Search

Although sarcoidosis is an established cause of multiorgan dysfunction, acute presentation with thrombotic microangiopathy resulting in severe renal and hematological sequelae has not been reported. We describe the case of a patient presenting with hypercalcemia, pancreatitis, and acute renal failure, followed by microangiopathic hemolytic anemia. Although there were no significant respiratory symptoms, thoracic radiology and mediastinal lymph node biopsy results were in keeping with sarcoidosis as the underlying cause of this multisystem presentation. Corticosteroids were commenced with clinical and biochemical improvement. This novel case highlights the need to consider sarcoidosis as part of the differential diagnosis for unusual multiorgan presentations and for early multidisciplinary involvement in such cases to permit optimal treatment.

The emergence and attendant mortality of vaccine-induced immune thrombocytopenia and thrombosis (VITT) as a consequence of vaccination against severe acute respiratory syndrome coronavirus 2 have resulted in some patients with VITT being considered as deceased organ donors. Outcomes after kidney transplantation in this context are poorly described. Because the disease seems to be mediated by antiplatelet factor 4 antibodies, there is a theoretical risk of transmission via passenger leukocytes within the allograft.We analyzed the experience of kidney transplantation from donors with VITT in the United Kingdom between January and June 2021. We followed-up all recipients of kidney-only transplants from donors with VITT to detect major postoperative complications or features of disease transmission and assess graft survival and function.There were 16 kidney donors and 30 single kidney transplant recipients in our study period. Of 11 preimplantation biopsies, 4 showed widespread glomerular microthrombi. After a median of 5 mo, patient and graft survival were 97% and 90%, respectively. The median 3-mo estimated glomerular filtration rate was 51 mL/min/1.73 m 2 . Two recipients had detectable antiplatelet factor 4 antibodies but no evidence of clinical disease after transplantation. Major hemorrhagic complications occurred in 3 recipients, all of whom had independent risk factors for bleeding, resulting in the loss of 2 grafts. The involvement of VITT could not be completely excluded in one of these cases.The UK experience to date shows that favorable outcomes are possible after kidney transplantation from donors with VITT but highlights the need for ongoing vigilance for donor-related complications in these patients.

Vaccine-induced thrombosis and thrombocytopenia (VITT) may follow immunisation with the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. Autoantibodies to platelet factor 4 (PF4) may mediate VITT through antibody-dependent platelet activation, though the underlying etiology is uncertain. Anti-PF4 antibodies are also seen in heparin-induced thrombocytopenia, though most cases of VITT do not have prior heparin exposure. More than 20 million people in the United Kingdom (UK) have received the ChAdOx1 nCoV-19 vaccine.

Background Dialysis patients and immunosuppressed renal patients are at increased risk of COVID-19 and were excluded from vaccine trials. We conducted a prospective multicentre study to assess SARS-CoV-2 vaccine antibody responses in dialysis patients and renal transplant recipients, and patients receiving immunosuppression for autoimmune disease. Methods Patients were recruited from three UK centres (ethics:20/EM/0180) and compared to healthy controls (ethics:17/EE/0025). SARS-CoV-2 IgG antibodies to spike protein were measured using a multiplex Luminex assay, after first and second doses of Pfizer BioNTech BNT162b2(Pfizer) or Oxford-AstraZeneca ChAdOx1nCoV-19(AZ) vaccine. Results Six hundred ninety-two patients were included (260 dialysis, 209 transplant, 223 autoimmune disease (prior rituximab 128(57%)) and 144 healthy controls. 299(43%) patients received Pfizer vaccine and 379(55%) received AZ. Following two vaccine doses, positive responses occurred in 96% dialysis, 52% transplant, 70% autoimmune patients and 100% of healthy controls. In dialysis patients, higher antibody responses were observed with the Pfizer vaccination. Predictors of poor antibody response were triple immunosuppression (adjusted odds ratio [aOR]0.016;95%CI0.002–0.13;p p p p = 0.021). Lower antibody responses were associated with a higher chance of a breakthrough infection. Conclusions Amongst dialysis, kidney transplant and autoimmune populations SARS-CoV-2 vaccine antibody responses are reduced compared to healthy controls. A reduced response to vaccination was associated with rituximab, MMF, triple immunosuppression CKD stage 4. Vaccine responses increased after the second dose, suggesting low-responder groups should be prioritised for repeated vaccination. Greater antibody responses were observed with the mRNA Pfizer vaccine compared to adenovirus AZ vaccine in dialysis patients suggesting that Pfizer SARS-CoV-2 vaccine should be the preferred vaccine choice in this sub-group.

