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The coronavirus disease, COVID-19, has caused widespread and sustained disruption to healthcare, not only in the delivery of emergency care, but knock-on consequences have resulted in major delays to the delivery of elective care, including surgery. COVID-19 has accelerated novel pathways for delivering clinical services, many of which have an increased reliance on technology. COVID-19 has impacted care for patients with both hypoparathyroidism and hyperparathyroidism. The role of vitamin D in the prevention of severe COVID-19 infection has also been widely debated. Severe hypocalcemia can be precipitated by infection in patients with hypoparathyroidism. With this in mind, compliance with medical management, including calcium and vitamin D supplementation, is crucial. Technology in the form of text message reminders and smartphone apps may have a key role in ensuring this. Furthermore, clinicians should ensure that patients are educated on the symptoms of hypocalcemia and the steps needing to be taken should these symptoms be experienced. Patients with primary hyperparathyroidism (PHPT) should be educated on the symptoms of hypercalcemia, as well as the importance of remaining adequately hydrated. In addition, patients should be reassured that the postponement of parathyroidectomy is likely to have negligible impact on their condition; for those with symptomatic hypercalcemia, cinacalcet can be considered as an interim measure.

Fluid shear stress is a key modulator of cellular physiology in vitro and in vivo, but its effects are under-investigated due to requirements for complicated induction methods. Herein we report the validation of ShearFAST; a smartphone application that measures the rocking profile on a standard laboratory cell rocker and calculates the resulting shear stress arising in tissue culture plates. The accuracy with which this novel approach measured rocking profiles was validated against a graphical analysis, and also against measures reported by an 8-camera motion tracking system. ShearFASTs angle assessments correlated well with both analyses (r ≥0.99, p ≤0.001) with no significant differences in pitch detected across the range of rocking angles tested. Rocking frequency assessment by ShearFAST also correlated well when compared to the two independent validatory techniques (r ≥0.99, p ≤0.0001), with excellent reproducibility between ShearFAST and video analysis (mean frequency measurement difference of 0.006 ± 0.005Hz) and motion capture analysis (mean frequency measurement difference of 0.008 ± 0.012Hz). These data make the ShearFAST assisted cell rocker model make it an attractive approach for economical, high throughput fluid shear stress experiments. Proof of concept data presented reveals a protective effect of low-level shear stress on renal proximal tubule cells submitted to simulations of pretransplant storage.

Evidence is currently lacking regarding the outcomes of kidneys undergoing hypothermic machine perfusion (HMP) in patients in the United Kingdom. Using the National Health Service Blood and Transplant database, the authors compared outcomes for recipients of single-organ donation after circulatory death (DCD) kidneys preserved with HMP with those preserved using only static cold storage (SCS). Between 2007 and 2015, HMP was used in 19.1% (864/4,529) of kidneys. Rates of delayed graft function (DGF) were significantly lower in organs preserved with HMP than for organs preserved with SCS (34.2% vs 42.0%, P

The aim of this study was to determine the effect of donor body mass index (BMI) on deceased donor kidney transplant outcomes. Data were collected from the UK Transplant Registry for all deceased donor kidney transplant recipients between January 2003 and January 2015. Univariable and multivariable analyses were undertaken to assess the impact of donor BMI on a range of outcomes. Donor BMI (kg/m2 ) was stratified as 35.0 (n = 1148). The prevalence of delayed graft function increased significantly with donor BMI (P 35.0 vs. 18.5-25.0 groups. However, there was no significant association between donor BMI and 12-month creatinine (P = 0.550), or patient (P = 0.109) or graft (P = 0.590) survival. In overweight patients, increasing donor BMI was associated with a significant increase in warm ischaemia time and functional warm ischaemia time, by an average of 4.6% (P = 0.043) and 5.2% (P = 0.013) per 10.0 kg/m2 . However, rising warm ischaemic time and functional warm ischaemic time was not significantly associated with delayed graft function, 12-month creatinine levels, graft loss or patient death. In this population cohort study, we identified no significant association between donor BMI and long-term clinical outcomes in deceased donor kidney transplantation.

Hypothermic machine perfusion (HMP) and static cold storage (SCS) are the two methods used to preserve deceased donor kidneys prior to transplant. This study seeks to characterise the metabolic profile of HMP and SCS porcine kidneys in a cardiac death donor model. Twenty kidneys were cold flushed and stored for two hours following retrieval. Paired kidneys then underwent 24 h of HMP or SCS or served as time zero controls. Metabolite quantification in both storage fluid and kidney tissue was performed using one dimensional 1H NMR spectroscopy. For each metabolite, the net gain for each storage modality was determined by comparing the total amount in each closed system (i.e. total amount in storage fluid and kidney combined) compared with controls. 26 metabolites were included for analysis. Total system metabolite quantities following HMP or SCS were greater for 14 compared with controls (all p The metabolic environments of both perfusion fluid and the kidney tissue are strikingly different between SCS and HMP systems in this animal model. The total amount of central metabolites such as lactate and glutamate observed in the HMP kidney system suggests a greater degree of de novo metabolic activity than in the SCS system. Maintenance of central metabolic pathways may contribute to the clinical benefits of HMP.

