Search

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47–77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37–7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56–5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

Relaxing living kidney donor criteria allows donor pool expansion, but the risks to marginal donors who are both older and hypertensive are not well defined. This single-centre study of donors compared post-nephrectomy changes in blood pressure and estimated kidney function stratified by age, gender and the presence of hypertension. Data from an additional group of hypertensive older patients undergoing unilateral nephrectomy for malignancy were also analysed.

Aim\ud\udTo report a protocol for a qualitative study to better understand the key factors that influence decision making about pregnancy from women's perspectives and to use these data to develop a theoretical model for shared decision-making tools for the multiple stakeholders.\udDesign\ud\udMixed-method design using online surveys (with validated components) and purposively sampled follow-up semi structured interviews.\udMethods\ud\udFunded from September 2020 for 12 months. Online surveys of adult women (aged 18–50) identified via all Wales kidney database (n ≥ 500), additional recruitment through multidisciplinary healthcare professionals, relevant third sector organizations and social media. Follow-up in-depth qualitative interviews with n = 30 women. Linear regression models to identify associations between shared decision-making preferences and clinical and psychosocial variables. Qualitative interviews will use a visual timeline task to empower women in taking control over their narratives. Qualitative data will be fully transcribed and analysed thematically, based around a chronological and theoretical (theoretical domains framework) structure that maps out key challenges and opportunities for improved decision support in the care pathway. Visual timelines will be used during stakeholder consultation activities, to enable us to co-create a map of current support, gaps in provision, and opportunities for interventions. Quantitative data will be analysed descriptively to characterize our cohort. We will assemble a multidisciplinary shared decision-making intervention development group and provide ongoing stakeholder consultation activities with patient and public representatives.\udDiscussion\ud\udOutcomes will support new learning into; the ways women's knowledge of kidney disease may affect family planning and pregnancy, their needs in terms of psychological and social support, and how they weigh up the pros and cons of starting a family.\udImpact\ud\udEvidence will inform the design of new shared decision-making tools to better support women with the complex and often emotional decisions about having children while living with kidney disease.

• Background: Kidney transplantation offers a better quality of life and a clear survival advantage compared to long-term dialysis. However, rates of transplantation are low for highly sensitized patients (HSP) who have a broad specificity of human leucocyte antigen (HLA) specific antibodies. This is because the presence of pre-formed HLA Donor Specific Antibodies can result in hyperacute rejection and is an immunological veto to transplantation. The proportion of eligible donors therefore decreases with increasing sensitization, resulting in increased waiting time prior to transplantation. This study aims to assess the efficacy of a combination of B cell depletion and proteasome inhibition, together with antibody removal and steroids, to reduce HLA antibodies in HSP, predicted to improve rates of transplantation, and to determine the feasibility of conducting a future definitive trial. • Methods: ITOPS is a multi-center, randomized parallel, non-blinded, controlled phase III feasibility trial. The participants will be allocated in a 1:1 ratio to either the trial intervention (rituximab followed by 1-2 cycles of plasmapheresis, bortezomib and dexamethasone) or control group (no intervention). • Discussion: The primary outcome is the proportion of patients achieving an absolute reduction in sensitization (calculated reaction frequency, cRF) of at least 10% at 12 weeks following their last intervention, compared to the control group. Secondary outcomes include recruitment and transplantation rates, durability of change and absolute percentage change in cRF, and acceptability of the intervention. We will proceed to development of a larger trial if at least 50% of the participants in the intervention arm achieve an absolute reduction in cRF of a minimum of 10% at 12 weeks following their last intervention. If the proportion is Trial Registration: International Standard Randomized Controlled Trial Number ISRCTN66441193 https://doi.org/10.1186/ISRCTN66441193

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Clinical Trial Registration: Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.