Background Tacrolimus is a narrow therapeutic index medication, which requires therapeutic drug monitoring to optimize dosing based on systemic exposure. MITRA microsampling offers a convenient, minimally invasive approach for the collection of capillary blood samples from a finger prick versus conventional venous blood sampling for quantitation of tacrolimus blood concentrations. However, the suitability of MITRA microsampling for the determination of tacrolimus concentrations requires assessment in clinical settings. Methods Paired venous (2 mL) and capillary (10 μL) blood samples were collected pre-tacrolimus dose and 1 and 3 hours postdose during routine outpatient visits from stable adult liver or kidney transplant patients receiving prolonged-release tacrolimus. Tacrolimus concentrations were determined by liquid chromatography-tandem mass spectrometry, and the concentrations obtained by the 2 sampling methods were compared by linear regression and Bland-Altman agreement analyses. Results Samples were available for 82 transplant recipients (kidney, n = 41; liver, n = 41). A high correlation was observed between tacrolimus concentrations in capillary and venous blood samples (Pearson correlation coefficient, 0.97; Lin concordance coefficient, 0.87; slope of the fitted line, >1.0). Tacrolimus concentrations in capillary samples were 22.5% higher on average than in the corresponding venous blood samples (95% limits of agreement, 0.5%-44.6%). Similar results were observed in both transplant subgroups. Conclusions MITRA finger prick sampling provides a convenient alternative to venipuncture for therapeutic drug monitoring in transplant recipients maintained on prolonged-release tacrolimus. When using the finger prick MITRA method, the positive bias in tacrolimus concentrations observed with this technique, when compared with venipuncture, needs to be taken into consideration.

Lay Summary During a kidney transplant, a plastic tube (stent) is placed in the ureter, connecting the new kidney to the bladder, in order to keep the new join open during the initial phase of transplantation. The stent is then removed after a few weeks via a camera procedure (cystoscopy), as it is no longer needed. The present study compared performing this in the operating theatre or in clinic for transplanted patients using a new single-use type of camera with an integrated grasper system. The results have shown that it is safe and cost-effective to do this in clinic, despite patients being susceptible to infection after transplantation.

There is uncertainty about the safety of kidney transplantation during the SARS-CoV-2 pandemic due to the risk of donor transmission, nosocomial infection and immunosuppression use. We describe organ donation and transplant practice in the UK and assess whether kidney transplantation conferred a substantial risk of harm. Data from the UK transplant registry were used to describe kidney donation and transplant activity in the UK, and a detailed analysis of short-term, single-center, patient results in two periods: during the pre-pandemic era from 30th December 2019 to 8th March 2020 ("Pre-COVID era") and the 9th March 2020 to 19th May 2020 ("COVID era"). Donor and recipient numbers fell by more than half in the COVID compared to the pre-COVID era in the UK, but there were more kidney transplants performed in our center (42 vs. 29 COVID vs. pre-COVID respectively). Overall outcomes, including re-operation, delayed graft function, primary non-function, acute rejection, length of stay and graft survival were similar between COVID and pre-COVID era. 6/71 patients became infected with SARS-CoV-2 but all were discharged without critical care requirement. Transplant outcomes have remained similar within the COVID period and no serious sequelae of SARS-CoV-2 infection were observed in the peri-transplant period.

