Search

All chronic and treatment-resistant acute rejections are "difficult-to-treat" and lead to progressive loss of graft function in kidney transplant recipients (KTR), as no effective treatment exists for such rejections to date. We review our experience with a novel strategy to treat such rejections by adding everolimus as a "rescue" to conventional triple maintenance therapy with prednisolone, mycophenolate mofetil and calcineurin inhibitor. We retrospectively analysed data in 28 KTR who received everolimus-based quadruple therapy at our institution for biopsy-proven chronic active T cell-mediated or antibody-mediated rejection (n = 19) or treatment-resistant acute rejections (n = 9) between 2011–2017. The primary outcome was 5-year death-censored graft survival. Main secondary outcomes were response to treatment defined by stable or improved graft function, 5-year patient survival and discontinuation rate of treatment. The Kaplan–Meier estimate for 5-year death-censored graft survival was 79% in all patients, 90% for patients with chronic active T cell-mediated rejections, 78% for chronic active antibody-mediated rejection and 67% for acute rejections. Response to treatment was achieved in 43% and 5-year patient survival was 94%. Treatment was stopped in 12 (43%) patients due to adverse events. Everolimus-based maintenance quadruple therapy, despite high rate of everolimus discontinuation due to adverse events, may be a valid approach in a subset of kidney transplant recipients with such difficult-to-treat rejections, which otherwise would lead to a high rate of graft loss. [ABSTRACT FROM AUTHOR]

Abstract: Background: The state of the evidence is unclear regarding the impact of cold ischemia time (CIT) on the outcome of kidney transplantation. The aim of this study was to investigate the effect of CIT on the short‐ and long‐term function of kidneys transplanted at the Sahlgrenska University Hospital in 2007‐2009 from donors after brain death (DBDs). Methods: This study was designed as a retrospective analysis of data from local and national transplantation registers. The study endpoints were as follows: delayed graft function (DGF), primary nonfunction (PNF), biopsy‐proven acute rejection (BPAR), serum creatinine (S‐creatinine) level at discharge, days of hospitalization after transplantation, and graft survival at 5 years post‐transplantation. Adjusted regression analyses were used to determine causal relationships with CIT. A further aim was to estimate a threshold for CIT by analyzing event rates and coordinates of the receiver‐operated characteristic (ROC) curve. Results: There was a causal relationship between CIT as a continuous variable and the following endpoints: graft survival at 5 years post‐transplantation, though this was not significant (hazard ratio (HR) 1.07, P = 0.057), DGF (odds ratio (OR) 1.09, P = 0.03) and S‐creatinine (P = 0.003). In our material, the risk for impaired outcome was higher with longer CIT. We were therefore able to estimate a threshold value for CIT, set to 14 hours for both graft survival at 5 years post‐transplantation and DGF. This was proved with significance by analyzing both event rates and the coordinates of the ROC curve. The risk of graft loss increased, with HR 2.3 (P = 0.023), when comparing a CIT cutoff of ≥14 hours with CIT < 14 hours. Delayed graft function increased, with an OR of 2.6 (P = 0.001). Conclusion: Our study confirms that, in this patient material, longer CIT was associated with increased risk for both impaired graft survival and incidence of DGF. We estimated a threshold for CIT of 14 hours. [ABSTRACT FROM AUTHOR]

The longer waiting time for a liver graft in patients with blood group O makes it necessary to expand the donor pool for these patients. This applies in both urgent situations and for elective patients. We report on our experience with ABO-incompatible liver transplantation using A2 and B non-secretor donors here. Patients and methods: Between 1996 and 2005, 12 adult blood group O recipients (seven male/five female) received ABO-incompatible cadaveric liver grafts (10 A2 donors, two B non-secretor donors). The indications were either rapid deterioration of liver function or hepatocellular cancer, in blood group O recipients, where an ABO-identical/compatible graft was not available. Mean recipient age was 54±8 (mean±SD) yr. All pre-operative CDC crossmatches were negative. The initial immunosuppression was induction therapy with antithymocyte globulin ( n=3), interleukin 2 receptor antagonists ( n=3) or anti-CD20 antibody (rituximab) ( n=1), followed by a tacrolimus-based protocol. Three patients underwent plasmapheresis post-transplantation. Baseline biopsies were taken before or immediately after reperfusion of the graft and after grafting when clinically indicated. No pre-operative plasmapheresis, immunoadsorption or splenectomies were performed. Results: Patient and graft survival was 10/12 (83%) and 8/12 (67%), respectively, with a 6.5-month median follow-up (range 10 days to 109 months). Two patients (B non-secretor grafts) died of multiorgan failure probably because of a poor condition before transplantation. Three patients were retransplanted. Causes of graft loss were bacterial arteritis ( n=1), death with a functioning graft ( n=1) and portal vein thrombosis ( n=2). In one of the patients with portal vein thrombosis, an anti-A titer increase occurred concomitantly, and ABO incompatibility as the cause of the thrombosis cannot be excluded. Seven acute rejections occurred in five patients and all were reversed by steroids or increased tacrolimus dosage. The pre-transplant anti-A titers tested against A1 red blood cells were 1 to 128 (NaCl technique) and 4 to 1024 (indirect antiglobulin technique, IAT); the maximum postoperative titers were 16 to 2048 (NaCl) and 256 to 32 000 (IAT). Conclusion: The favorable outcome of A2 to O grafting, with a patient survival of 10/10 and a graft survival of 8/10, makes it possible to also consider this blood group combination in non-urgent situations. The use of non-secretor donor grafts is interesting but has to be further documented. There was no hyperacute rejection or increased rate of rejection. Anti-A/B titer changes seem not to play a significant role in the monitoring of ABO-incompatible liver transplantation. [ABSTRACT FROM AUTHOR]