Background: Kidney transplant recipients (KTRs) with “operational tolerance” (OT) maintain a functioning graft without immunosuppressive (IS) drugs, thus avoiding treatment complications. Nevertheless, IS drugs can influence gene-expression signatures aiming to identify OT among treated KTRs. Methods: We compared five published signatures of OT in peripheral blood samples from 18 tolerant, 183 stable, and 34 chronic rejector KTRs, using gene-expression levels with and without adjustment for IS drugs and regularised logistic regression. Findings: IS drugs explained up to 50% of the variability in gene-expression and 20–30% of the variability in the probability of OT predicted by signatures without drug adjustment. We present a parsimonious consensus gene-set to identify OT, derived from joint analysis of IS-drug-adjusted expression of five published signature gene-sets. This signature, including CD40, CTLA4, HSD11B1, IGKV4–1, MZB1, NR3C2, and RAB40C genes, showed an area under the curve 0⋅92 (95% confidence interval 0⋅88–0⋅94) in cross-validation and 0⋅97 (0⋅93–1⋅00) in six months follow-up samples. Interpretation: We advocate including adjustment for IS drug therapy in the development stage of gene-expression signatures of OT to reduce the risk of capturing features of treatment, which could be lost following IS drug minimisation or withdrawal. Our signature, however, would require further validation in an independent dataset and a biomarker-led trial. Funding: FP7-HEALTH-2012-INNOVATION-1 [305147:BIO-DrIM] (SC,IR-M,PM,DSt); MRC [G0801537/ID:88245] (MPH-F); MRC [MR/J006742/1] (IR-M); Guy's&StThomas’ Charity [R080530]&[R090782]; CONICYT-Bicentennial-Becas-Chile (EN-L); EU:FP7/2007–2013 [HEALTH-F5–2010–260687: The ONE Study] (MPH-F); Czech Ministry of Health [NV19–06–00031] (OV); NIHR-BRC Guy's&StThomas' NHS Foundation Trust and KCL (SC); UK Clinical Research Networks [portfolio:7521].

We aimed to analyse the efficacy of the Thymoglobulin dose used for induction in controlled DCD kidneys, and its initial impact on blood cell and CD3 count, as predictors of efficacy.140 DCD patients who received ATG induction, were analysed. Intended dose was 1.25 mg/kg/day over 5 days, rounded to nearest 25 mg and not exceeding 125 mg/dose. Outcomes included the total dose in relation with rejection, DGF, graft survival, eGFR. The cell count response to ATG was assessed as predictors of outcome.Graft survival, was 96.2%, 92.4%, 85% at 1, 3 and 5 years. Rejection was 7% at 1 year and associated with eGFR at 3 (p = 0.003) and 5 years. ATG dose was not predictive of rejection but was associated with the day5 leucocyte and lymphocyte count (p 0.001) and negatively with DGF (p = 0.05). In 31 patients day3 CD3 count was available and it was associated with rejection (p = 0.002), less DGF (p = 0.09), and 3 years eGFR (p = 0.01).Thymoglobulin provides excellent results in DCD kidneys that do not significantly differ with small dose variations. In higher doses it reduces DGF. Lymphocytes and CD3 count, may be useful surrogate markers of efficacy and outcome.

BACKGROUND ABO blood group-incompatible kidney transplantation (ABOiKTx) outcomes are good, but complications are more common than in conventional transplantation. Regimens that use extracorporeal antibody removal therapy (EART) and enhanced immunosuppression are guided by titration of ABO blood group antibodies (using hemagglutination [HA] dilution assays), and these assays vary significantly in performance between centers. This study aims to describe the differences in titer measurement and the effect on clinical practice and outcomes. STUDY DESIGN AND METHODS This multicentre, prospective cohort study of 100 ABOiKTx recipients assessed treatment and outcome data, including HA assay results measured retrospectively in a single central laboratory. RESULTS Patient and allograft survival at 1 year was 99% and 94%, respectively. There were significant differences in the number of pretransplantation EART sessions in centers undertaking plasma exchange (PEx), compared with immunoadsorption (IA) (median, 6 vs. 4 sessions; p = 0.007). The pre-EART HA titer in both groups was the same when centrally assayed. The local HA assay used to guide treatment yielded significantly higher titers in centers undertaking PEx compared with IA (median, 128 vs. 32; p