BACKGROUND Current transplant immunosuppression regimens have numerous limitations. Recent evidence suggests histone deacetylase inhibitors (HDACis) may represent a class of drug with immunosuppressive properties. This study compares cyclosporin A (CyA) with the pan-HDACi suberoylanilide hydroxamic acid (SAHA) and a novel HDAC6-specific inhibitor (KA1010) in models of alloreactivity. METHODS Proliferation and mixed lymphocyte reaction (MLR)-based assays were used to determine the immunosuppressive effect of compounds, and a murine model of allogeneic skin transplantation was adopted to assess the in vivo effects of HDAC6 inhibition. RESULTS KA1010 displayed superior inhibitory effects on the activation of peripheral mononuclear cells using in vitro models of transplantation. In a 1-way MLR, KA1010 (5 μΜ) reduced parent cell proliferation from 92% to 64% (P = 0.001). A 2-way MLR, adopting IFN-γ production as a marker of alloresponse, resulting in up to 91% reduction. Dose-response curves revealed dose-dependent profiles with greater potency of HDACis over CyA (IC50 values of 82.0 nM and 13.4 nM for KA1010 and SAHA).Mice treated with KA1010 displayed no significant features of skin allograft rejection upon histological analysis at 70 days and graft survival of 80% in subjects treated with 160 mg/kg. Immunological assessment, revealed a significant increase in CD4CD25forkhead box P3 regulatory T cells (from 18% to 25%, P = 0.0002) and a corresponding reduction in CD4 T cells (from 58% to 42%, P = 0.0009). CONCLUSIONS HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this article, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted.

Background The aim of the present study was to determine the effects of cold ischaemia time (CIT) on living donor kidney transplant recipients in a large national data set. Methods Data from the National Health Service Blood and Transplant and UK Renal Registry databases for all patients receiving a living donor kidney transplant in the UK between January 2001 and December 2014 were analysed. Patients were divided into three groups depending on CIT (less than 2 h, 2–4 h, 4–8 h). Risk-adjusted outcomes were assessed by multivariable analysis adjusting for discordance in both donor and recipient characteristics. Results Outcomes of 9156 transplants were analysed (CIT less than 2 h in 2662, 2–4 h in 4652, and 4–8 h in 1842). After adjusting for confounders, there was no significant difference in patient survival between CIT groups. Recipients of kidneys with a CIT of 4–8 h had excellent graft outcomes, although these were slightly inferior to outcomes in those with a CIT of less than 2 h, with risk-adjusted rates of delayed graft function of 8·6 versus 4·3 per cent, and 1-year graft survival rates of 96·2 versus 97·1 per cent, respectively. Conclusion The detrimental effect of prolonging CIT for up to 8 h in living donation kidney transplantation is marginal.

Summary South Asians have increased risk for type 2 diabetes mellitus compared with Caucasians in the general population, but data for the development of post-transplantation diabetes mellitus (PTDM) is scarce. In this retrospective analysis, data was extracted from electronic patient records at a single centre (2004–2014). Caucasians were more likely to be male, with higher age and BMI than South Asians. Case–control matching was therefore undertaken to remove this bias, resulting in 102 recipient pairs. Median follow-up was 50 months (range 4–127 months). Matched groups had similar baseline characteristics, although South Asians compared with Caucasians received more deceased-donor kidneys (74% vs. 43%, respectively, P < 0.001) and were more likely to be CMV positive (77% vs. 43%, respectively, P < 0.001). PTDM incidence was significantly higher in South Asians versus Caucasians (35% vs. 10%, respectively, subhazard ratio 4.2 [95% CI: 2.1–8.5, P < 0.001]). Donor type had significant interaction with ethnicity, with the observed difference in PTDM rates between ethnicities most visible with receipt of deceased-donor kidneys. No significant difference was detected in allograft function, rejection episodes, adverse cardiovascular events or patient/graft survival. South Asians have increased risk of PTDM, especially recipients of deceased kidneys, and recognition of this allows appropriate patient counselling and development of targeted strategies.

BACKGROUND Supplemental oxygenation of the standard hypothermic machine perfusion (HMP) circuit has the potential to invoke favorable changes in metabolism, optimizing cadaveric organs before transplantation. METHODS Eight pairs of porcine kidneys underwent 18 hours of either oxygenated (HMP/O2) or aerated (HMP/Air) HMP in a paired donation after circulatory death model of transplantation. Circulating perfusion fluid was supplemented with the metabolic tracer universally labeled glucose.Perfusate, end-point renal cortex, and medulla samples underwent metabolomic analysis using 1-dimension and 2-dimension nuclear magnetic resonance experiments in addition to gas chromatography-mass spectrometry. Analysis of C-labeled metabolic products was combined with adenosine nucleotide levels and differences in tissue architecture. RESULTS Metabolomic analysis revealed significantly higher concentrations of universally labeled lactate in the cortex of HMP/Air versus HMP/O2 kidneys (0.056 mM vs 0.026 mM, P < 0.05). Conversely, newly synthesized [4,5-C] glutamate concentrations were higher in the cortex of HMP/O2 kidneys inferring relative increases in tricarboxylic acid cycle activity versus HMP/Air kidneys (0.013 mmol/L vs 0.003 mmol/L, P < 0.05). This was associated with greater amounts of adenoside triphosphate in the cortex HMP/O2 versus HMP/Air kidneys (19.8 mmol/mg protein vs 2.8 mmol/mg protein, P < 0.05). Improved flow dynamics and favorable ultrastructural features were also observed in HMP/O2 kidneys. There were no differences in thiobarbituric acid reactive substances and reduced glutathione levels, tissue markers of oxidative stress, between groups. CONCLUSIONS The supplementation of perfusion fluid with high-concentration oxygen (95%) results in a greater degree of aerobic metabolism versus aeration (21%) in the nonphysiological environment of HMP, with reciprocal changes in adenoside triphosphate levels.