Background and Aims Hyperkalaemia is a common and life-threatening medical emergency present in up to 10% of acute hospital admissions. End-stage Kidney Disease (ESKD) patients undergoing transplantation are at increased risk of hyperkalaemia, a potentially life-threatening medical emergency. Although the prevalence of hyperkalaemia in ESKD is well described, few studies have assessed the incidence and associations of hyperkalaemia in kidney transplant recipients. We evaluated post-transplant hyperkalaemia in a single centre using a large electronic health record dataset of emergency admissions. Methods Prevalent kidney transplant recipients were identified using ICD-10 codes from a complete Electronic Health Records database of all emergency admissions to Addenbrooke’s Hospital, Cambridge between April 2015 and August 2018. We abstracted demographics, comorbidities, concomitant medications, biochemistry results including all blood potassium values, in-hospital prescribing and admission and discharge dates. Data were summarised as frequency (%), mean± standard deviation (SD) or median with interquartile range (IQR) as appropriate. Categorical variables were compared by Chi-squared test and continuous variables by Student's t-test or Mann–Whitney U-test based on their distribution. Factors associated with developing hyperkalaemia were explored using mixed-effects logistic regression and odds ratios (OR) are reported. Results 421 prevalent kidney transplant recipients were admitted a total of 1,065 times via the Emergency Department and a further 475 times direct to the Transplant ward. 324 (77%) were deceased-donor recipients with 83 (20%) living-donor recipients and 14 (3%) simultaneous pancreas kidney (SPK) recipients. Median age of admitted recipients was 56 (IQR 44-65) years and 87% were of white ethnic origin. Mean serum potassium was 4.56±0.72 mmol/L compared to 4.21±0.61 mmol/L amongst the 170,913 non-kidney transplant patients admitted over the same time period (p Hyperkalaemia >5.5mmol/L occurred in 282 (67%) of 421 prevalent kidney transplant recipients with 203 (48%) patients including all SPK recipients experiencing moderate-severe hyperkalaemia (K >=6.0mmol/L). Of these, 110 (39%) received emergency treatment with insulin/dextrose. Potassium concentration immediately (≤ 60 min) pre-treatment was 6.26±0.76 mmol/L. The mean reduction in potassium at 4-hours post treatment was 0.89±0.90 mmol/L. Twenty-five of 110 (23%) patients developed hypoglycaemia (glucose Kidney transplant recipients were at significantly increased risk of developing hyperkalaemia (OR 19.8, 95% Confidence Interval (CI) 16.2-24.4, p Conclusion Kidney transplant recipients are at greatly increased risk of developing hyperkalaemia. Recipients who become hyperkalaemic are more likely to have received a deceased-donor transplant and be prescribed beta-blockers and calcineurin inhibitors than those who do not. Insulin/dextrose for hyperkalaemia is associated with hypoglycaemia in almost 1 in 4 recipients treated and re-treatment is required in one third of recipients.

Background Hyperkalaemia is a common and life-threatening medical emergency present in up to 10% of acute hospital admissions. End-stage Kidney Disease (ESKD) patients undergoing transplantation are at increased risk of hyperkalaemia and although the prevalence of hyperkalaemia in ESKD is well described, few studies have assessed the incidence and treatment of hyperkalaemia in kidney transplant recipients. Here, we describe the results from a retrospective review of peri-operative hyperkalaemia in incident deceased-donor kidney transplant recipients. Methods We conducted a retrospective electronic health record review of 172 consecutive deceased-donor kidney recipients at Addenbrooke’s Hospital, Cambridge between November 2018 and November 2019. Patients receiving simultaneous pancreas/kidney transplants, simultaneous liver/kidney or multi-visceral transplants were excluded as were living-donor kidney recipients. Variables abstracted included demographics, the type of organ received, pre-transplant renal replacement modality, treatments received for hyperkalaemia, serum potassium values and admission and discharge dates. Data were summarised as frequency (%), mean ± standard deviation (SD) or median with interquartile range (IQR) as appropriate. Categorical variables were compared by Chi-squared test and continuous variables by Student's t-test or Mann–Whitney U-test based on their distribution. Results 172 patients received a deceased-donor kidney during the study period and the median age of all recipients was 56 (IQR 46-64.5) years. 110 (64%) patients received a DCD (donation after circulatory death) kidney with the remaining 62 (36%) receiving DBD (donation after brainstem death) kidneys. 110 (64%) of recipients received haemodialysis prior to transplant. Mean serum potassium prior to transplant was 4.22±0.61 mmol/L and immediately post-operatively was 4.69±0.61 mmol/L. 85 (49%) recipients required emergency treatment for hyperkalaemia post-operatively. The median serum potassium prior to treatment was 5.98mmol/L (IQR 5.7-6.2) with median time to treatment of 6.8 hours (IQR 2.4-9.6) after kidney reperfusion. Of these patients 64% underwent emergency haemodialysis as the first line treatment for hyperkalaemia, whilst 24 of the 31 patients treated with insulin/dextrose for hyperkalaemia went on to receive haemodialysis for hyperkalaemia. Median length of stay was longer in those receiving treatment for hyperkalaemia (9 days (7-13) vs 7 days (6-10), p=0.005). Additional data is described in the figure below. Conclusion Hyperkalaemia amongst kidney transplant recipients is common, particularly in the peri-operative period. Current management strategies contribute to morbidity, with haemodialysis in the first week also independently associated with increased healthcare costs per patient in the first year following transplantation. New oral potassium binders may offer an alternative or adjunct to current management but there is a lack of data for their use in transplant patients. Clinical trials in the transplant peri-operative setting are warranted.

