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Background: Patient Blood Management (PBM), endorsed by the World Health Organisation is an evidence-based, multi-disciplinary approach to minimise inappropriate blood product transfusions. Kidney transplantation presents a particular challenge to PBM, as comprehensive evidence of the risk of transfusion is lacking. The aim of this study is to investigate the prevalence of post-transplant blood transfusions across multiple centres, to analyse risk factors for transfusion and to compare transplant outcomes by transfusion status. Methods: This analysis was co-ordinated via the UK Transplant Registry within NHS Blood and Transplant (NHSBT), and was performed across 4 centres. Patients who had received a kidney transplant over a 1-year period, had their transfusion status identified and linked to data held within the national registry. Results: Of 720 patients, 221(30.7%) were transfused, with 214(29.7%) receiving a red blood cell (RBC) transfusion. The proportion of patients transfused at each centre ranged from 20% to 35%, with a median time to transfusion of 4 (IQR:0-12) days post-transplant. On multivariate analysis, age [OR: 1.02(1.01-1.03), p=0.001], gender [OR: 2.11(1.50-2.98), p<0.0001], ethnicity [OR: 1.28(1.28-2.60), p=0.0008], and dialysis dependence pre-transplant [OR: 1.67(1.08-2.68), p=0.02], were associated with transfusion. A risk-adjusted Cox proportional hazards model showed transfusion was associated with inferior 1-year patient survival [HR 7.94(2.08-30.27), p=0.002] and allograft survival [HR: 3.33(1.65-6.71), p=0.0008], and inferior allograft function. Conclusion: RBC transfusions are common and are independently associated with inferior transplant outcomes. We urge that further research is needed to understand the mechanisms behind the outcomes, to support the urgent development of transplant-specific anaemia guidelines.

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Introduction: Red blood cell transfusions (RBCT) represent a potentially modifiable risk factor for HLA sensitisation and adverse outcomes post transplantation. Evidence of the clinical impact of post-transplant RBCT has been infrequently reported. Herein, we performed a systematic review of available literature to assess the prevalence of RBCT post kidney transplant, and the effect of transfusion on transplant outcomes. Methods: We included studies from 2000 to July 2022, published on Medline, Embase and the Transplant Library. Results: Ten studies were analysed which included a total of 32,817 kidney transplant recipients, with a median transfusion prevalence of 40% (range 18-64%). There was significant heterogeneity between studies in terms of patient and allograft characteristics, immunological risk, and immunosuppression protocols. Analysis of unadjusted outcomes showed that post-transplant RBCTs are associated with inferior patient survival, allograft loss, rejection and donor specific antibodies. Adjusted outcomes were described where available, and supported the adverse associations seen in the unadjusted models in many studies. Discussion: This review demonstrates that RBCT post-transplant are common and maybe associated with inferior outcomes, highlighting the urgent need for high quality prospective evidence of the effect of RBCTs on transplant outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier, CRD42022348763767.

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Whether reexposure to mismatched HLA antigens (RMM) in the setting of a negative crossmatch is associated with increased immunological risk remains an area of uncertainty. This is due to evidence derived predominantly from registry data, which lacks comprehensive information on alloantibody and rejection. In this study, we analyze the impact of low-level preformed donor-specific antibodies (DSA) against an RMM on transplant outcomes. From 1988 consecutive renal transplant recipients, we analyzed 179 patients undergoing retransplantation, of whom 55 had a RMM. All patients were crossmatch negative and preformed DSA were detected by single antigen beads alone. Multivariate analysis revealed that patients with preformed DSA against an RMM were independently at risk of antibody-mediated rejection (HR 8.70 [3.42-22.10], P < .0001) and death-censored allograft loss (HR 3.08 [1.17-8.14], P = .023). In addition, prior transplant nephrectomy (HR 2.04 [1.00-4.17], P = .0495) was also associated with allograft failure, whereas receiving a retransplant that was matched at HLA class II was associated with a favorable outcome (HR 0.37 [0.14-0.99], P = .047). In the absence of preformed DSA, an RMM was not associated with de novo DSA development, rejection, or allograft loss. In conclusion, an RMM portends increased immunological risk only in the presence of a preformed DSA in patients undergoing retransplantation.

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There are conflicting data about the role of transplant nephrectomy and immunosuppression withdrawal on the development of allosensitization and the impact on re-transplantation. We divided 109 first graft recipients into two groups according to whether they underwent nephrectomy (NX+, n = 61) or their graft was left in situ (NX-, n = 48). Sera were assessed for HLA-A/B/Cw/DR/DQ antibodies at the time of NX/transplant failure and after 3, 6, 12, 24 months. The NX+ group showed a higher rate of donor specific antibody (DSA) and non-DSA human leukocyte antigen (HLA) antibody production at all the time points. Multivariable analysis showed that nephrectomy was a strong, independent risk factor for the development of DSAs after 12 and 24 months (P = 0.005 and 0.008). In the NX- group, low tacrolimus levels correlated with DSA formation (AUC 0.817, P = 0.002; best cut-off level 2.9 ng/ml). Analysis with a standardized pool of UK donors showed a more difficult grade of HLA matchability following nephrectomy compared with the NX- group. Nephrectomy is followed by the long-term production of DSA and non-DSA HLA antibodies and negatively impacts on the chances of finding a HLA-compatible kidney. Tacrolimus levels ≥3 ng/ml are protective against the development of allosensitization and could facilitate re-transplantation in the NX- group.

