Spleen tyrosine kinase (Syk) is involved in the antibody response (via B-cell receptor signalling) and antibody-dependent activation of macrophages, neutrophils and NK cells (via FcgR signalling), whereas Syk is not expressed by T-cells. However, the role of Syk in antibody-mediated rejection has not been examined. Therefore, this study investigated the function of Syk signalling in a model of acute renal allograft rejection. Groups of 6 Sprague-Dawley rats underwent bilateral nephrectomy and an orthotopic transplant with a MHC mis-matched Wistar rat kidney. Recipient rats were treated with a Syk inhibitor (CC0482417, 30mg/kg/bid) or vehicle from 1hr before surgery until being killed on day 5. Vehicle treated recipients developed severe allograft failure (serum creatinine 304±130 vs 46±7umol/L in isograft; P<0.001). Histologic damage included glomerular and peritubular capillaritis, tubular injury (tubulitis, necrosis, dilation) affecting 90±9% of tubules, and T-cell, macrophage and neutrophil infiltration. Allografts showed IgG and C3 deposition and circulating donor-specific antibodies (DSA) were identified by flow cytometry. CC0482417 improved allograft function (serum creatinine 149±18umol/L; P<0.05 vs vehicle), with reduced tubular damage (47±19%; P<0.001) and a reduction in capillaritis. CC0482417 treatment did not affect T-cell infiltration or activation (IL-2, granzyme B, IL-2Ra). However, CC0482417 treatment reduced macrophage and neutrophil infiltration by 40 and 45%, respectively (P<0.05 vs vehicle). Of note, CC0482417 reduced serum IgM and IgG DSA levels by 60% (P<0.01). In conclusion, this study has identified a functional role for Syk signalling in antibody-mediated, but not T-cell mediated, acute renal allograft rejection. Further studies should examine Syk inhibition in a specific model of antibody-mediated rejection. DISCLOSURE:Blease, K.: Employee, Celgene.
ABSTRACT Background Diabetes mellitus (DM) is associated with a greater risk of mortality in kidney transplant patients, primarily driven by a greater risk of cardiovascular disease (CVD)-related mortality. However, the associations between diabetes status at time of first allograft loss and mortality on dialysis remain unknown. Methods All patients with failed first kidney allografts transplanted in Australia and New Zealand between 2000 and 2020 were included. The associations between diabetes status at first allograft loss, all-cause and cause-specific mortality were examined using competing risk analyses, separating patients with diabetes into those with pre-transplant DM or post-transplant diabetes mellitus (PTDM). Results Of 3782 patients with a median (IQR) follow-up duration of 2.7 (1.1–5.4) years, 539 (14%) and 390 (10%) patients had pre-transplant DM or developed PTDM, respectively. In the follow-up period, 1336 (35%) patients died, with 424 (32%), 264 (20%) and 199 (15%) deaths attributed to CVD, dialysis withdrawal and infection, respectively. Compared to patients without DM, the adjusted subdistribution HRs (95% CI) for pre-transplant DM and PTDM for all-cause mortality on dialysis were 1.47 (1.17–1.84) and 1.47 (1.23–1.76), respectively; for CVD-related mortality were 0.81 (0.51–1.29) and 1.02 (0.70–1.47), respectively; for infection-related mortality were 1.84 (1.02–3.35) and 2.70 (1.73–4.20), respectively; and for dialysis withdrawal-related mortality were 1.71 (1.05–2.77) and 1.51 (1.02–2.22), respectively. Conclusions Patients with diabetes at the time of kidney allograft loss have a significant survival disadvantage, with the excess mortality risk attributed to infection and dialysis withdrawal.
Highly sensitised patients are at increased risk for antibody mediated rejection (AMR) and reduced graft survival. Highly sensitive assays for detecting recipient preformed anti-HLA antibodies have been developed and identify high immunological risk donors. A 62yo male with end stage renal failure secondary to glomerulonephritis received a T-cell crossmatch negative, deceased donor, renal transplant mismatched at 3 of 6 HLA loci. A donor specific antibody (DSAb) to DR17 (MFI 2073) was present. Given his advancing age, multiple medical comorbidities and broad HLA sensitisation the transplant was accepted, however, shortly before transplantation two atypical results were made available. Firstly a B-cell crossmatch was performed and found to be negative in current serum but strongly positive in peak serum, secondly a further potential DSAb was predicted based on linkage disequilibrium with known donor HLA typing. The donor HLA typing would not be clarified until after the transplant. Despite the increased risk of AMR the transplant proceeded with pre-emptive plasma exchange. The patient developed severe AMR requiring extensive therapy. Incomplete prospective donor HLA typing can generate uncertainty in the interpretation of the virtual crossmatch performed for deceased donor transplants. This may result in clinically relevant sequelae. Advances in antibody detection techniques need to be matched by timely donor HLA typing for its full benefit to be realised.
ABSTRACT Tissue typing is the process by which an individual's human leukocyte antigens (HLA) are determined. In transplantation, this vital process allows the immunologic or rejection risk of a donor–recipient pairing to be assessed through reviewing their HLA matching and whether any anti‐HLA antibodies present in recipient serum are donor specific. Tissue typing has increased in sophistication over time which has allowed a deeper appreciation of the antigenically important parts of HLA and increased the complexity of determining immunologic risk.
To determine factors associated with early pancreatic allograft thrombosis (EPAT). Thrombosis is the leading non-immunological cause of early pancreatic allograft failure. Multiple risk factors have been postulated. We hypothesized that recipient perioperative hypotension was a major risk factor and evaluated the correlation of this and other parameters with EPAT.We retrospectively reviewed the records of the 118 patients who received a pancreatic allograft at our center between October 1992 and January 2010. Multiple donor and recipient parameters were analyzed as associates of EPAT by univariate and multivariate analysis.There were 12 episodes of EPAT, resulting in an incidence of 10.2%. On univariate analysis, EPAT was associated with perioperative hypotension, vasopressor use, and neuropathy in the recipient (p ≤ 0.04 for all). On multivariate analysis corrected for age, sex, and peripheral vascular disease, only vasopressor use retained a significant association with EPAT with a hazard ratio of 8.74 (CI 1.11-68.9, p = 0.04). Factors associated with vasopressor use included recipient ischemic heart disease, peripheral vascular disease, retinopathy or neuropathy, and any surgical complication.Significant hypotension, measured by the need for perioperative vasopressor use was associated with EPAT, suggesting that maintenance of higher perfusion pressures may avoid this complication.
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