Renal transplantation is the preferred option for the treatment of endstage chronic renal failure in patients for whom there are no major medical contraindications. In well-selected recipients, both life expectancy and quality of life are superior to treatment with long-term dialysis. However, as the dialysis population continues to grow, the gap between supply and demand for renal transplantation is widening. Immunosuppression—excepting for transplants between HLA-identical twins, immunosuppression is required to prevent rejection, but there is no clear consensus on the best immunosuppressive regimen. Most centres use an induction antibody directed against CD25 or a T-lymphocyte-depleting antibody (thymoglobulin or alemtuzumab), followed by what is now called standard triple therapy—comprising a calcineurin inhibitor (almost always tacrolimus), combined with either mycophenolate mofetil or azathioprine, and steroids. Steroids are not infrequently tailed off rapidly in the early post-transplant period. Transplant rejection can be classified into four main categories: (1) hyperacute, (2) accelerated, (3) acute cellular, and (4) humoral. Complications of renal transplantation—this chapter discusses specific and nonspecific side effects of immunosuppressive agents, infective complications (including viral, bacterial, fungal, and parasitic infections), malignant complications, and other complications (including hypertension, accelerated atherosclerosis, and electrolyte, musculoskeletal, haematological, gastrointestinal, and cosmetic disorders) in detail. Prognosis—first-year transplant losses from rejection have been dramatically reduced from about 40% in the 1970s to 5%. However, the rate of chronic graft loss remains at about 4% per year. The commonest cause of insidious late graft failure is probably chronic antibody-mediated rejection, frequently associated with poor adherence to immunosuppression. Calcineurin toxicity may also contribute. A major focus of research is to identify non-nephrotoxic immunosuppressive agents able to suppress antibody-mediated rejection.

Summary Background B cells produce alloantibodies and activate alloreactive T cells, negatively affecting kidney transplant survival. By contrast, regulatory B cells are associated with transplant tolerance. Immunotherapies are needed that inhibit B-cell effector function, including antibody secretion, while sparing regulators and minimising infection risk. B lymphocyte stimulator (BLyS) is a cytokine that promotes B-cell activation and has not previously been targeted in kidney transplant recipients. We aimed to determine the safety and activity of an anti-BLyS antibody, belimumab, in addition to standard-of-care immunosuppression in adult kidney transplant recipients. We used an experimental medicine study design with multiple secondary and exploratory endpoints to gain further insight into the effect of belimumab on the generation of de-novo IgG and on the regulatory B-cell compartment. Methods We undertook a double-blind, randomised, placebo-controlled phase 2 trial of belimumab, in addition to standard-of-care immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, and prednisolone) at two centres, Addenbrooke's Hospital, Cambridge, UK, and Guy's and St Thomas' Hospital, London, UK. Participants were eligible if they were aged 18–75 years and receiving a kidney transplant and were planned to receive standard-of-care immunosuppression. Participants were randomly assigned (1:1) to receive either intravenous belimumab 10 mg per kg bodyweight or placebo, given at day 0, 14, and 28, and then every 4 weeks for a total of seven infusions. The co-primary endpoints were safety and change in the concentration of naive B cells from baseline to week 24, both of which were analysed in all patients who received a transplant and at least one dose of drug or placebo (the modified intention-to-treat [mITT] population). This trial has been completed and is registered with ClinicalTrials.gov, NCT01536379, and EudraCT, 2011–006215–56. Findings Between Sept 13, 2013, and Feb 8, 2015, of 303 patients assessed for eligibility, 28 kidney transplant recipients were randomly assigned to receive belimumab (n=14) or placebo (n=14). 25 patients (12 [86%] patients assigned to the belimumab group and 13 [93%] patients assigned to the placebo group) received a transplant and were included in the mITT population. We observed similar proportions of adverse events in the belimumab and placebo groups, including serious infections (one [8%] of 12 in the belimumab group and five [38%] of 13 in the placebo group during the 6-month on-treatment phase; and none in the belimumab group and two [15%] in the placebo group during the 6-month follow-up). In the on-treatment phase, one patient in the placebo group died because of fatal myocardial infarction and acute cardiac failure. The co-primary endpoint of a reduction in naive B cells from baseline to week 24 was not met. Treatment with belimumab did not significantly reduce the number of naive B cells from baseline to week 24 (adjusted mean difference between the belimumab and placebo treatment groups −34·4 cells per μL, 95% CI −109·5 to 40·7). Interpretation Belimumab might be a useful adjunct to standard-of-care immunosuppression in renal transplantation, with no major increased risk of infection and potential beneficial effects on humoral alloimmunity. Funding GlaxoSmithKline.