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De novo HLA donor-specific antibodies (DSA) following transplantation are associated with alloimmune injury and allograft failure. Blood transfusions are allogeneic, and when given posttransplant (PTBT) they may independently increase the risk of HLA antibody development. This study aims to analyze the development of HLA transfusion-specific antibodies (TSA) to blood donors of transfusions given posttransplant and examine the impact on clinical outcomes. A total of 244 blood donors of transfusions received by 86 transplant patients (46 who developed a DSA post transfusion and 40 who remained DSA negative) were HLA typed. De novo TSA developed against 150/244 (61.5%) blood donors. In 70/150 (46.7%) cases the TSA was of shared HLA antibody specificity with a DSA response in the recipient (DSA+ = TSA+). This occurred when there was a greater overall HLA match between the blood and transplant donor. DSA+ = TSA+ patients had increased risk of allograft failure (P = .0025) and AMR (P = .02) compared with the DSA+ ≠ TSA+ patients. To conclude, PTBT may elicit de novo HLA antibodies. Enhanced HLA matching between the blood and transplant donor is more likely to result in a DSA and TSA of shared antibody specificities. Transfusion avoidance or the use of HLA matched or selected blood may reduce this risk and improve outcomes.

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BACKGROUND: Although clinical practice guidelines (CPGs) are used for the development of local protocols in kidney transplantation (Ktx), the quality of their methodology is variable. This systematic review aimed to critically appraise international CPGs in all aspects of Ktx using the Appraisal of Guidelines for Research and Evaluation II tool. METHODS: Clinical Practice Guidelines in Ktx and donation published between 2010 and 2017 were identified from MEDLINE, Embase, National Guideline Clearinghouse, National Health Service and National Institute for Health and Care Excellence Evidence Searches, and the websites of transplant societies. Using Appraisal of Guidelines for Research and Evaluation II, 3 appraisers assessed the quality of CPGs. Interrater reliability was measured using the intraclass correlation coefficient (ICC). RESULTS: Searches identified 3168 records, and 115 CPGs were included. The highest scoring Appraisal of Guidelines for Research and Evaluation II domain was "scope and purpose" (80%; range, 30%-100%), followed by "clarity of presentation" (77%; range, 43%-98%), "editorial independence" (52%; range, 0%-94%), "rigor of development" (47%; range 6%-97%) and "stakeholder involvement" (41%; range, 11%-85%). The poorest scoring domain was "applicability" (31%; range, 3%-74%). Most CPGs were recommended for future use either with (63%) or without (18%) modifications. A small number (14%) were not recommended for future use or reviewers (5%) did not agree on recommending the CPG. The overall mean CPG quality score was 4 of 7 (range, 2-7). The mean ICC of 0.74 indicated substantial agreement between reviewers. CONCLUSIONS: The quality of international CPGs in Ktx was variable, and most CPGs lacked key aspects of methodological robustness and transparency. Improvements in methodology, patient involvement, and strategies for implementation are required.

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Thrombotic microangiopathies (TMAs) are frequently difficult to differentiate clinically, and measurement of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) remains vital in thrombotic thrombocytopenic purpura (TTP) diagnosis. We retrospectively reviewed cases referred for ADAMTS13 testing, using UK TTP Registry screening data. Of a total 810 cases, 350 were confirmed as TTP. The 460 non-TTP cases comprised secondary TMAs (24·57%) and haemolytic uraemic syndrome (HUS) (27·17% aHUS, 2·83% Shiga-like toxin-producing E. coli [STEC]-HUS); the remainder were TMAs with no clear association, not TMAs, or had no confirmed diagnosis. ADAMTS13 levels were significantly lower in TTP than STEC-HUS, aHUS and other TMAs. TTP patients had significantly lower platelet count (15 × 10(9) /l; range 0-96) than aHUS (57 × 10(9) /l; range 13-145, P < 0·0001) or STEC-HUS (35 × 10(9) /l; range 14-106, P < 0·0001); they also had lower creatinine levels (92 µmol/l; range 43-374) than aHUS (255 µmol/l; range 23-941, P < 0·0001) and STEC-HUS (324 µmol/l; range 117-639, P < 0·0001). However, 12/34 (35·3%) aHUS patients had a platelet count <30 × 10(9) /l and 26/150 (17·3%) of TTP patients had a platelet count >30 × 10(9) /l; 23/150 (15·3%) of TTP patients had a creatinine level >150 µmol/l. This study highlights the wide variety of TMA presentations, and confirms the utility of ADAMTS13 testing in TTP diagnosis.