Blood group ABO-incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO-incompatible LD renal transplantation using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (mAb) treatment. Patients and treatment protocol: Recipients were blood group O ( n=12), A ( n=1) and B ( n=1). Donors were A1 ( n=2), A2 ( n=3), A2B ( n=1) and B ( n=8), and all were secretor positive. Anti-human leukocyte antigen (HLA) Ab panel reactivity was negative in all recipients except one. All recipients were pre-treated with 3 to 6 IA sessions, using A or B carbohydrate antigen columns, until their anti-A1/B RBC panel indirect antiglobulin test (IAT) titers were ≤8. CDC crossmatch was negative in all cases. Recipients received preoperative mycophenolic acid, and steroids/tacrolimus were started at transplantation. No splenectomy was performed. Eight recipients received one dose of anti-CD20 mAb (rituximab, 375 mg/m2) pre-operatively and 11 recipients had postoperative protocol IA. Results: In the initial protocol, anti-CD20 mAbs were used only for recipients receiving A1 grafts. One B graft (HLA-identical donor, 84% panel reactivity) was lost in a severe anti-B Ab-mediated acute rejection. Subsequently, the protocol included anti-CD20 for recipients of both A1 and B grafts and postoperative protocol IA to all recipients. The subsequent 10 grafts had excellent function, giving a total graft survival of 13/14 (observation range 2 to 41 months). At 1 yr, mean serum creatinine was 113 μmol/l ( n=8) and mean glomerular filtration rate was 55 ml/min/1.73 m2 (range 24 to 77). In the remaining five cases, with less than 1 yr follow up, mean serum creatinine was 145 μmol/l at 2 to 9 months follow up. Pre-IA anti-A/B titers were in the range of 2 to 32 (NaCl technique) and 16 to 512 (IAT). More than 90 IA sessions were performed in 14 recipients without any significant side effects. Recipient anti-A/B titers returned after transplantation to pre-IA levels or slightly lower. Postoperative renal biopsies were performed in 10 patients. In the 13 patients with long-term function, one patient experienced cellular rejection (Banff IIB) at 3 months without anti-B titer rise. This rejection was concomitant with low tacrolimus plasma levels and was easily reversed by steroids. In 8 of 10 cases, C4d staining was positive in peritubular capillaries. Conclusion: Blood group ABO-incompatible LD renal transplantation using A and B carbohydrate-specific IA and anti-CD20 mAbs has excellent graft survival and function. [ABSTRACT FROM AUTHOR]

FK 506 (FK) has a strong immunosuppressive effect, but a low-grade, dose-dependent nephrotoxicity and diabetogenicity, which means that reducing the dose of FK is of considerable interest. Lipo-prostaglandin E1 (LPGE1) is a preparation of PGE1 that has potent immunosuppressive properties, and its duration of action is longer than that of ordinary PGE1. The purpose of this study was to investigate whether LPGE1 can enhance the immunosuppressive effect of FK. Heterotopic cardiac transplantations to the neck vessels were performed, and recipient rats were treated with intramuscular injections of FK and LPGE1 once daily for 10 days. All grafts without any treatment were rejected within 14 days. In comparison, the FK doses of 0.07, 0.2 and 1.0 mg/kg/day for 10 days significantly increased the long-term graft survival (>100 days) to 8%, 44% and 100%, respectively. The addition of LPGE1 to the first two dosages caused a further significant increase in the graft survival, to 18% and 80%, respectively, when compared with the control. LPGE1 appears to enhance the immunosuppressive effect of FK. [ABSTRACT FROM AUTHOR]

The effect in vivo of the angiotensin converting enzyme (ACE) inhibitors captopril and enalapril and the calcium antagonist verapamil was studied in an experimental model using rat heart allografts. Daily post-transplant treatment of recipient rats (DA strain) with verapamil (75 mg kg[sup -1] day[sup -1]) or captopril (40 mg kg[sup -1] day[sup -1]) significantly prolonged survival of allografts from donors (PVG/c strain) when compared with an untreated control group (p < 0.05). No synergistic effect was observed when the two drugs were used for combined treatment. An equipotent does of enalapril (12.5 mg kg[sup -1] day[sup -1]) caused no change in allograft survival of statistical significance. The results support the hypothesis that verapamil and captopril have effects on the immune reactivity in vivo, and that this is not a characteristic shared by all ACE inhibitors. [ABSTRACT FROM AUTHOR]

Presents two cases of acute hepatic artery thrombosis, after whole liver transplantation in children. Viability of bile ducts and the liver parenchyma; Use of streptokinase to resolve a hepatic arterial thrombosis after liver transplantation; Cause of morbidity after liver transplantation; Use of Doppler ultrasound in treating hepatic arterial thrombosis.