Background Laparoscopic living-donor nephrectomy (LDN) exerts systemic effects causing transaminitis and increased urinary neutrophil gelatinase-associated lipocalm (NGAL) excretion. Hand-assisted laparoscopic donor nephrectomy, which tends to be shorter with less pneumoperitoneum, may be hypothesized to produce less systemic stimulation than total laparoscopic LDN. Methods Serial urine and serum samples were collected from 15 patients undergoing HALDN. Samples were analyzed for NGAL and kidney injury molecule 1 (KIM-1) levels preoperatively and 24 hours post-surgery. Data relating to alanine aminotransferase, creatinine, and estimated glomerular filtration rate was also analyzed in 48 live donors preoperatively and at 24 hours and 48 hours post-surgery and compared to published data on LDN. Results Expected changes to creatinine and estimated glomerular filtration rates were observed in the donors. Compared to the preoperative levels, alanine aminotransferase levels showed a significant decrease at 24 hours (P = .004) and were not significantly different from baseline levels at 48 hours (P = .08). Serum KIM-1 and NGAL levels remained unchanged (P = .89 and P = .14, respectively) at 24 hours after donation. Similarly, urinary levels of KIM-1 and NGAL were not statistically significantly different after donation. Mean operating time for this cohort was 1 hour, 36 minutes. Conclusions In contrast to other published data, our cohort did not exhibit changes to liver function tests or biomarker changes after donor nephrectomy. This could be because of the lower operative time (96 minutes vs. 216 minutes) or because of the intermittent release of the pneumoperitoneum in the hand-assisted method which may exert less of a systemic inflammatory response.

Conflicting evidence surrounds clinical outcomes in obese individuals after transplantation; nonetheless, many are denied the opportunity to receive a transplant. Allografts with complex vascular anatomy are regularly used in both deceased and living donor settings. We established the risk of transplanting kidneys with multiple renal arteries into obese recipients. A retrospective analysis of data from 1095 patients undergoing renal transplantation between January 2004 and July 2013 at a single centre was conducted. Of these, 24.2% were obese (body mass index >30 kg/m 2 ), whereas 25.1% of kidneys transplanted had multiple arteries, thereby making the transplantation of kidneys of complex anatomy into obese recipients a relatively common clinical occurrence. Vessel multiplicity was associated with inferior 1-year graft survival (85.8.% vs 92.1%, P = .004). Obese patients had worse 1-graft survival compared to those of normal BMI (86.8% vs 93.8%, P = .001). The risk of vascular complications and of graft loss within a year after transplantation were greater when grafts with multiple arteries were transplanted into obese recipients as compared to their nonobese counterparts (RR 2.00, CI 95% 1.07–3.65, and RR 1.95, CI 95% 1.02–3.65). Additionally, obese patients faced significantly higher risk of graft loss if receiving a kidney with multiple arteries compared to one of normal anatomy (RR 1.97, 95% CI 1.02–3.72). Thus, obese patients receiving complex anatomy kidneys face poorer outcomes, which should be considered when allocating organs, seeking consent, and arranging for aftercare.

The need to introduce complex medical technologies in low- and middle-income countries (LMIC) is increasing, to improve quality of life and life expectancy. Despite improvements in medical infrastructure, many countries do not have the skills required to implement such technologies and need support from overseas organizations. Transplant Links (TLC) is a UK charity supporting the development of sustainable kidney transplant programs in LMIC countries. TLC's experience demonstrates health literacy challenges encountered in introducing a complex medical technology, of which transplantation is a good example. Such challenges were found to be wide-ranging, in a specialty already associated with low levels of health literacy. Nevertheless, such challenges need to be addressed and measures undertaken to improve the level of understanding of renal failure and transplantation by patients, families, healthcare workers, and other stakeholders including politicians, healthcare managers, and the media. These measures may be transferable to the development of other complex medical technologies.

Background Deceased kidney donors are increasingly “marginal,” and many have risk factors for acute kidney injury (AKI) that may impact on subsequent renal transplant outcome. Despite this, determining the presence of AKI at the time of deceased organ donation remains difficult. Methods Urine samples from 182 brainstem dead multi-organ donors (all of whom donated hearts that were transplanted) were analyzed for a Luminex™ panel of biomarkers linked with AKI. This included KIM-1, NGAL, IFN-γ, TNF-α, cystatin C, Fractalkine and vascular endothelial growth factor. Levels were correlated to early renal transplant outcomes, most specifically delayed graft function. Results Donor urinary KIM-1 levels were significantly higher in donors whose kidneys displayed aberrant early function (p = 0.011). Fractalkine levels showed a trend toward elevation in such donors but uncorrected this did not attain significance. No correlation occurred with the remaining biomarkers. Conclusions KIM-1 appears to show promise as a marker for AKI in deceased cardiac organ donors. The availability of a lateral flow device (Renastick™) for KIM-1 that also demonstrates higher urinary KIM-1 levels in donors whose kidneys show aberrant initial function (p = 0.03), makes KIM-1 a potential indicator of AKI that may merit further evaluation for its application at the donor bedside.

