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The recurrence of primary focal segmental glomerulosclerosis (FSGS) after kidney transplantation is associated with a high graft loss rate with standard treatments based on plasmapheresis with/without rituximab. We present 2 consecutive cases of nongenetic early severe recurrent FSGS refractory to rituximab and anti-interleukin 1 treatment and with a partial response to plasmapheresis. Case 1 was a 22-year-old man who was rescue-treated for recurrence 36 weeks after transplantation with obinutuzumab (1000 mg/1.73 m 2 , 1 dose) and daratumumab (18 mg/kg each dose, 8 doses), resulting in plasmapheresis discontinuation and a drop of proteinuria from 29 to 2.3 g/d. Proteinuria increased with circulating CD38 + plasma cells and responded to an additional daratumumab dose. Currently, the proteinuria is 1.8 g/d, 14.5 months after discontinuing plasmapheresis and starting obinutuzumab and daratumumab therapy. Case 2 was a 15-year-old girl who was plasmapheresis dependent with 2 g/d proteinuria 82 weeks after transplantation, with a Tesio catheter in the right jugular vein as the only possible vascular access. After treatment with obinutuzumab and daratumumab (1 dose each), she achieved stable complete remission (0.3 g/d proteinuria) with persistent plasmapheresis discontinuation. These cases suggest the potential of combining obinutuzumab with daratumumab for the treatment of recurrent FSGS., Competing Interests: Declaration of competing interests The authors of this manuscript have no conflicts of interest to disclose as described in the American Journal of Transplantation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Based on the current projection of the general population and the combined increase in end-stage kidney disease with age, the number of elderly donors and recipients is increasing, raising crucial questions about how to minimize the discard rate of organs from elderly donors and improve graft and patient outcomes. In 2002, extended criteria donors were the focus of a meeting in Crystal City (VA, USA), with a goal of maximizing the use of organs from deceased donors. Since then, extended criteria donors have progressively contributed to a large number of transplanted grafts worldwide, posing specific issues for allocation systems, recipient management, and therapeutic approaches. This review analyzes what we have learned in the last 20 years about extended criteria donor utilization, the promising innovations in immunosuppressive management, and the molecular pathways involved in the aging process, which constitute potential targets for novel therapies., (© 2024. The Author(s).)

A meeting entitled Renal BIopsy for Kidney Transplantation Therapy (ReBIrth) took place on May 31 st , 2022 in Bologna, Italy. The meeting drew together nephrologists, surgeons, and pathologists and recognized as experts in the field of kidney transplantation in Italy. In this paper, we present our experience working with kidney transplants in the current era of immunosuppression therapy. The primary aim is to report the histopathological characteristics of failed kidney allografts after a consensus of experts reviewed the cases on a wholeslide imaging digital platform. Regardless of the cases discussed, digital pathology was reliable in identifying all the morphological and immunohistochemical features required to improve the correct use of immunosuppressive therapy to prevent graft failure and optimize patient management., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: In kidney transplant patients, polyomavirus-associated nephropathy (PVAN) represents a serious complication; the key factor for the development of PVAN is immunosuppression level and modulation of anti-rejection treatment represents the first line of intervention. Allograft biopsy and histology remain the criterion standard for diagnosing PVAN., Methods: All consecutive renal biopsies with the diagnosis of PVAN carried out at the University Hospital City of Health and Science of Turin over a five-years period were studied. Renal allograft biopsy was performed due to renal function alterations associated to medium-high polyomavirus BK (BKV)-DNA levels on plasma specimen., Results: A total of 21 patients underwent a first biopsy to diagnose a possible BKV nephropathy, in 18, a second biopsy was made, in eight, a third biopsy, and finally, three underwent the fourth renal biopsy; following the results of each biopsies, immunosuppressant agents dosages were modified in order to reduce the effect of PVAN., Conclusions: In this study, the clinical and histological features of 21 kidney transplant recipients with BKV reactivation and development of PVAN are described. To date, the only treatment for PVAN consists in the reduction of immunosuppressive agents, constantly monitoring viral load.