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OBJECTIVES: Diabetes mellitus (DM) and renal impairment (RI) are both independent predictors of mortality after coronary artery bypass graft surgery (CABG). The two conditions often coexist, yet the impact on long-term prognosis after CABG of each factor relative to the other and the two in combination is uncertain. METHODS: We undertook a prospective cohort study of 4869 patients who underwent CABG between 2003 and 2007. The cohort was divided into four groups according to preoperative diabetic status and renal function: patients without either DM or RI (reference group), patients with DM alone, patients with RI alone and patients with both DM and RI. Clinical outcomes were compared between groups. Patients receiving renal replacement therapy were excluded. The primary outcome was 5-year all-cause mortality. RESULTS: The crude 5-year all-cause mortality rate was 9.0% for patients in the reference group, 11.1% for patients with DM alone, 20.3% for patients with RI alone and 28.5% for patients with both DM and RI (P < 0.0001). Five-year survival adjusted for potential confounding factors was significantly worse for patients with DM (hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.06-1.59), patients with RI (HR 1.32; 95% CI 1.08-1.61) and patients with both DM and RI (HR 2.04; 95% CI 1.65-2.53) when compared with patients with neither condition. CONCLUSIONS: Preoperative DM and RI were important predictors of 5-year mortality after CABG. Patients with RI alone had a higher mortality rate than patients with DM alone, but this difference was largely accounted for by age and other comorbidities. The combination of DM and RI doubled the 5-year mortality rate after CABG independently of potential confounding factors.

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BACKGROUND: The development of acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with increased short- and long-term mortality. Whether AKI has a causal relationship with subsequent mortality or whether the development of AKI simply occurs in patients with more comorbidity undergoing more complex procedures remains unresolved. METHODS AND RESULTS: This was an observational cohort study of prospectively collected data from 4694 patients discharged from the hospital after first-time CABG surgery at a tertiary cardiac center between 2003 and 2008. AKI was defined using the Risk, Injury, Failure, Loss, and End stage (RIFLE) criteria, which require at least a 50% increase in serum creatinine. The primary outcome measure was all-cause mortality determined via UK Office of National Statistics. A total of 562 (12.0%) of patients developed AKI after CABG surgery. Patients who developed AKI were older, more likely to be female, and had more comorbidity than patients who did not develop AKI. In a Cox multivariable analysis, the development of AKI was an independent predictor of midterm mortality (hazard ratio, 1.80; 95% confidence interval, 1.50-2.16). Subsequently, a comparison of 562 patients who sustained AKI with 562 propensity score-matched patients who did not sustain AKI was undertaken. After propensity matching, baseline clinical and operative characteristics were similar between both groups. After Cox multivariable analysis of the propensity-matched cohort, AKI remained an independent predictor of midterm mortality (hazard ratio, 1.52; 95% confidence interval, 1.19-1.93). CONCLUSIONS: The development of AKI after CABG is a serious event associated with worse midterm survival. This excess mortality cannot be explained simply by coexisting comorbidity and surgical complexity.

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CONTEXT: Mutations have been identified in the aryl hydrocarbon receptor-interacting protein (AIP) gene in familial isolated pituitary adenomas (FIPA). It is not clear, however, how this molecular chaperone is involved in tumorigenesis. OBJECTIVE: AIP sequence changes and expression were studied in FIPA and sporadic adenomas. The function of normal and mutated AIP molecules was studied on cell proliferation and protein-protein interaction. Cellular and ultrastructural AIP localization was determined in pituitary cells. PATIENTS: Twenty-six FIPA kindreds and 85 sporadic pituitary adenoma patients were included in the study. RESULTS: Nine families harbored AIP mutations. Overexpression of wild-type AIP in TIG3 and HEK293 human fibroblast and GH3 pituitary cell lines dramatically reduced cell proliferation, whereas mutant AIP lost this ability. All the mutations led to a disruption of the protein-protein interaction between AIP and phosphodiesterase-4A5. In normal pituitary, AIP colocalizes exclusively with GH and prolactin, and it is found in association with the secretory vesicle, as shown by double-immunofluorescence and electron microscopy staining. In sporadic pituitary adenomas, however, AIP is expressed in all tumor types. In addition, whereas AIP is expressed in the secretory vesicle in GH-secreting tumors, similar to normal GH-secreting cells, in lactotroph, corticotroph, and nonfunctioning adenomas, it is localized to the cytoplasm and not in the secretory vesicles. CONCLUSIONS: Our functional evaluation of AIP mutations is consistent with a tumor-suppressor role for AIP and its involvement in familial acromegaly. The abnormal expression and subcellular localization of AIP in sporadic pituitary adenomas indicate deranged regulation of this protein during tumorigenesis.

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