs). However, waiting time was shorter and delayed graft function, primary non-function and biopsy-proven rejections were comparable to SA. Five-year graft and patient survival after RA were similar to SA. In multivariate models accounting for confounding factors, graft survival and mortality after RA and SA were comparable as well.ConclusionsFacing relevant comorbidities and rapid deterioration with the risk of being removed from the waiting list, kidney transplantation after RA was identified to allow for earlier transplantation with excellent outcome. Data from this survey propose not to reject categorically organs from multimorbid donors with older age and a history of hypertension or diabetes to aim for the best possible HLA matching and to carefully calculate overall expected CIT.

Background and Aims Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier is normally size selective and impermeable for antibodies. Method Kidney biopsies from patients with MGN, cell culture, zebrafish and mice models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the glomerular filtration barrier. Results We found that endothelial cell-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in patients with anti-phospholipase A2 receptor antibody positive (PLA2R-ab+) iMGN and regulate glomerular NPNT expression (Fig. 1). Overexpression of miR-378a-3p and miR-192-5p as well as morpholino mediated npnt knockdown in zebrafish induced edema, proteinuria, loss of podocyte markers and podocyte effacement. The most prominent phenotype however were structural changes of the glomerular basement membrane (GBM) with increased lucidity, slicing and lamellation especially of the lamina rara interna (Fig. 2, Fig. 3). The phenotype was comparable to ultrastructural findings seen in iMGN. IgG sized nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte specific Npnt knockout mice (Fig. 4). Conclusion Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by podocyte and glomerular endothelial cell derived miRs. We hypothesize that loss of NPNT in the GBM is part of the pathophysiology of iMGN and enables subepithelial immune complex deposition in iMGN.

Background and Aims Crescent formation is a severe glomerular damage in the pathogenesis of different kidney diseases. However the exact pathomechanism of crescent formation is unclear up to now. In human kidney biopsies we observed high dipeptidyl peptidase 4 (DPP4) expression in early crescent formation. Therefore, we investigated the potential involvement of DPP4 in the pathogenesis of crescentic anti-GBM nephritis in a rat model using a DPP4- inhibitor independent of his present use in the treatment of type 2 diabetes. Method Anti-GBM nephritis was induced in Wistar Kyoto rats for investigation of short and long term effects of the DPP4- inhibitor linagliptin treatment (3 mg/kg bw). In the short term experiment (endpoint 2 weeks) linagliptin treatment was started either with model induction or one week later. In the long term experiment (endpoint 8 weeks) linagliptin treatment was started either on day 0 or on week 4. In both experiments we included an untreated healthy and anti-GBM nephritic group. All groups consisted of 11 animals. Kidney function was monitored on weeks 1, 2, 3, 5 and 8. Kidney tissue was used to determine DPP4 expression and activity, morphologic changes and mRNA expression. Results Similarly to our observation in human kidney biopsies the in situ DPP4 activity and DPP4 expression were both increased in nephritic glomeruli especially within the crescents. Linagliptin could almost completely inhibit all renal DPP4 activity without any effect on DPP4 expression. Short-term treatment had no significant effect on crescent formation. However, long-term preventive treatment resulted in reduced number of crescents (51±3% vs 65±3%), glomerulosclerosis (score 1.2±0.07 vs 1.6±0.1), tubulointerstitial injury (score 1.2±0.1 vs 1.8±0.2), renal fibrosis (score 1.3±0.13 vs 1.9±0.14) and proteinuria (265±29 vs 363±22 mg/24h) compared to untreated nephritic rats. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease at week 8, but also significantly reduced renal fibrosis (score 1.4±0.13 vs. 1.9±0.14) and crescent formation (52±4% vs. 65±3%) compared with vehicle. About 20% of all glomeruli showed Pax8+ parietal epithelial cells (PECs) on the tuft in short term treatment, being significantly reduced by therapeutic linagliptin treatment on day 14. In the long term experiment the number of Pax8+ PECs on glomerular tuft was reduced by more than 50% in both treatment groups and confirmed by quantitative mRNA analysis using isolated glomeruli. Despite the number of Pax8-positive cells on glomerular tuft was reduced by linagliptin therapy, a subpopulation of PECs positive for the transcription factor SOX9 was significantly increased on glomerular tuft compared to healthy and non-treated rats on day 14. Conclusion DPP4- inhibition with linagliptin reduced Pax8+ cells on glomerular tuft, indicating accelerated resolution of formed crescents and improvement in renal injury. This DDP4 effect might be mediated by differential regulation of a subpopulation of PECs expressing the transcription factor SOX9.

Background Progressive diabetic nephropathy (DN) is characterized by tubulointerstitial fibrosis that is caused by accumulation of extracellular matrix. Induced by several factors, matrix-producing myofibroblasts may to some extent originate from tubular cells by epithelial-to-mesenchymal transition (EMT). Although previous data document that activation of hypoxia-inducible factor (HIF) signalling can be renoprotective in acute kidney disease, this issue remains controversial in chronic kidney injury. Here, we studied whether DN and EMT-like changes are ameliorated in a mouse model of type 2 diabetes mellitus with increased stability and activity of the HIF. Methods We used db/db mice that were crossed with transgenic mice expressing reduced levels of mitogen-activated protein kinase organizer 1 (MORG1), a scaffold protein interacting with prolyl hydroxylase domain 3 (PHD3), because of deletion of one MORG1 allele. Results We found significantly reduced nephropathy in diabetic MORG1+/- heterozygous mice compared with the diabetic wild-types (db/dbXMORG1+/+). Furthermore, we demonstrated that EMT-like changes in the tubulointerstitium of diabetic wild-type MORG1+/+ mice are present, whereas diabetic mice with reduced expression of MORG1 showed significantly fewer EMT-like changes. Conclusions These findings reveal that a deletion of one MORG1 allele inhibits the development of DN in db/db mice. The data suggest that the diminished interstitial fibrosis in these mice is a likely consequence of suppressed EMT-like changes.