Rationale & Objective: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs., Study Design: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial., Setting & Participants: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m 2 ), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion., Intervention: Continuation with a CNI-based regimen or switch to belatacept for 12 months., Outcomes: Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness., Results: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss., Limitations: The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year., Conclusions: We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate., Funding: The trial has received a financial grant from Bristol-Myers Squibb., Trial Registration: EudraCT no. 2013-001178-20., (© 2022 The Authors.)

Background: Corticosteroids and calcineurin inhibitors (CNIs) are included in renal transplantation immunosuppressive protocols around the world. Well-known side effects are associated with the use of these drugs, including new onset of diabetes after transplantation (NODAT). Long-term patient survival rates are lower among patients with NODAT. The optimal immunosuppressive protocol would therefore include not using corticosteroids and minimization of CNI use., Methods/design: This is a prospective, multi-centre, controlled, randomized, parallel group, open-label study involving kidney transplant patients. The study compares a steroid-free immunosuppressive protocol (study arm A), which is based on low-dose tacrolimus and mycophenolate mofetil (MMF) maintenance therapy together with antithymocyte globulin (ATG) induction, with the conventional immunosuppressive protocol (study arm B), being based on low-dose tacrolimus, MMF and steroids together with interleukin-2 receptor (IL2-R) induction. The study is designed to include most normal-risk patients. It will exclude patients seen as at a high risk of rejection. The primary objective of the study is to assess the cumulative incidence of NODAT in the two study arms 12 months after transplantation using the American Diabetes Association type 2 diabetes diagnostic criteria. The composite measure of freedom from acute rejection, graft survival and patient survival will be evaluated. Renal function and chronic changes in the transplanted kidney will be assessed., Discussion: If this study confirms conceptual expectations, namely decreased incidence of NODAT, the steroid-free study protocol could be used with all patients. The regimen could be especially beneficial for patients at a high risk of diabetes mellitus., Trial Registration: EudraCT 2012-000451-13.

Background: The longer waiting time for a liver graft in patients with blood group O makes it necessary to expand the donor pool for these patients. This applies in both urgent situations and for elective patients. We report on our experience with ABO-incompatible liver transplantation using A2 and B non-secretor donors here., Patients and Methods: Between 1996 and 2005, 12 adult blood group O recipients (seven male/five female) received ABO-incompatible cadaveric liver grafts (10 A2 donors, two B non-secretor donors). The indications were either rapid deterioration of liver function or hepatocellular cancer, in blood group O recipients, where an ABO-identical/compatible graft was not available. Mean recipient age was 54+/-8 (mean+/-SD) yr. All pre-operative CDC crossmatches were negative. The initial immunosuppression was induction therapy with antithymocyte globulin (n = 3), interleukin 2 receptor antagonists (n = 3) or anti-CD20 antibody (rituximab) (n = 1), followed by a tacrolimus-based protocol. Three patients underwent plasmapheresis post-transplantation. Baseline biopsies were taken before or immediately after reperfusion of the graft and after grafting when clinically indicated. No pre-operative plasmapheresis, immunoadsorption or splenectomies were performed., Results: Patient and graft survival was 10/12 (83%) and 8/12 (67%), respectively, with a 6.5-month median follow-up (range 10 days to 109 months). Two patients (B non-secretor grafts) died of multiorgan failure probably because of a poor condition before transplantation. Three patients were retransplanted. Causes of graft loss were bacterial arteritis (n = 1), death with a functioning graft (n = 1) and portal vein thrombosis (n = 2). In one of the patients with portal vein thrombosis, an anti-A titer increase occurred concomitantly, and ABO incompatibility as the cause of the thrombosis cannot be excluded. Seven acute rejections occurred in five patients and all were reversed by steroids or increased tacrolimus dosage. The pre-transplant anti-A titers tested against A1 red blood cells were 1 to 128 (NaCl technique) and 4 to 1024 (indirect antiglobulin technique, IAT); the maximum postoperative titers were 16 to 2048 (NaCl) and 256 to 32,000 (IAT)., Conclusion: The favorable outcome of A2 to O grafting, with a patient survival of 10/10 and a graft survival of 8/10, makes it possible to also consider this blood group combination in non-urgent situations. The use of non-secretor donor grafts is interesting but has to be further documented. There was no hyperacute rejection or increased rate of rejection. Anti-A/B titer changes seem not to play a significant role in the monitoring of ABO-incompatible liver transplantation.