Background. ABO and HLA antibody incompatible (HLAi) renal transplants (AIT) now comprise around 10% of living donor kidney transplants. However, the relationship between pretransplant factors and medium-term outcomes are not fully understood, especially in relation to factors that may vary between centers. Methods. The comprehensive national registry of AIT in the United Kingdom was investigated to describe the donor, recipient and transplant characteristics of AIT. Kaplan-Meier analysis was used to compare survival of AIT to all other compatible kidney transplants performed in the United Kingdom. Cox proportional hazards regression modeling was used to determine which pretransplant factors were associated with transplant survival in HLAi and ABOi separately. The primary outcome was transplant survival, taking account of death and graft failure. Results. For 522 HLAi and 357 ABO incompatible (ABOi) transplants, 5-year transplant survival rates were 71% (95% confidence interval [CI], 66-75%) for HLAi and 83% (95% CI, 78-87%) for ABOi, compared with 88% (95% CI, 87-89%) for 7290 standard living donor transplants, and 78% (95% CI, 77-79%) for 15 322 standard deceased donor transplants (P < 0.0001). Increased chance of transplant loss in HLAi was associated with increasing number of donor specific HLA antibodies, center performing the transplant, antibody level at the time of transplant, and an interaction between donor age and dialysis status. In ABOi, transplant loss was associated with no use of IVIg, cytomegalovirus seronegative recipient, 000 HLA donor-recipient mismatch; and increasing recipient age. Conclusions. Results of AIT were acceptable, certainly in the context of a choice between living donor AIT and an antibody compatible deceased donor transplant. Several factors were associated with increased chance of transplant loss, and these can lead to testable hypotheses for further improving therapy.

Nephrotic-range proteinuria is due to glomerular diseases characterized by podocyte injury. Glucocorticoids are the standard of care for most forms of nephrotic syndrome. However, the precise mechanisms underlying the beneficial effects of glucocorticoids on podocytes, beyond its general immunosuppressive and anti-inflammatory effects, are still unknown. This study tested the hypothesis that the synthetic glucocorticoid dexamethasone directly reduces podocyte apoptosis. Growth-restricted immortalized mouse podocytes in culture were exposed to puromycin aminonucleoside (PA) to induce apoptosis. Our results showed that dexamethasone significantly reduced PA-induced apoptosis by 2.81-fold. Dexamethasone also rescued podocyte viability when exposed to PA. PA-induced apoptosis was associated with increased p53 expression, which was completely blocked by dexamethasone. Furthermore, the inhibition of p53 by the p53 inhibitor pifithrin-alpha protected against PA-induced apoptosis. Dexamethasone also lowered the increase in the proapoptotic Bax, which was increased by PA, and increased expression of the antiapoptotic Bcl-xL protein. Moreover, the decrease in p53 by dexamethasone was associated with increased Bcl-xL levels. Podocyte apoptosis induced by PA was caspase-3 independent but was associated with the translocation of apoptosis-inducing factor (AIF) from the cytoplasm to nuclei. AIF translocation was inhibited by dexamethasone. These results show that PA-induced podocyte apoptosis is p53 dependent and associated with changes in Bcl-2-related proteins and AIF translocation. The protective effects of dexamethasone on PA-induced apoptosis were associated with decreasing p53, increasing Bcl-xL, and inhibition of AIF translocation. These novel findings provide new insights into the beneficial effects of corticosteroids on podocytes directly, independent of its immunosuppressive effects.

Background: Delayed graft function (DGF) following transplantationnecessitates support in the form of hemodialyis (HD) orperitoneal dialysis (PD). However, post-transplant PD-related complicationand failure rates are unknown.Methods: We studies patients who were on PD at the time of kidneytransplantation over a 4-year period at two separate institutions.Results: Of the 137 PD patients, 19 had their catheters removedat the time of transplant. Of the remaining 118 patients, 89% hadimmediate graft function. PD-related complications in this groupincluded peritonitis (n=5), catheter-related infections (n=2) andemergency laparotomy (n=1). Of the 15 patients requiring posttransplantPD, 33% developed peritonitis and 20% had fluid-leaksnecessitating HD. Overall, leaving a PD catheter in situ post- transplantationis associated with 7% rate of peritonitis versus 0% ifremoved (p < 0.05).Conclusions: PD catheter removal should be considered at thetime of renal transplantation, as postoperative PD-related failure/complication rates are high.

The tight regulation of cell growth and division within an organ is essential for the development and maintenance of correct structure and function. Perturbations of renal growth occurring either developmentally or following injury to mature renal cells contribute to the abnormalities observed in a wide range of diseases. The changes in growth are increasingly recognized as an influence on the progression of the initial disease process, and the ultimate clinical outcome. Abnormal cell growth is classified according to the presence of an increase in cell number or cell size. Hyperplasia refers to abnormal growth resulting in an increased absolute number of cells, whereas hypertrophy refers to an increase in individual cell size. Both processes may be present in a given cell population and contribute to the increase in overall kidney size.