Introduction: Chronic active antibody-mediated rejection (cAMR) is a major determinant of late allograft failure. Rituximab/immunoglobulins (IVIg) + plasma exchange (PLEX) showed controversial results in cAMR treatment. Tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, has been recently used as rescue therapy in patients non-responsive to rituximab/IVIg/PLEX with favorable outcomes. Whether TCZ acts "per se" or requires a priming effect from previous treatments is currently unknown., Methods: Fifteen patients with cAMR were treated with TCZ as a first-line therapy and followed for a median time of 20.7 months., Results: Despite the majority of patients experiencing advanced transplant glomerulopathy (TG) at diagnosis (60% with cg3), glomerular filtration rate and proteinuria stabilized during the follow-up, with a significant reduction in donor-specific antibodies. Protocol biopsies after 6 months demonstrated significant amelioration of microvascular inflammation and no TG, C4d deposition, or IF/TA progression. Gene-expression and immunofluorescence analysis showed upregulation of three genes (TJP-1, AKR1C3, and CASK) involved in podocyte, mesangial, and tubular restoration., Conclusion: Tocilizumab adopted as a first-line approach in cAMR was associated with early serological and histological improvements and functional stabilization even in advanced TG, suggesting a role for the use of TCZ alone with the avoidance of unnecessary previous immunosuppressants., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Transplant glomerulopathy (TG) is an important cause of late graft loss. The role of angiotensin type 1-receptor antibodies (AT 1 R-Ab) in TG is not known., Methods: All the TG cases (N = 137) between January 2007 and December 2014 (N = 1410) were analyzed. Donor-specific anti-HLA antibodies (DSA) at the time of biopsy and AT 1 R-Ab IgG (positive, >17 UI/mL; "at risk," 10-17 UI/mL; negative, <10 UI/mL) in pre-transplant sera (PT-Ab) and at biopsy time (BT-Ab) were studied., Results: AT 1 R-PT-Ab + and AT 1 R-BT-Ab + patients were 16.5% (51.5% "at risk") and 11.5% (27.4% "at risk"), respectively. Clinical correlations were found between AT 1 R-Ab and HCV infection, number of transplants, and age. Considering Banff scores, ptc was higher in DSA + patients vs AT 1 R-PT-Ab + (P = 0.002) or AT 1 R-BT-Ab + (P = 0.001) without differences in g and chronicity score (ci + ct); cg showed lower scores in DSA + patients vs AT 1 R-BT-Ab + (P = 0.001). Graft survival was not influenced by the presence of AT 1 R-Ab, AT1-R-Ab titer or MFI, but we observed a longer graft survival in patients with both AT 1 R-BT-Ab + or "at risk" and DSA + vs patients positive only for DSA (P = 0.02), for AT 1 R-BT-Ab (P = 0.019) or AT 1 R-BT-Ab "at risk" (P = 0.039)., Conclusion: AT 1 R-Ab showed no independent prognostic role in TG in this pilot analysis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis; the reported recurrence rate of IgAN after renal transplantation is as high as 13%-50%. The impact of immunosuppressive therapy and steroid withdrawal on the risk of recurrence of IgAN is still under debate. We performed a retrospective single-center study, selecting 123 kidney transplants (rtx) in 120 patients, between January 1995 and December 2012, with IgAN on the native kidney. In 51 of 123 transplants, at least one post-transplantation biopsy for clinical indication was performed; in 28 of 51 transplants, IgAN recurrence (IgANr) was demonstrated. This group (G1; N = 28) was compared with a group without IgANr (G2; N = 23). In our study, clinically evident IgANr rate was 54.9% (28/51) on biopsied patients. At discharge, the use of the immunosuppressant drugs (tacrolimus, cyclosporine A, mycophenolate mofetil, azathioprine, mTor inhibitors) was not associated with an increased risk of IgANr (P = NS). At discharge, all patients were steroid treated. Neither the use of tacrolimus, mycophenolate mofetil, nor mTor inhibitors (mTori) at biopsy time were associated with IgANr. However, IgANr was significantly higher in patients who experienced steroid withdrawal at any post-transplantation time (OR 7.7 P = .03). The median time to recurrence after steroid withdrawal was 59 months (min 4.18, max 113.2)., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Increased acute rejection risk in rescue protocols with Belatacept may limit its use particularly in medically complex patients where preexisting increased risk of rejection couples with CNI toxicity. Methods: Retrospective analysis was performed in 19 KTs shifted to a Belatacept-based immunosuppression with low-dose Tacrolimus (2–3 ng/mL) after evidence of allograft disfunction, including patients with primary non-function (PNF), chronic-active antibody-mediated rejection (cAMR), history of previous KTs and/or other concomitant transplants (liver, pancreas). Evaluation of CD28+ CD4+ effector memory T cell (TEM) before conversion was performed in 10/19. Results: Kidney function significantly improved (median eGFR 16.5 ml/min/1.73m2 before vs 25 ml/min after; p = 0.001) at a median time after conversion of 12.5 months (9.1–17.8). Overall graft and patient survival were 89.5% and 100% respectively. Definitive weaning from dialysis in 5/5 KTs with PNF was observed, whereas 7/8 patients lost their graft within first year in a control group. eGFR significantly ameliorated in re-trasplants (p = 0.001) and stabilized in KTs with other organ transplants or cAMR. No acute rejection episodes occurred, despite the significant risk suggested by high frequency of CD28+ CD4+ TEM in most patients. Opportunistic infections were limited and most common in early vs late-converted. Conclusions: Rescue association of Belatacept with low-dose Tacrolimus in medically complex KTs is a feasible option that allows prevention of acute rejection and amelioration of graft function. [ABSTRACT FROM AUTHOR]

