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Introduction: Neutropenia post‐kidney transplantation is associated with adverse graft and patient outcomes. We aimed to analyze the effect of granulocyte colony‐stimulating factor (G‐CSF) use with and without immunosuppression reduction on graft outcomes in neutropenic recipients. Methods: In this retrospective cohort study, we identified 120 recipients with neutropenia, within the first‐year post‐transplant. Results: Of these, 45.0% underwent no intervention, 17.5% had immunosuppression reduced, 18.3% were only given G‐CSF, and 19.2% had both interventions. Overall, 61 patients experienced the composite outcome of de‐novo DSA, biopsy‐proven acute rejection, and all‐cause graft failure and the cumulative incidence of this outcome did not vary by any of the four interventions (p =.93). When stratifying the cohort by G‐CSF use alone, those who received G‐CSF were more likely to have had severe neutropenia (<500/mm3: 51.1% vs. 12.0%, p <.001), and immunosuppression reduction (51.1% vs. 28.0%, p =.003). However, the composite outcome was not different in the G‐CSF and no G‐CSF cohort (53.3% vs. 49.3%, p =.67), and in a multivariate model, G‐CSF use was not associated with this outcome (aHR = 1.18, 95% CI:.61–2.30). However, a trend towards higher DSA production was noted in the G‐CSF cohort (87.5% vs. 62.2%) and this observation warrants prospective evaluation. Conclusion: Overall, we conclude that G‐CSF use with or without immunosuppression reduction was not associated with graft outcomes. [ABSTRACT FROM AUTHOR]

Background: Once‐daily extended‐release tacrolimus (TACER) is commonly administered following kidney transplantation (KTx); however, its optimal dosage remains unknown. Methods: In this multi‐center, randomized controlled trial, 62 living donor KTx recipients were assigned to either standard‐exposure (SE; n = 32) or low‐exposure (LE; n = 30) TACER (Graceptor®, Astellas Pharm Inc.) groups. All patients received basiliximab and mycophenolate mofetil (MMF). The primary outcomes were acute rejection, graft/patient survival, and the secondary outcomes were incidence of cytomegalovirus infection, and de novo donor‐specific antibodies (dnDSA) production. Results: The tacrolimus trough level and estimated area under the blood concentration–time curve (eAUC) were significantly higher in SE than in LE (SE vs. LE; 1 year: 5.0 ± 0.9 ng/ml and 206.9 ± 26.8 ng h/ml vs. 3.4 ± 1.0 ng/ml and 153.9 ± 26.4 ng h/ml; 2 years: 4.8 ± 1.0 ng/ml and 204.9 ± 30.1 ng h/ml vs. 3.8 ± 0.9 ng/ml and 164.4 ± 27.0 ng h/ml). In contrast, the dosage and eAUC of MMF did not differ between groups. Two‐year graft and patient survival rates were 100% in both groups, and acute rejection rates were 0% and 10% in the SE and LE, respectively (p = 0.11). The mean estimated glomerular filtration rates did not differ between the groups. Cytomegalovirus infection was slightly lower in the LE (SE: 12.5% and LE: 6.7%, p = 0.37). In the LE, four cases of dnDSA were noted within 2 years of transplantation; no case was observed in the SE (p = 0.034). Conclusions: Although the LE TACER regimen showed similar rates of acute rejection, as well as graft and patient survival compared with SE after KTx, LE was significantly more associated with dnDSA. Further investigation of its long‐term effect on graft survival is warranted. (University Hospital Medical Information Network Clinical Trials Registry ID: UMIN000033089). [ABSTRACT FROM AUTHOR]

Abstract: Background and objectives: The risk of de novo donor‐specific antibody (dnDSA) development following BK viremia (BKV) or nephropathy (BKN) after kidney transplant remains unclear. We aimed to evaluate the relationships among dnDSA, BKV (BK blood PCR > 15 000 copies), BKN, antibody‐mediated rejection (AMR), and allograft loss. Patients and methods: We performed a retrospective cohort study of 904 solitary kidney transplant recipients transplanted between 10/2007 and 5/2014. Cox proportional hazards regression with time‐dependent covariates were used to assess the relationships among BKN, isolated BKV, dnDSA, and the subsequent risk of AMR and allograft loss. Results: In multivariate analysis, we observed that BKN, but not BKV was a risk factor for dnDSA (HR, 3.18, P = .008). Of the patients with BK nephropathy, 14.0% (6/43) developed dnDSA, which occurred within 14 months of BK diagnosis. DnDSA in this setting remains a risk factor for subsequent AMR (HR 4.75, P = .0001) and allograft loss (HR 2.63, P = .018). Conclusions: BKN is an independent risk factor for development of dnDSA. Improved understanding of the characteristics of patients with BKN who are at highest risk for development of dnDSA would be valuable to customize immunosuppression reduction in this population. [ABSTRACT FROM AUTHOR]