Background The aim of this study is to determine the feasibility of using nuclear magnetic resonance (NMR) tracer studies (13C-enriched glucose) to detect ex vivo de novo metabolism in the perfusion fluid and cortical tissue of porcine kidneys during hypothermic machine perfusion (HMP). Methods Porcine kidneys (n = 6) were subjected to 24 h of HMP using the Organ Recovery Systems LifePort Kidney perfusion device. Glucose, uniformly enriched with the stable isotope 13C ([U-13C] glucose), was incorporated into KPS-1-like perfusion fluid at a concentration of 10 mM. Analysis of perfusate was performed using both 1D 1H and 2D 1H,13C heteronuclear single quantum coherence (HSQC) NMR spectroscopy. The metabolic activity was then studied by quantifying the proportion of key metabolites containing 13C in both perfusate and tissue samples. Results There was significant enrichment of 13C in a number of central metabolites present in both the perfusate and tissue extracts and was most pronounced for lactate and alanine. The total amount of enriched lactate (per sample) in perfusion fluid increased during HMP (31.1 ± 12.2 nmol at 6 h vs 93.4 ± 25.6 nmol at 24 h p

Sickle cell disease is an inherited, structural hemoglobin defect with multisystemic sequelae including renal failure. Patients with sickle cell disease are thought to benefit from renal transplant, but the long-term outcomes in such patients are unclear and have not been supported by any large prospective studies. Similarly, the renal morbidity and outcome after transplant in patients with sickle cell trait is also unclear. There is little evidence concerning living donation in donors with sickle cell disease or sickle cell trait, either for the donor health or for the graft outcome, and there are no United Kingdom guidelines. The aim of this study is to review the evidence surrounding renal transplant in recipients and donors with sickle syndromes and to determine the attitudes and current practices of United Kingdom transplant centers to performing such operations.

Background Guidelines suggest tuberculosis (TB) prophylaxis in renal transplant recipients originating in endemic areas or in those at risk from non-endemic countries. Concern remains that these guidelines may fail to provide adequate prophylaxis for a cohort of patients who remain at potential risk. We aimed to determine variation patterns among different transplant units within the United Kingdom (UK) with regard to TB prophylaxis policy. Methods The renal pharmacist at each of the 25 UK renal transplant centers was contacted. Specific information was obtained relating to drug prophylaxis given, duration of treatment, as well as which transplant recipients were eligible for treatment. Results A 96% response rate (24/25 centers) was achieved. Prophylaxis regimens varied from no prophylaxis to isoniazid 300 mg given life-long. The most common duration of treatment was 6 months post transplantation (at 7 centers). Variations existed in the concurrent use of pyridoxine. A wide discrepancy was seen in the determination of who should receive prophylaxis, with no clear association with frequency of TB incidence in the region. Conclusions A marked discrepancy exists among national renal transplant units in pharmacologic prophylaxis for TB, as well in the selection of individuals for this treatment.

Background. The early identification of kidney allografts at risk of later dysfunction has implications for clinical practice. Donor quality scoring systems (preoperative) and measures of early allograft function (first week postoperative) have previously shown practical utility. This study aimed to determine the optimal parameter(s) (preoperative and postoperative) with greatest predictive power for the development of subsequent allograft dysfunction. Methods. Consecutive deceased donor renal transplants (n=217) were studied. In each, the following measures were assessed: Preoperative donor quality scores: expanded criteria donor status; Deceased Donor Score (Nyberg et al., Am J Transplant 2003;3:715); Donor Risk Score (Schold et al., Am J Transplant 2005; 5(4 pt 1): 757); and delayed graft function (DGF) Nomogram (Irish et al., J Am Soc Nephrol 2003; 14:2967). Postoperative early function measures: dialysis requirement and duration; extended DGF definition (Boom et al., Kidney Int 2000; 58:859); creatinine at day 5 and day 7; creatinine reduction ratios at day 2 and day 7; and urine output posttransplantation. Primary outcome measures were creatinine at 12 months and the development of chronic kidney disease stage 4T. Results. Of donor scoring systems, Donor Risk Score was best associated with subsequent allograft function. Of early function measures: the extended definition of DGF, creatinine at day 5, and dialysis duration showed greatest predictive power in the patient population overall, those not requiring postoperative dialysis, and those requiring dialysis, respectively. No scores or early function measures were associated with change in creatinine between 6 and 12 months. Conclusions. This study validates and identifies the optimal early predictive parameter available for kidney transplant recipients, with implications for refining early postoperative management and potential utility in organ allocation policy.

Acute rejection (AR) superimposed upon delayed graft function (DGF) following renal transplantation worsens graft outcomes. However, risk factors for AR in patients displaying DGF remain unclear. In this study, 71 patients displaying DGF >/= 5 d were investigated. All received cyclosporine, adjunctive azathioprine or mycophenolate mofetil (MMF), and corticosteroids, with 43 receiving anti-CD25 monoclonal antibody induction. AR episodes were seen in 20 of 71 (28%) patients. Higher C2 levels at days 3 and 5 and the use of MMF were associated with a reduced incidence of AR, with increased HLA-DR mismatch associated with an increased risk for AR. C2 levels at days 3 and 5 below 885 and 1096 ng/mL, respectively, showed best discriminatory values for AR. C2 levels showed no correlation with DGF duration. This study suggests that optimizing immunosuppression in patients with DGF (by ensuring adequate calcineurin inhibitor exposure and the use of potent adjunctive immunosuppression) may reduce the incidence of AR without prolonging the duration of dialysis requirement.

Renal transplantation is the gold standard treatment for end stage renal disease; however, there are currently not enough suitable organs to meet a growing demand. The Hypoxia Inducible Factor (HIF) pathway comprises a number of oxygen sensitive transcription factors which activate cellular protective functions. Allografts from cadaveric organs make up a large proportion of the organ pool. These organs are subjected to hypoxic and ischemic conditions during the harvesting and transplant process. Manipulation of the HIF pathway may reduce organ damage and improve outcomes. This review evaluates the current evidence for the use of the HIF pathway in renal transplantation and also adds new research conducted into the effect on organ metabolism.