Background. Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. Methods. RNA extracted from archival formalin-fixed, paraffinembedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The resultswere validated in an independent set of kidney biopsies. Results. We identified 616 and 243 differentially expressed genes with a fold change =1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens. Conclusions. These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR. [ABSTRACT FROM AUTHOR]

Caveolin-1 overexpression has previously been reported as a marker of endothelial injury in kidney chronic antibody-mediated rejection (c-ABMR), but conclusive evidence supporting its use for daily diagnostic practice is missing. This study aims to evaluate if Caveolin-1 can be considered an immunohistochemical surrogate marker of c-ABMR. Caveolin-1 expression was analyzed in a selected series of 22 c-ABMR samples and 11 controls. Caveolin-1 immunohistochemistry proved positive in peritubular and glomerular capillaries of c-ABMR specimens, irrespective of C4d status whereas all controls were negative. Multiplex gene expression profiling in c-ABMR cases confirmed Caveolin-1 overexpression and identified additional genes (n = 220) and pathways, including MHC Class II antigen presentation and Type II interferon signaling. No differences in terms of gene expression (including Caveolin-1 gene) were observed according to C4d status. Conversely, immune cell signatures showed a NK-cell prevalence in C4d-negative samples compared with a B-cell predominance in C4d-positive cases, a finding confirmed by immunohistochemical assessment. Finally, differentially expressed genes were observed between c-ABMR and controls in pathways associated with Caveolin-1 functions (angiogenesis, cell metabolism and cell–ECM interaction). Based on our findings, Caveolin-1 resulted as a key player in c-ABMR, supporting its role as a marker of this condition irrespective of C4d status. [ABSTRACT FROM AUTHOR]

In kidney transplantations, the evaluation of the vascular structures and stromal areas is crucial for determining kidney acceptance, which is currently based on the pathologist's visual evaluation. In this context, an accurate assessment of the vascular and stromal injury is fundamental to assessing the nephron status. In the present paper, the authors present a fully automated algorithm, called RENFAST (Rapid EvaluatioN of Fibrosis And vesselS Thickness), for the segmentation of kidney blood vessels and fibrosis in histopathological images. The proposed method employs a novel strategy based on deep learning to accurately segment blood vessels, while interstitial fibrosis is assessed using an adaptive stain separation method. The RENFAST algorithm is developed and tested on 350 periodic acid–Schiff (PAS) images for blood vessel segmentation and on 300 Massone's trichrome (TRIC) stained images for the detection of renal fibrosis. In the TEST set, the algorithm exhibits excellent segmentation performance in both blood vessels (accuracy: 0.8936) and fibrosis (accuracy: 0.9227) and outperforms all the compared methods. To the best of our knowledge, the RENFAST algorithm is the first fully automated method capable of detecting both blood vessels and fibrosis in digital histological images. Being very fast (average computational time 2.91 s), this algorithm paves the way for automated, quantitative, and real-time kidney graft assessments. [ABSTRACT FROM AUTHOR]

• Architecture of glomeruli and tubules play a crucial role during transplantations. • Histological assessment is subjected to inter- and intra-observer variability. • A new deep learning method is presented for kidney histopathological images. • A Dice of 95.29 % and 91.74 % was achieved for glomeruli and tubules, respectively. • Our approach could improve the diagnostic workflow in kidney transplantation. In kidney transplantations, pathologists evaluate the architecture of both glomeruli, interstitium and tubules to assess the nephron status. An accurate assessment of glomerulosclerosis and tubular atrophy is crucial for determining kidney acceptance, which is currently based on the pathologists' histological evaluations on renal biopsies in addition to clinical data. In this work, we present an automated algorithm, called RENTAG (Robust EvaluatioN of Tubular Atrophy & Glomerulosclerosis), for the segmentation and classification of glomerular and tubular structures in histopathological images. The proposed novel strategy combines the accuracy of a level-set with the semantic segmentation of convolutional neural networks to detect the glomeruli and tubules contours. In the TEST set, our method exhibited excellent performance in both glomeruli (dice score: 0.9529) and tubule (dice score: 0.9174) detection and outperformed all the compared methods. To the best of our knowledge, the RENTAG algorithm is the first fully automated method capable of quantifying glomerulosclerosis and tubular atrophy in digital histological images. The developed software can be employed for the analysis of pre-transplantation biopsies to support the pathologists' diagnostic activity. [ABSTRACT FROM AUTHOR]