Background: Post-transplant lymphoproliferative disease (PTLD) confers a high morbidity and mortality in a vulnerable population. We present the epidemiology and outcomes of PTLD in a large UK cohort of solid organ transplant (SOT) recipients who were transplanted over a 20-year period. Methods: This is a retrospective study of 5365 SOT recipients who had their first transplant between 2000 and 2021 at two UK transplant centres (Addenbrooke's Hospital and Papworth Hospital). We reviewed the records of all patients and found 142 who subsequently developed PTLD. For each type of transplant, we calculated the incidence rate of PTLD and cumulative incidence using a competing risk of death model. Survival was compared with the age-adjusted life expectancy of the UK population using the National life tables and a landmark analysis was performed to compare overall survival (OS) of PTLD patients from the date of diagnosis with the background survival of the transplant population. To compare treatment outcomes, a subset of 90 cases of monomorphic PTLD, DLBCL subtype were identified. 66 were treated with first-line Rituximab monotherapy and 24 received first-line R-Chemotherapy. Demographics, treatment response, and survival data were analysed with univariate and multivariate analysis to identify covariates associated with death in the first year post diagnosis of PTLD. Results: With a median follow-up time of 5.3 years, 142 of 5365 solid organ transplant recipients have developed PTLD (56/1965 kidney, 22/1428 liver, 12/327 simultaneous kidney-pancreas (SPK), 21/113 multivisceral (MVT), 10/778 heart, 15/503 bilateral lung, 3/148 single lung and 3/85 heart and lung). The incidence rate of PTLD was highest in the first year post-transplant in lung and MVT recipients. Cumulative incidence (shown in Figure 1) was 18% at 5 years post-MVT and 1-3% at 5 years following the other SOT types. Cumulative incidence was lowest for liver and heart transplants and was 10% at 20 years post-kidney transplantation. Median OS following SOT was 16 years which is significantly reduced compared with the age-adjusted UK population. There is a relatively high early mortality rate following diagnosis of PTLD and only patients surviving two years post diagnosis regained a similar longer-term survival to the non-PTLD SOT cohort. Treatment with rituximab monotherapy (RM) is now a standard of care for monomorphic PTLD 1. Outcomes for monomorphic patients were compared between those treated with RM (n=66, median follow-up 2.2 y) and R-Chemotherapy (n=24, median follow-up 5.2 y). The two groups were well matched for age and IPI. Of the 66 RM patients, 22 (33%) achieved complete remission with RM and required no further treatment. A further 18 (27%) patients achieved remission following further treatment with chemotherapy/surgery/CTL. 6/66 (9%) patients died of progressive disease (PD), 9/66 (14%) died pre-remission of non-PTLD causes and 11/66 (17%) died in remission of unrelated causes. In the R-Chemotherapy group, 22 patients received R-CHOP and 2 received R-CVP (n=24). 8 (33%) patients are alive and in remission after first line treatment and a further 3 patients (13%) after second line treatment. 2/24 (8%) patients died of PD, 4/24 (17%) died pre-remission of non-PTLD causes and 7/24 (30%) died post-remission of unrelated causes. There is no significant difference in OS between the two groups. Only a minority of deaths were due to PD and death from non-lymphoma causes pre and post remission remain considerably higher than non-PTLD SOT patients up to 2 years post treatment (Figure 1). Multivariate analysis of all 90 monomorphic PTLD patients identified IPI3+ as the strongest pre-treatment variable associating with inferior 1 year OS. Interestingly IPI3+ did not retain this significance when R-chemo patients were analysed alone. Conclusion: With this large SOT dataset we have mapped the cumulative incidence of PTLD over a 20 year period and highlight transplanted organ-specific differences in PTLD incidence over time. Treating monomorphic DLBL patients first-line with RM rather than R-chemotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes pre- and post-treatment remains high with both treatment approaches, with poor OS compared with age-matched non-PTLD SOT recipients. 1Trappe et al. Lancet Oncol; 2012 13(2):196-206 Figure 1 Figure 1. Disclosures Santarsieri: Janssen: Honoraria. Uttenthal: Roche: Other; Takeda: Other; Jazz: Other. Follows: Janssen, Abvie, Roche, AZ: Other.

Aims: Post-transplant thrombotic microangiopathy (TMA) is a rare and clinically challenging finding in renal transplant biopsies. In addition to recurrent atypical haemolytic uraemic syndrome, TMA in renal transplants is associated with various conditions, such as calcineurin inhibitor (CNI) treatment, antibody-mediated rejection (ABMR), viral infections, sepsis, pregnancy, malignancies, and surgery. The therapeutic implications of this diagnosis are considerable. In order to better understand post-transplant TMA and to identify histological or clinical differences between associated causes, we conducted a multicentre retrospective study. Methods and results: Clinical parameters and transplant renal biopsy findings from 81 patients with TMA were analysed. Biopsies from 38 patients were also analysed with electron microscopy. On the basis of clinical–pathological correlation, TMA was attributed to a main aetiology, whenever possible. TMA occurred at a median of 30 days post-transplantation. Systemic features of TMA were present in only 18% of cases. Twenty-two per cent of cases were attributed to CNI and 11% to ABMR. Although other potentially contributing factors were found in 56% of patients, in most cases (63%) no clearly attributable cause of TMA was identified. Histological differences between groups were minimal. The detection of ultrastructural features that are usually associated with ABMR may help to establish ABMR as the cause of TMA. Conclusions: Although CNI and ABMR appear to be the main contributors to post-transplant TMA, the aetiology of most cases is probably multifactorial, and TMA cannot be unequivocally attributed to a single underlying aetiology. Morphological features of TMA are not discriminating, but electron microscopy may help to identify ABMR-associated TMA.