As renal transplantation continues to evolve, there appears to be a change in both donor and recipient populations. Traditional markers of high-risk donor (e.g. donation after cardiac death [DCD]/expanded criteria donor [ECD]) and recipient (e.g. obese, highly sensitized) operations appear to be more common without any noticeable worsening of patient outcome. The present study aimed to compare outcome and define the change in donor and recipient populations for cadaveric transplants over a 10-year period at a large U.K. center.Single-center analysis of all adult patients undergoing cadaveric renal transplantation between January 2004 and January 2014 (n = 754). Transplants were divided into 3 groups (early, middle, and late) depending on the era, with donor, recipient and outcomes compared.There were considerable changes in both donor and recipient factors between the 3 eras, with a greater proportion of high-risk operations performed, as reflected by significant increases in Donor Risk Index (median: 1.11-1.16, P = .022), and the proportions of ECD (22.2%-33.9%, P = .003) and DCD kidneys (10.8%-19.4% P = .011). However, 1-year graft survival was comparable between the eras, with a decrease in the average 1-year serum creatinine between the early and late cohort (median: 161 μmol/L vs 132 μmol/L, P.001). There was no significant increase in body mass index (BMI) in either the donor or recipient population across the eras.Improvement in transplant outcome continues despite a greater proportion of transplants previously considered as high risk being performed. This is likely to reflect a considerable improvement in pre- and postoperative management. BMI remains a major continuing block to transplantation.

BACKGROUND: Blood group ABO-incompatible live donor (LD) renal transplantation may provide a significant source of organs. We report the results of our first 14 cases of ABO-incompatible LD renal transplantation using specific anti-A/B antibody (Ab) immunoadsorption (IA) and anti-CD20 monoclonal Ab (mAb) treatment. PATIENTS AND TREATMENT PROTOCOL: Recipients were blood group O (n = 12), A (n = 1) and B (n = 1). Donors were A1 (n = 2), A2 (n = 3), A2B (n = 1) and B (n = 8), and all were secretor positive. Anti-human leukocyte antigen (HLA) Ab panel reactivity was negative in all recipients except one. All recipients were pre-treated with 3 to 6 IA sessions, using A or B carbohydrate antigen columns, until their anti-A1/B RBC panel indirect antiglobulin test (IAT) titers were < or =8. CDC crossmatch was negative in all cases. Recipients received preoperative mycophenolic acid, and steroids/tacrolimus were started at transplantation. No splenectomy was performed. Eight recipients received one dose of anti-CD20 mAb (rituximab, 375 mg/m2) pre-operatively and 11 recipients had postoperative protocol IA. RESULTS: In the initial protocol, anti-CD20 mAbs were used only for recipients receiving A1 grafts. One B graft (HLA-identical donor, 84% panel reactivity) was lost in a severe anti-B Ab-mediated acute rejection. Subsequently, the protocol included anti-CD20 for recipients of both A1 and B grafts and postoperative protocol IA to all recipients. The subsequent 10 grafts had excellent function, giving a total graft survival of 13/14 (observation range 2 to 41 months). At 1 yr, mean serum creatinine was 113 micromol/l (n = 8) and mean glomerular filtration rate was 55 ml/min/1.73 m2 (range 24 to 77). In the remaining five cases, with less than 1 yr follow up, mean serum creatinine was 145 micromol/l at 2 to 9 months follow up. Pre-IA anti-A/B titers were in the range of 2 to 32 (NaCl technique) and 16 to 512 (IAT). More than 90 IA sessions were performed in 14 recipients without any significant side effects. Recipient anti-A/B titers returned after transplantation to pre-IA levels or slightly lower. Postoperative renal biopsies were performed in 10 patients. In the 13 patients with long-term function, one patient experienced cellular rejection (Banff IIB) at 3 months without anti-B titer rise. This rejection was concomitant with low tacrolimus plasma levels and was easily reversed by steroids. In 8 of 10 cases, C4d staining was positive in peritubular capillaries. CONCLUSION: Blood group ABO-incompatible LD renal transplantation using A and B carbohydrate-specific IA and anti-CD20 mAbs has excellent graft survival and function.

Background. A reduction in acute rejection may reduce graft losses from chronic rejection, benefiting the recipient and helping ease the huge donor organ shortfall in the UK. The prediction of recipients at greater risk of acute rejection might justify the administration to them of more potent immunosuppression, but defining this group on clinical parameters has been largely unsuccessful. Events impacting on the kidney by the time of donation may, if detectable histologically, predict those kidneys more likely to undergo rejection. Methods. A prospective immunohistochemical analysis was undertaken to detect P-Selectin (PS), E-Selectin (ES), platelets, leukocyte common antigen, macrophages, T cells, and neutrophils in the pretransplant biopsies of 77 adult renal transplant recipients. Twenty-nine (38%) of this group rejected. Results. A significantly increased number of recipients rejected if the donor biopsy was PS positive (63 vs. 24%, P=0.0007), contained five or more leukocytes/ glomerulus (48 vs. 21%, P=0.03), contained >9.3 leukocytes/high power field (46.5 vs. 10.5%, P=0.006) or was both PS positive and contained >9.3 leukocytes/high power field (61.9 vs. 0.0%, P=0.0001). The PS was mostly of platelet origin and the majority of leukocytes were macrophages. Only previous CMV or any current infection in the donor correlated with the immunohistochemical changes. Conclusions. These immuno-histochemical changes are present before transplantation, which allows the prediction of recipients at both a higher and a lower risk of acute rejection, enabling the administration of recipient tailored immunosuppression, and supports the use of additional therapeutic intervention to reduce the injury response both within the recipient and the donor.