Background The natural history of de novo donor-specific antibodies ( dn DSA) after lung transplantation is not well-described. We sought to determine the incidence and risk factors associated with dn DSA and compare outcomes between recipients with transient (or isolated) vs persistent dn DSA after transplantation. Methods A single-center review of all lung transplants from 1/2009-7/2013. DSAs were tested eight times in the first year and every 4 months thereafter. Outcomes examined included acute rejection and graft failure. Results Median follow-up was 18 months (range: 1-61 months), and 24.6% of 333 first-time lung-only transplant recipients developed a dn DSA. Ethnicity, HLA- DQ mismatches, post-transplantation platelet transfusion and Lung Allocation Score >60 were associated with dn DSA ( P<.05). Overall graft survival was worse for dn DSA-positive vs negative recipients ( P=.025). Of 323 recipients with 1-year follow-up, 72 (22.2%) developed dn DSA, and in 25 (34.7%), the dn DSA was transient and cleared. Recipients with transient dn DSA were less likely to develop acute rejection than those with persistent dn DSA ( P=.007). Conclusions Early post-lung transplantation, dn DSA occurred in 1/4 of recipients, was associated with peri-transplant risk factors and resulted in decreased survival. Spontaneous clearance of dn DSA, seen in one-third of recipients, was associated with a lower risk of acute rejection. [ABSTRACT FROM AUTHOR]

Background: De novo donor-specific antibodies (dnDSA) post-transplant correlate with a higher risk of immunologic graft injury and loss following kidney and pancreas transplantation. Post-transplant dnDSA can occur within the first post-transplant year. Methods: In this study, 817 of 1290 kidney and simultaneous kidney/pancreas recipients were tested for dnDSA post-transplant. Recipient immunosuppressive treatment at one, three, six, and 12 months post-transplant was correlated with dnDSA incidence by univariate and multivariate analyses. Results: The overall incidence of dnDSA was 21.3% detected a median of 3.5 yr post-transplant. By univariate analysis, the immunosuppressive treatment at all time points correlated with dnDSA (p < 0.01). Month 6 treatment correlated best in multivariable analysis (p = 0.004). At six months, recipients receiving rapamune/mycophenolic acid (Rapa/MPA) had the highest dnDSA incidence at five yr (25.3%) and last follow-up (30.7%), those treated with cyclosporine/rapamune (CNI/Rapa) had the lowest incidence at five yr (10.8%) and last follow-up (18.6%), and cyclosporine/mycophenolic acid (CNI/MPA) treatment had an intermediate incidence at five yr (16.7%) and last follow-up (20.4%) (p < 0.01). Six-month CNI/MPA and Rapa/MPA treatment significantly correlated with dnDSA (hazard ratios of 2.36 and 1.80, respectively) by Cox proportional hazards regression modeling. Conclusion: The risk of post-transplant dnDSA development correlates with early immunosuppressive management. [ABSTRACT FROM AUTHOR]

Barth RN, Campos L, Kukuruga DL, Drachenberg C, Philosophe B. Antibody-mediated rejection of renal allograft in combined liver-kidney transplant. Clin Transplant 2009 DOI: 10.1111/j.1399-0012.2009.01161.x © 2009 John Wiley & Sons A/S. Liver transplantation is performed based on ABO blood type compatibility without dependence on crossmatch results. Combined liver-kidney transplantation (CLKT) is similarly performed without dependence of crossmatch results as the liver is thought to confer protection to the renal allograft against alloantibody. We report a case of CLKT in a sensitized patient with antibody-mediated rejection (AMR) of the renal allograft. AMR was confirmed with C4d staining and serial monitoring of donor-specific antibody (DSA). Despite intensive therapy directed against AMR and the presence of the liver allograft, the patient demonstrated increasing titers of alloantibody, never demonstrated adequate renal function, and ultimately expired after two months. This result demonstrates the potential for AMR of the renal allograft in sensitized recipients of CLKT. [ABSTRACT FROM AUTHOR]