Introduction Although national guidance does not recommend screening of coronary artery disease in asymptomatic patients with established renal failure, cardiovascular disease is a leading cause of death in patients on dialysis and transplant recipients.Therefore “Cardiac assessment pathway” was developed in the UHW, Cardiff, for renal transplant candidates, to assess fitness for surgery in patients mainly of intermediate to high cardiovascular risk, even if asymptomatic from cardiovascular perspective, and to identify high risk patients who require targeted investigation and revascularisation prior to renal transplant. Method Audit included data of 104 patients referred for cardiac assessment with MPI for suitability for renal transplant between April 2011 and October 2013. Data obtained from risk assessments questionnaires, MPI, Echo, angiogram and perioperative transplant notes.MPI results categorised as: normal, reversible ischaemia, fixed defect, mixed defect and inconclusive.104 MPI performed in 25% females, 75%, males age 33–79, initial cardiovascular risk categorised as low (9.7%), intermediate (42.3%) or high (48%). Adenosine used in 79%, exercise in 16%, dobutamine in 4% of patients. Results 51% of MPI results were normal (SSS 0–5, average 0.3), 13.5% revealed reversible ischaemia (SSS 3–11, average 5.9), 24% showed fixed (SSS 0–16, average 2.8) and 11.5% (SSS 5–18, average 9.6) mixed defect. 11/56 (20%) of asymptomatic patients were referred for coronary angiogram following MPI (coronary artery disease confirmed in 4, all for medical management, 7 patients awaiting angiogram). In 50% of low risk patients MPI was normal, 40% had a fixed defect and 10% had small reversible ischaemia, all deemed fit for surgery, 3 have had a transplant with uneventful perioperative period. 61% of MPI in an intermediate risk group were normal, 18% showed fixed, 9% mixeddefect and 11% showed reversible ischaemia, out of which 1(20%) subsequently underwent PCI, 1 was referred for medical management and further 5 are awaiting angiogram. 9 patients (deemed fit for surgery following MPI) have already had a transplant with no cardiac events perioperatively. 22 patients (44%) in the high risk group had a normal scan and were deemed fit for surgery, 1 deemed not fit for transplant following MPI. 8 out of remaining 28 patients were referred for angiogram, 5 subsequently referred for medical management and deemed fit for transplant. 16 had a transplant with 1cardiacevent perioperatively.Overall 83/104 (80%) were deemed fit for surgery following MPI, 1 turned down from surgery, 16 referred for further coronary assessment, 5 for MDT discussion. Conclusion MPI is a valuable tool in cardiovascular risk stratification of renal transplant candidates and identifies high risk patients for further coronary investigations and intervention prior to them being considered for renal transplantation.

Activation of a local tissue angiotensin system in podocytes by mechanical strain.BackgroundGlomerular capillary hypertension, a common denominator in various forms of progressive glomerular disease, results in mechanical distention of the capillary tuft, and subsequent injury of the overlying podocyte layer. The mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Angiotensin II plays a central role in the pathogenesis of chronic renal injury, largely through its actions on the subtype 1 receptor. Accordingly, we have tested the hypothesis that mechanical strain up-regulates local angiotensin II in podocytes, thereby resulting in a progressive reduction in podocyte number.MethodsConditionally immortalized mouse podocytes were subjected to cyclical stretch of 10% amplitude. Nonstretched podocytes served as controls. Angiotensin II levels were measured in whole cell lysate by competitive enzyme-linked immunosorbent assay (ELISA). Expression of angiotensin II receptors (AT1R, AT2R) was measured by quantitative polymerase chain reaction (PCR) and Western blot analysis. Apoptosis was measured by Hoechst staining. Immunostaining for AT1R was performed in tissue sections from rats with 5/6 remnant kidney disease, a model of glomerular hypertension.ResultsMechanical strain increased angiotensin II production in podocytes at 24, 48, and 72hours (P < 0.05 vs. nonstretched controls). Stretching podocytes resulted in a fivefold increase in AT1R mRNA expression at 24hours and a twofold increase in protein levels vs. controls (P < 0.05), and also an increase in transforming growth hormone-β (TGF-β) mRNA expression. AT1R staining was increased in a podocyte distribution in the 5/6 remnant kidney, consistent with our in vitro findings. Mechanical strain resulted in a 2.5-fold increase in apoptosis (P < 0.001 vs. nonstretched controls) in an angiotensin II–dependent fashion.ConclusionMechanical strain leads to up-regulation of the AT1R and increased angiotensin II production in conditionally immortalized podocytes. The resulting activation of a local tissue angiotensin system leads to an increase in podocyte apoptosis, mainly in an AT1R-mediated fashion.