The metabolic processes occurring within the preserved kidney during hypothermic machine perfusion (HMP) are not well characterized. The aim of this study was to use nuclear magnetic resonance (NMR) spectroscopy to examine the metabolomic profile of HMP perfusate from human cadaveric kidneys awaiting transplantation and to identify possible discriminators between the profiles of kidneys with delayed graft function (DGF) and immediate graft function (IGF).Perfusates from HMP kidneys were sampled at 45 min and 4 hr of preservation with the LifePort Kidney Transporter 1.0 (Organ Recovery Systems, Chicago, IL) using KPS-1. Prepared samples underwent 1-D Proton-NMR spectroscopy, and resultant spectra were analyzed. Clinical parameters were collected prospectively.Perfusate of 26 transplanted cadaveric kidneys was analyzed; 19(73%) with IGF and 7(27%) with DGF. Glucose concentrations were significantly lower in DGF kidneys compared to those with IGF at both 45 min (7.772 vs. 9.459 mM, P = 0.006) and 4 hr (8.202 vs. 10.235 mM, P = 0.003). Concentrations of inosine and leucine were significantly different between DGF and IGF kidneys at 45 min (0.002 vs. 0.013 mM, P = 0.009 and 0.011 vs. 0.006 mM, P = 0.036), and gluconate levels were also significantly different between DGF and IGF kidneys at 4 hr (49.099 vs. 59.513 mM, P = 0.009).Significant metabolic activity may be occurring in kidneys during HMP. The NMR spectroscopy of the perfusate can identify differences in the metabolomic profiles of DGF and IGF kidneys that might have a predictive role in viability assessment. Modification of harmful metabolic processes may improve outcomes for HMP kidneys.

Indexed mitochondrial complex activities (MCA;) were determined in biopsies obtained from 52 donor kidneys at the end of cold ischemia (8-32 hr) to see if longer anoxia affected MCA i and accounted for the increased risk of delayed graft function (DGF) in recipients of grafts with longer cold ischemia time (CIT) or from non-heart-beating donors (NHBD). CITs were significantly different between those with and without DGF (P=0.02), being shorter in the latter, but MCA i were similar. CIT was correlated (r=0.43, P=0.003) with the time taken for creatinine concentration to fall to half the perioperative value (Cr t ½) but not with MCA i . Frequency of DGF, greater in NHBD, was significantly different from that of heart-beating donors (P= 0.04), but CIT and MCA i were similar. However, Cr t ½, was significantly different being longer in NHBD. Thus, the frequency of DGF increased and the speed of recovery diminished with longer CIT, whereas MCA, remained stable suggesting other factors determined tissue recovery.

Background. The microemulsion preconcentrate formulation of cyclosporine A (CsA) (Neoral) exhibits more uniform pharmacokinetics than the conventional formulation (Sandimmun; SIM). This randomized, open-label, U.K. multicenter study compared the efficacy, safety, and tolerability of Neoral and SIM in preventing acute rejection in de novo renal transplant recipients. Methods. Adult cadaveric kidney recipients (n=293) received Neoral or SIM twice daily for 12 months. Initially identical Neoral and SIM doses were titrated, maintaining trough CsA levels within locally defined therapeutic limits. Results. In the year after transplantation, acute rejection occurred in 34% of the Neoral and 47% of the SIM recipients (P=0.037). In the intent-to-treat population, fewer treatment failures (defined as acute rejection, graft loss, withdrawal, or death) occurred in the Neoral (45%) than the SIM recipients (58%) (P=0.015) and therapeutic CsA levels (≥250 μg/L) were reached faster with Neoral than SIM (P=0.0017). Antibody treatment of refractory rejection was used slightly less in the Neoral group (Neoral: 10%; SIM: 12%). One-year patient and graft survival rates (excluding deaths with functioning grafts) were 95% and 88%, respectively, for Neoral and 96% and 89% for SIM. Both formulations were well tolerated. No differences were observed between therapies in the nature, frequency, or severity of adverse events. Neoral use was not associated with increased nephrotoxicity or excessive immunosuppression. Conclusions. Neoral reduced the incidence of acute rejection compared with SIM, without significant increases in adverse events. This was achieved without altering existing SIM protocols and was attributed to improved absorption of CsA from Neoral and less variability in whole blood CsA concentrations.

The ethical debate surrounding the payment of living unrelated donors continues despite very little evidence regarding the outcome. The aim of this audit was to identify the scale of the problem and assess the results of patients undergoing these procedures. The large Indo-Asian population within our region has a high demand for renal replacement therapy and transplantation. These patients have a limited chance of receiving a transplant for several reasons and some resort to traveling abroad, against medical advice, to procure an unrelated donor kidney transplant. Following an initial audit in our region, a national audit was conducted within the UK. A total of 23 patients were identified, all of whom had done so against medical advice. Mortality from causes directly related to transplantation was high in this group (35%), as was graft loss. The overall rate of successful transplants was only 44% (overall graft loss was 56%) in the short term. The information regarding both donor and recipient, provided from the transplanting center, was inadequate in all cases. These results, which almost certainly represent an underestimate of an ongoing situation, reinforce the standpoint that organ trading is associated with unacceptable risks and poor outcomes. The basis of this trade in organs is based on monetary rather than clinical criteria and such exploitation of both donor and recipient lead us to conclude that this practice cannot be endorsed and even the most desperate dialysis patients should be reminded of the unacceptable risks involved in this practice.

Acute rejection is a significant problem for patients undergoing HLA-incompatible renal transplantation, affecting between 12 and 53% of patients. Any mechanism of detecting rejection in advance of current methods would offer significant benefit. This study aimed to evaluate whether serum biomarkers could predict rejection in HLAi transplants recipients. Sera from 94 HLAi transplant recipients from a single centre were analysed for a panel of biomarkers including: NGAL, KIM-1, IP-10, cystatin C, cathepsin L and VEGF. Biomarker levels pre-operatively, day 1 and at day 30 post-transplant were correlated with the development of early rejection. Significantly higher levels of IP-10 and NGAL were seen on day 1 following transplant in those patients who developed acute rejection (P < 0.001 and 0.005) and generated AUC of 0.73 and 0.67, respectively. No differences were seen for the other biomarkers or at the other time points. In this study cohort, IP-10 and NGAL have demonstrated good predictive ability for the development of acute rejection at a very early time point. They may have a role in identifying patients at higher risk for rejection and stratifying immunosuppression or surveillance.