Most kidneys from potential elderly circulatory death (DCD) donors are declined. We report single center outcomes for kidneys transplanted from DCD donors over 70 years old, using preimplantation biopsy Remuzzi grading to inform implantation as single or dual transplants. Between 2009 and 2012, 43 single transplants and 12 dual transplants were performed from elderly DCD donors. Remuzzi scores were higher for dual than single implants (4.4 vs. 3.4, p

Histological assessment of baseline chronic kidney injury may discriminate kidneys that are suitable for transplantation, but has not been validated for appraisal of donation after circulatory death (DCD) kidneys. 'Time-zero' biopsies for 371 consecutive, solitary, deceased-donor kidneys transplanted at our center between 2006 and 2010 (65.5% DCD, 34.5% donation after brain death [DBD]) were reviewed and baseline chronic degenerative injury scored using Remuzzi's classification. High scores correlated with donor age and extended criteria donors (42% of donors), but the spectrum of scores was similar for DCD and DBD kidneys. Transplant outcomes for kidneys scoring from 0 to 4 were comparable (1 and 3 year graft survival 95% and 92%), but were much poorer for kidneys scoring ≥5, with 1 year graft survival only 73%, and 12.5% suffering primary nonfunction. Critically, high Remuzzi scores conferred the same survival disadvantage for DCD and DBD kidneys. On multi-variable regression analysis, time-zero biopsy score was the only independent predictor for graft survival, whereas one-year graft estimated glomerular filtration rate (eGFR) correlated with donor age and biopsy score. In conclusion, the relationship between severity of chronic kidney injury and transplant outcome is similar for DCD and DBD kidneys. Kidneys with Remuzzi scores of ≤4 can be implanted singly with acceptable results.

We have analyzed the relationship between donor mismatches at each HLA locus and development of HLA locus-specific antibodies in patients listed for repeat transplantation. HLA antibody screening was undertaken using single-antigen beads in 131 kidney transplant recipients returning to the transplant waiting list following first graft failure. The number of HLA mismatches and the calculated reaction frequency of antibody reactivity against 10,000 consecutive deceased organ donors were determined for each HLA locus. Two-thirds of patients awaiting repeat transplantation were sensitized (calculated reaction frequency over 15%) and half were highly sensitized (calculated reaction frequency of 85% and greater). Antibody levels peaked after re-listing for repeat transplantation, were independent of graft nephrectomy and were associated with length of time on the waiting list (odds ratio 8.4) and with maintenance on dual immunosuppression (odds ratio 0.2). Sensitization was independently associated with increasing number of donor HLA mismatches (odds ratio 1.4). All mismatched HLA loci contributed to the development of HLA locus-specific antibodies (HLA-A: odds ratio 3.2, HLA-B: odds ratio 3.4, HLA-C: odds ratio 2.5, HLA-DRB1: odds ratio 3.5, HLA-DRB3/4/5: odds ratio 3.9, and HLA-DQ: odds ratio 3.0 (all significant)). Thus, the risk of allosensitization following failure of a first renal transplant increases incrementally with the number of mismatches at all HLA loci assessed. Maintenance of re-listed patients on dual immunosuppression was associated with a reduced risk of sensitization.

With calcineurin inhibitors potentiating damage from ischaemia-reperfusion injury in kidneys from donors after cardiac death we wanted to investigate the role of substituting sirolimus for tacrolimus in the delayed introduction of calcineurin inhibitor regime used in our centre.A prospective randomised paired open-label study was performed taking pairs of kidneys from each donor and randomising one to a tacrolimus-based regime and the other to a similar regime based on sirolimus. Graft function at one year was the primary endpoint.Total 31 pairs of kidneys were randomised to each group, with 19 pairs of recipients available for analysis after post-randomisation study exclusions. Despite a higher incidence of biopsy proven acute rejection in the sirolimus group, renal allograft function was similar in both groups at three-monthly intervals up to one year post-transplant. All episodes of acute rejection in the sirolimus group occurred in the first three months. Graft and patient survival at one year was 100% in the tacrolimus group, with one death with functioning graft in the sirolimus group (95% survival). Unfortunately, 10 of the 19 patients in the sirolimus arm required switch of medication to tacrolimus due to acute rejection or intolerable drug side effects.Graft survival and function were very similar in the two groups despite the higher rate of acute rejection in the sirolimus arm, raising the possibility that the damage done by acute rejection was adequately offset by the nephron-sparing effect of sirolimus compared to tacrolimus. Sirolimus may have a role as a longer-term maintenance immunosuppressant after initial treatment with a different agent such as tacrolimus or belatacept.