A 43-yr-old woman with end-stage renal disease caused by lupus nephritis received living kidney transplantation with ABO minor mismatch from her mother. Urine output decreased rapidly from fifth postoperative day, and serum creatinine (sCr) concentration increased rapidly. The clinical diagnosis was antibody-mediated rejection. The patient was treated with pulse methylprednisolone, plasma exchange (PEX), and OKT3. A graft biopsy revealed vascular rejection with linear C4d deposition on peritubular capillary (PTC). She was treated with additional PEX and intravenous cyclophosphamide, which improved urine output and resulted in a gradual decrease in sCr. She subsequently developed frequent episodes of acute rejection (AR) with a rise in sCr. Repeated graft biopsies revealed acute T-cell-mediated rejection with progressive interstitial fibrosis and tubular atrophy. Severe peritubular capillaritis with mononuclear infiltrates were present, but C4d deposition on PTC was persistently negative or weak. Flow-cytometric panel reactive antibody performed retrospectively revealed both donor- and non-donor-specific HLA antibodies, which were persistently present after the treatment of the first AR. We added rituximab to the treatment of AR, but she developed cytomegalovirus enteritis, and eventually hemodialysis was induced again 45 months after the transplantation. Recent flow-cytometry-based antibody detection methods are useful even in cases lacking diffuse and strong C4d deposition on PTC. [ABSTRACT FROM AUTHOR]

The impact of post-transplant donor-specific antibody (DSA) on the development of chronic rejection has been focused recently. The aim of this study was to evaluate the significance of DSA, graft function and pathological factors of chronic rejection. Seventy-three kidney recipients who underwent protocol biopsy were included in the study. The median follow-up period after transplant was 40 months. The presence of anti-HLA antibody (aHLAAb) and DSA was tested using flow beads analysis (FlowPRA®). The patients were divided into a group with DSA, a group with non-donor-specific aHLAAb and a group without aHLAAb. Protocol biopsy specimen were compared for transplant glomerulopathy (cg), vasculopathy (cv), C4d deposition at peritubular capillary (PTC), peritubular capillaritis (ptc score 0–3) and thickening of PTC basement membrane (ptcbm score 0–3) as recently proposed. The presence of DSA was significantly associated with the presence of cg, ptcbm. The group with non-donor-specific aHLAAb had ptcbm but did not have cg. The group without aHLAAb rarely showed ptcbm. The presence of DSA was associated with impaired graft function. C4d was not specific for the patients with DSA. These histopathological markers are useful in the detection of immunological chronic rejection. Early detection by screening tests will be important for treatment before irreversible change occurs. [ABSTRACT FROM AUTHOR]

Background: Assessment of human leukocyte antigen (HLA) matching by using high‐resolution allele typing and knowledge of HLA molecule structure may lead to better prediction of de novo donor‐specific antibody (dnDSA) development. Methods: We conducted a single‐center cohort study among 150 non‐sensitized first kidney transplant recipients to compare the association between antigenic (Ag), allelic (Al), eplet (Ep), amino acid (AAMS) HLA matching and electrostatic (EMS) and hydrophobic (HMS) mismatch scores, and the development of dnDSA. Results: After a mean follow‐up time of 49.3 ± 17.7 months, 18 patients (12%) developed dnDSA. The number of HLA mismatches (MM) was significantly associated with the development of dnDSA. The optimal threshold, determined by Harrell's C‐index, varied according to the method (5 MM for Ag, P = 0.006; 6 for Al, P = 0.009; 22 for Ep, P = 0.005; 42 for AAMS, P = 0.0007; 45 for EMS, P = 0.009 and 44 for HMS, P = 0.026). C‐indices were similar for all matching approaches, suggesting a similar prediction of dnDSA development. Conclusion: In this cohort of low immunological risk transplant patients, the use of Al or Ep matching did not improve the prediction of dnDSA development in comparison with the traditional approach. [ABSTRACT FROM AUTHOR]