Background. Hand port devices (HPD) are used routinely for hand-assisted laparoscopic surgery including hand-assisted laparoscopic donor nephrectomy (HALDN). However, the cost of such devices may prove prohibitive, particularly in centers with financial constraints. The authors aimed to identify any adverse effects of performing device-free HALDN. Methods. A retrospective analysis was performed of patients undergoing HALDN at the authors’ unit over a 3-year period (2007-2010). Eighty-four patients underwent device-free HALDN, whereas in 80 patients a HPD was used. The primary endpoint was duration of operation, with secondary endpoints including postoperative wound infections and incisional hernias. Results. here was no difference in duration of operation for the device free (98 minutes; range = 43-215 minutes) compared with the HPD group (94 minutes; range = 36-180 minutes; P = .37). A device was required in 3 (3.6%) patients in which a device-free approach was attempted. There was no difference in either group in terms of rates of postoperative wound infections (0% vs 2.5%, respectively; P = .24) or incisional hernia incidence (1.5% vs 1.4%, respectively; P = .50). Conclusion. Device-free HALDN can be performed with no discernable compromise in operating time or patient outcome. This has implications in both cost benefit and translation of this technique to developing units.

Hand-assisted laparoscopic donor nephrectomy has become an established technique for live-donor organ retrieval. In most cases, the left kidney is removed because of its more favorable anatomic relations, particularly with the major abdominal vessels.We present 2 cases of live donation in which a hand-assisted laparoscopic approach was used to remove the right kidney as indicated by the presence of aberrant vascular anatomy, 1 being situs inversus totalis, the other a left-sided inferior vena cava.A 41-year-old woman and a 51-year-old man underwent assessment for live-kidney donation. During preoperative investigation, they underwent magnetic resonance imaging that demonstrated situs inversus totalis and a left-sided inferior vena cava. No contraindications to live donation were found during the investigation. In both cases, a right donor nephrectomy was performed owing to an anatomically longer right renal vein. Living donation proceeded without complication in both cases, and both patients had uneventful recoveries.Abnormalities in vascular anatomy should not be considered an absolute contraindication to donation, even by the hand-assisted laparoscopic donor approach. The use of magnetic resonance scanning preoperatively allows detailed planning of the approach required.

Some Indoasian (IA) patients with established renal failure travel abroad for commercial kidney transplantation. We compared the 1-year outcomes of IA patients from one UK region who received overseas transplants with IA patients receiving local living donor (LD) kidney transplantation, deceased donor (DD) transplantation, and dialysis.Between 1996 and 2006, 40 adults were transplanted overseas; 38 were IA, and follow-up data were available on 36 patients. Forty IA patients received LD transplants, and 156 patients received DD transplants locally. A cohort of 120 prospective dialysis patients was also used as a comparator group.In the overseas cohort, 20 patients (56%) were not active in the UK transplant waiting list at the time of kidney transplantation overseas. One-year graft survival was 87%, and 1-year patient survival was 83%. Composite graft and patient survival was 69.5% at 1 year. In the local LD transplant recipients, patient survival was 97.5% (39 of 40; P=0.03), and graft survival was 97.5% (39 of 40; P=0.06). Composite graft and patient survival was 95% (P=0.003). In the overseas group, 42% had major infections compared with 15% in the local group (P=0.02). One-year graft survival for DD transplant was 84.6% (132 of 156), and 1-year patient survival was 93% (145 of 156; P=NS and P=0.06, respectively). In the dialysis group, 1-year patient survival was 96.7% (116 of 120; P=0.001).IA patients who choose to travel overseas for kidney transplantation have poor clinical outcomes and should be counseled accordingly.

Introduction Calciphylaxis occurring after kidney transplantation is rare and rarely reported. It results in chronic non-healing wounds and is associated with a poor prognosis and is often fatal. We present a case of proximal lower limb calciphylaxis that occurred early after kidney transplantation. The patient had no classic associated risk factors. He had previously had a total parathyroidectomy but had normal serum calcium-phosphate product and parathyroid hormone levels. The clinical outcome of this case was favorable and highlights some fundamental issues relating to management. Case presentation A 70-year-old British Caucasian man with end-stage renal failure secondary to IgA nephropathy presented six months post kidney transplantation with cutaneous calciphylaxis lesions involving the medial aspect of the thigh bilaterally. Conclusion To the best of our knowledge, this is the first reported case of rapid onset cutaneous calciphylaxis occurring soon after kidney transplantation that was associated with a favorable outcome. Cutaneous calciphylaxis lesions should be promptly managed with meticulous wound care, antimicrobial therapy and the correction of calcium-phosphate product where indicated.