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.

In the United Kingdom, donation after circulatory death (DCD) kidney transplant activity has increased rapidly, but marked regional variation persists. We report how increased DCD kidney transplant activity influenced waitlisted outcomes for a single center. Between 2002–2003 and 2011–2012, 430 (54%) DCD and 361 (46%) donation after brain death (DBD) kidney-only transplants were performed at the Cambridge Transplant Centre, with a higher proportion of DCD donors fulfilling expanded criteria status (41% DCD vs. 32% DBD; p = 0.01). Compared with U.K. outcomes, for which the proportion of DCD:DBD kidney transplants performed is lower (25%; p < 0.0001), listed patients at our center waited less time for transplantation (645 vs. 1045 days; p < 0.0001), and our center had higher transplantation rates and lower numbers of waiting list deaths. This was most apparent for older patients (aged >65 years; waiting time 730 vs. 1357 days nationally; p < 0.001), who received predominantly DCD kidneys from older donors (mean donor age 64 years), whereas younger recipients received equal proportions of living donor, DBD and DCD kidney transplants. Death-censored kidney graft survival was nevertheless comparable for younger and older recipients, although transplantation conferred a survival benefit from listing for only younger recipients. Local expansion in DCD kidney transplant activity improves survival outcomes for younger patients and addresses inequity of access to transplantation for older recipients.

Donor-specific alloantibodies (DSA) mediate hyperacute and acute antibody-mediated rejection (AMR), which can lead to early graft damage and loss, and are also associated with chronic AMR and reduced long-term graft survival. Such alloantibodies can be generated by previous exposure to major histocompatibility (MHC) antigens (usually via blood transfusions, previous allografts or pregnancy) or can occur de novo after transplantation. Recent studies also suggest that non-MHC antibodies, including those recognising major histocompatibility complex class I-related chain A (MICA), MICB, vimentin, angiotensin II type I receptor may also have an adverse impact on allograft outcomes. In this review, we consider how the dose, route and context of antigen exposure influences DSA induction and describe factors which control the generation, maintenance and survival of alloantibody-producing plasma cells. Finally, we discuss the implications of these variables on therapeutic approaches to DSA.

Background. Acute tubulo-interstitial nephritis (TIN) is an important cause of acute renal failure, and is often caused by hypersensitivity to drugs. The aim of this study was to determine the aetiology of interstitial nephritis among an unselected cohort of patients, and to identify those drugs commonly implicated. Methods. A single-centre retrospective analysis was carried out of renal biopsy results from 296 consecutive patients between 1995 and 1999. Results. Acute TIN was identified in 24 (8.1%) biopsies. Eight out of 14 cases with presumed drugrelated TIN could be attributed to the proton pump inhibitors omeprazole and lansoprazole. The two cases of lansoprazole-associated TIN are the first to be reported with this drug. The presentation and favourable response to treatment of these patients are described. Conclusion. Drugs are the most common cause of interstitial nephritis in the population studied. Those drugs most commonly associated with interstitial nephritis were the proton pump inhibitors omeprazole and lansoprazole.

Early graft loss (EGL) after kidney transplantation is a catastrophic outcome that is assumed to be more likely after the use of kidneys from suboptimal donors. We therefore examined its incidence, risk factors and consequences in our center in relation to different donor types. Of 801 recipients who received a kidney-only transplant from deceased donors, 50 (6.2%) suffered EGL within 30 days of transplantation. Significant risks factors for EGL were donation after circulatory death (DCD) (odds ratio [OR] 2.88; p = 0.006), expanded criteria donor (ECD) transplantation (OR 4.22; p = 0.010), donor age (OR 1.03; p = 0.044) and recipient past history of thrombosis (OR 4.91; p = 0.001). Recipients with EGL had 12.28 times increased risk of death within the first year, but long-term survival was worse for patients remaining on the waiting list. In comparison with patients on the waiting list but not transplanted, and with all patients on the waiting list, the risk of death after EGL decreased to baseline 4 and 23 months after transplantation, respectively. Our findings suggest that DCD and ECD transplantation are significant risk factors for EGL, which is a major risk factor for recipient death. However, long-term mortality is even greater for those remaining on the waiting list.