Limiting the exposure of kidney transplant recipients to calcineurin inhibitors (CNIs) has potential merit, but there is no clear consensus on the utility of current strategies. In an attempt to aid clarification, we conducted a systematic review and meta-analysis of randomized trials that assessed CNI sparing (minimization or elimination) with mycophenolate as sole adjunctive immunosuppression.The search strategy identified trials where CNI sparing was accompanied by the continuation of, or conversion to, mycophenolate and compared with standard or higher dose CNI therapy. Two investigators independently examined each trial for eligibility, quality, and outcome measures. Additional subgroup analyses were assessed: (1) de novo CNI sparing; (2) elective CNI sparing beyond 2 months posttransplantation; and (3) CNI sparing for transplant dysfunction.Nineteen randomized controlled trials met the inclusion criteria permitting analysis of 3312 renal transplant recipients with median follow-up of 12 months. CNI sparing significantly improved glomerular filtration rate (weighted mean difference 4.4 mL/min, 95% confidence interval [CI] 2.9-5.9, P0.001); with some evidence, albeit weak, of improved graft survival (odds ratio 0.72, 95% CI 0.52-1.01, P=0.06). Acute rejection rates were only increased after elective CNI elimination (odds ratio 2.23, 95% CI 1.57-3.17, P0.001). There were no significant differences in mortality, malignancy or incidence of infections.CNI sparing strategies with adjunctive mycophenolate may play an important role in kidney transplant recipients. Improvements in short-term graft function, and possibly graft survival, are achievable. Longer term studies are needed to substantiate the short-term benefits, and refining elective CNI elimination protocols may help to reduce the risk of rejection.

Background. Suboptimal early graft function following renal transplantation remains a significant challenge. It is suggested that clinical variables (or scoring systems based thereon) may predict the occurrence of delayed graft function (DGF), defined as post-operative dialysis requirement. However, data is conflicting, and suboptimal renal function not requiring dialysis has been little investigated. This study tested the ability of clinical variables to predict suboptimal early function variably assessed by: (i) DGF (dialysis requirement during the first week); (ii) DGF duration; (iii) slow graft function (creatinine >3 mg/dl on day 5); (iv) creatinine reduction ratio on day 2. Methods. Details on 217 consecutive renal transplant recipients were collected. All received ciclosporinbased immunosuppression. Multiple regression analysis was used to assess the association between individual clinical variables and suboptimal early graft function. Also tested were three scoring systems incorporating clinical variables [US Renal Database System (USRDS score), deceased donor score (DDS) and expanded criteria donor kidneys]. Receiver operatedcharacteristic curve analysis was used to assess the predictive power of clinical variables and scoring systems. Results: Early graft function was associated with donor age, donor body mass index, donor hypertension, donation following cardiac death, black recipient ethnicity, recipient weight and cold ischaemic time (P � 0.05 for all). All scoring systems showed associations with early graft function, although only USRDS score remained in the multiple regression model. The overall utility of the USRDS score in predicting DGF was moderate at best, although improved at extreme scores (specificity: 95%; positive predictive value: 73%; for USRDS score � 150). Conclusions. Clinical variables and scores have moderate predictive ability for early graft function and although of potential use in clinical practice, caution should be exercised before altering patient management based solely on them.

A 49-year-old man underwent living donor renal transplantation in November 2005. The transplant renal artery was anastomosed to the right internal iliac artery with an end-to-end anastomosis. The patient achieved immediate graft function and the allograft was normally perfused. Seven weeks later, renal allograft function deteriorated with a serum creatinine level increased to 244 micromol/L. An ultrasound scan revealed adequate perfusion to the kidney and the absence of hydronephrosis. A transplant biopsy revealed Banff IB rejection, which was treated with high-dose prednisolone. Following biopsy, the patient's renal function rapidly deteriorated with a serum creatinine level increased to 627 micromol/L, requiring hemodialysis. A computed tomography (CT) angiogram demonstrated a 6-cm diameter pseudoaneurysm arising from the internal iliac artery with absence of kidney perfusion. The aneurysm was accessed percutaneously with a 4-F catheter and 1000 U of human thrombin injected, resulting in partial thrombosis of the pseudoaneurysm. A balloon expandable covered metal stent was then placed across the site of the transplant renal artery anastomosis, resulting in successful occlusion of the aneurysm. Intrarenal blood flow was established by dilating 2 intrarenal branches with 3-mm diameter balloons. The serum creatinine level started to decrease within 24 hours of the procedure and renal function improved rapidly to a level achieved immediately after transplantation. Three months later the patient had a well-functioning allograft with a serum creatinine level of 176 micromol/L, follow-up CT scan demonstrated good perfusion of the transplanted kidney with no further change in the pseudoaneurysm. At 12 months follow-up the patient remains with a well-functioning allograft.

A reduction in acute rejection may reduce graft losses from chronic rejection, benefiting the recipient and helping ease the huge donor organ shortfall in the UK. The prediction of recipients at greater risk of acute rejection might justify the administration to them of more potent immunosuppression, but defining this group on clinical parameters has been largely unsuccessful. Events impacting on the kidney by the time of donation may, if detectable histologically, predict those kidneys more likely to undergo rejection.A prospective immunohistochemical analysis was undertaken to detect P-Selectin (PS), E-Selectin (ES), platelets, leukocyte common antigen, macrophages, T cells, and neutrophils in the pretransplant biopsies of 77 adult renal transplant recipients. Twenty-nine (38%) of this group rejected.A significantly increased number of recipients rejected if the donor biopsy was PS positive (63 vs. 24%, P=0.0007), contained five or more leukocytes/glomerulus (48 vs. 21%, P=0.03), contained9.3 leukocytes/high power field (46.5 vs. 10.5%, P=0.006) or was both PS positive and contained9.3 leukocytes/high power field (61.9 vs. 0.0%, P=0.0001). The PS was mostly of platelet origin and the majority of leukocytes were macrophages. Only previous CMV or any current infection in the donor correlated with the immunohistochemical changes.These immuno-histochemical changes are present before transplantation, which allows the prediction of recipients at both a higher and a lower risk of acute rejection, enabling the administration of recipient tailored immunosuppression, and supports the use of additional therapeutic intervention to reduce the injury response both within the recipient and the donor.