The mammalian c-kit receptor tyrosine kinase gene is required during embryogenesis for the survival and/or proliferation of three migrating stem cell populations: primordial germ cells, haematopoietic stem cells and neural crest-derived melanoblasts. We have cloned a Xenopus gene, XKrk1, whose closest relative is c-kit. Differences in the expression pattern suggest that XKrk1 is not the Xenopus homologue of c-kit; however, it is expressed in a migrating stem cell population, the precursor cells for the mechanosensory lateral line system. XKrk1 is the first reported marker for lateral line stem cells.

Atypical hemolytic uremic syndrome was diagnosed in a 62-year-old man. Sequencing of the CFH gene, which encodes complement factor H, revealed a heterozygous adenine to guanine mutation at nucleotide 3550 of the complementary DNA, leading to a predicted substitution of alanine for threonine at amino acid position 1184 in the protein (c.3550A>G, p.Thr1184Ala). Three years later, he received a simultaneous liver-kidney transplant with plasmapheresis and intratransplant plasma infusion. The postoperative course was complicated by an anastomotic biliary stricture that was treated successfully using endoscopic stenting. One year later, he has excellent function of both transplants, emphasizing that simultaneous liver-kidney transplant is a valuable treatment option in the management of adult patients with atypical hemolytic uremic syndrome.

The effects of depleting a maternal cytokeratin mRNA on the developing embryo are described. Cytokeratins are members of the intermediate filament family of cytoskeletal proteins, and are expressed in a cortical network of the superficial cytoplasm of the oocyte. After fertilisation, a new cortical network is built up, which comes to occupy only the most superficial cells of the blastula. The maternal cytokeratin mRNA is abundantly translated, both during oogenesis, and during oocyte maturation and after fertilisation. Depletion of the mRNA results in depletion of the cortical filaments at the blastula stage and leads to gastrulation abnormalities. We discuss the various possible control experiments required for antisense oligo depletion studies and the implications of these results for cytokeratin function.

A 63-year-old woman presented with a 2-day history of nausea, vomiting and abdominal pain. She deteriorated rapidly with the development of anuric acute kidney injury and respiratory failure, requiring admission to the intensive care unit for CVVH and ventilation. Her past medical history included type 2 diabetes mellitus, treated with insulin therapy and a previous right nephrectomy (12 years previously) for a renal cell carcinoma. Her pre-admission serum creatinine was 89 μmol/l, but previous HbA1c readings of 14.5% indicated suboptimal glycaemic control. Initial investigations confirmed sepsis; Escherichia coli grown from blood cultures was treated with i.v. tazocin. An abdominal CT scan (Figures ​(Figures11 and ​and2)2) demonstrated a dilated left kidney with air in the renal parenchyma, typical of emphysematous pyelonephritis, staged as Class 4 [4]. A plain AXR also demonstrated air within the left kidney (Figure ​(Figure3).3). Treatment consisted of continuous i.v. antibiotics for 4 weeks and subsequently two percutaneous nephrostomies to facilitate drainage. Fig. 1 Axial CT scan demonstrating dilatation and gas within the left kidney. Fig. 2 Axial CT scan image of left kidney reveals emphysematous pyelonephritis. Fig. 3 Plain AXR demonstrating gas within the left kidney. Urine output improved following treatment, but 3 months later the patient remains dialysis dependent and continues to suffer from urinary tract infections. Emphysematous pyelonephritis is typically seen in female diabetic patients and E. coli is the commonest isolated organism [4]. Low oxygen tension within the kidney enforces anaerobic metabolism in E. coli, which are facultative anaerobes [2]. Gas production is secondary to rapid tissue catabolism with fermentation of glucose to carbon dioxide, which is not effectively transported away and remains localized at the site of inflammation. Further ischaemia results in tissue necrosis and perpetuates an environment for gas formation. The resulting appearances on imaging are dramatic. Management should include fluid resuscitation, glycaemic control, antibiotics and drainage [3], but nephrectomy is sometimes necessary. Following recovery of the acute episode, function of the affected kidney, as in this case, is often very poor [1]. Conflict of interest statement. None declared.

As demand for donor pancreases increases, attempts are being made to utilize even marginal grafts for transplantation. Injury during pancreas recovery can predispose to posttransplant complications and graft loss. Early recognition and correction can salvage these grafts. The authors report an instance of poor segmental perfusion of the pancreas graft that was salvaged by pancreas head resection and enteric drainage through a Roux-en-Y pancreatico-jejunostomy.