Kidney transplantation in low- and middle-income countries: the Transplant Links experience.

Paediatric kidney failure is a global problem responsible for significant childhood morbidity and mortality. The gold-standard treatment is kidney transplantation. However, the availability of kidney transplantation remains limited in some low- and middle-income countries (LMICs). Transplant Links Community (TLC) is a UK-based charity that mentors units in LMICs wishing to start kidney transplantation; the ultimate goal is for these units to become self-sufficient. TLC provides this support through in-person training visits and skill transfer, plus direct mentorship from the UK that is maintained over many years. From such mentoring programmes, it is evident that there are numerous challenges in the initial establishment and long-term maintenance of kidney transplant services, with specific and unique barriers applying to setting up paediatric transplant programmes compared to their adult counterparts. This review summarises TLC's first-hand experience of developing paediatric kidney transplantation services in LMICs over the past 15 years, the challenges encountered, and the major ongoing barriers that must be addressed to facilitate further progress in delivering transplantation services to children globally.

Maternal schistosomiasis impairs offspring Interleukin-4 production and B cell expansion.

Epidemiological studies have identified a correlation between maternal helminth infections and reduced immunity to some early childhood vaccinations, but the cellular basis for this is poorly understood. Here, we investigated the effects of maternal Schistosoma mansoni infection on steady-state offspring immunity, as well as immunity induced by a commercial tetanus/diphtheria vaccine using a dual IL-4 reporter mouse model of maternal schistosomiasis. We demonstrate that offspring born to S. mansoni infected mothers have reduced circulating plasma cells and peripheral lymph node follicular dendritic cells at steady state. These reductions correlate with reduced production of IL-4 by iNKT cells, the cellular source of IL-4 in the peripheral lymph node during early life. These defects in follicular dendritic cells and IL-4 production were maintained long-term with reduced secretion of IL-4 in the germinal center and reduced generation of TFH, memory B, and memory T cells in response to immunization with tetanus/diphtheria. Using single-cell RNASeq following tetanus/diphtheria immunization of offspring, we identified a defect in cell-cycle and cell-proliferation pathways in addition to a reduction in Ebf-1, a key B-cell transcription factor, in the majority of follicular B cells. These reductions are dependent on the presence of egg antigens in the mother, as offspring born to single-sex infected mothers do not have these transcriptional defects. These data indicate that maternal schistosomiasis leads to long-term defects in antigen-induced cellular immunity, and for the first time provide key mechanistic insight into the factors regulating reduced immunity in offspring born to S. mansoni infected mothers.

IL-4 promotes stromal cell expansion and is critical for development of a type-2, but not a type 1 immune response.

IL-4 is critical for differentiation of Th2 cells and antibody isotype switching, but our work demonstrated that it is produced in the peripheral LN under both Type 2, and Type 1 conditions, raising the possibility of other functions. We found that IL-4 is vital for proper positioning of hematopoietic and stromal cells in steady state, and the lack of IL-4 or IL-4Rα correlates with disarrangement of both follicular dendritic cells and CD31+ endothelial cells. We observed a marked disorganization of B cells in these mice, suggesting that the lymphocyte-stromal cell axis is maintained by the IL-4 signaling pathway. This study showed that absence of IL-4 correlates with significant downregulation of Lymphotoxin alpha (LTα) and Lymphotoxin beta (LTß), critical lymphokines for the development and maintenance of lymphoid organs. Moreover, immunization of IL-4 deficient mice with Type 2 antigens failed to induce lymphotoxin production, LN reorganization, or germinal center formation, while this process is IL-4 independent following Type 1 immunization. Additionally, we found that Type 1 antigen mediated LN reorganization is dependent on IFN-γ in the absence of IL-4. Our findings reveal a role of IL-4 in the maintenance of peripheral lymphoid organ microenvironments during homeostasis and antigenic challenge.

Outcomes of donation after circulatory death kidneys undergoing hypothermic machine perfusion following static cold storage: A UK population-based cohort study.

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 < .001), despite a slightly longer cold ischemic time (median: 14.8 vs 14.1 hours, P < .001). Multivariable analysis found the effect of preservation modality to remain significant, with HMP organs having a significantly lower rate of DGF (odds ratio 0.65, 95% confidence interval 0.53-0.80, P < .001) and significantly shorter times to DGF resolution (average: 6.1 vs 7.4 days, P = .003) than SCS organs. The patient (P = .313) and graft (P = .263) survival rates were similar in the 2 preservation groups. HMP was associated with a marginal functional benefit in 1-year creatinine values (P = .044), with adjusted averages of 1.36 mg/dL (HMP) versus 1.40 mg/dL (SCS). This study supports the use of HMP and aids decision-making over its instigation, which may improve short-term patient outcomes.

The impact of donor body mass index on outcomes after deceased kidney transplantation - a national population-cohort study.

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 <18.5 (n = 380), 18.5-25.0 (n = 6890), 25.1-30.0 (n = 6669), 30.1-35.0 (n = 2503) and >35.0 (n = 1148). The prevalence of delayed graft function increased significantly with donor BMI (P < 0.001), with an adjusted odds ratio of 1.38 (95% CI: 1.16-1.63) for the >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.

Metabolic differences between cold stored and machine perfused porcine kidneys: A 1H NMR based study.

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 < 0.05). In addition to metabolic differences with control kidneys, the net metabolic gain during HMP was greater than SCS for 8 metabolites (all p < 0.05). These included metabolites related to central metabolism (lactate, glutamate, aspartate, fumarate and acetate). 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.

Risk of post-transplantation diabetes mellitus is greater in South Asian versus Caucasian kidney allograft recipients.

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.

Urinary biomarkers of acute kidney injury in deceased organ donors--kidney injury molecule-1 as an adjunct to predicting outcome.

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.

The use of NGAL and IP-10 in the prediction of early acute rejection in highly sensitized patients following HLA-incompatible renal transplantation.

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.

Hand-assisted laparoscopic donor nephrectomy: are hand port devices really necessary?

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.

Management of Parathyroid Disease during the COVID-19 Pandemic.

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.

The Effects of Oxygenation on Ex Vivo Kidneys Undergoing Hypothermic Machine Perfusion.

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.

Risk factors for acute rejection in renal transplant recipients experiencing delayed graft function.

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.

Schistosoma mansoni Infection-Induced Transcriptional Changes in Hepatic Macrophage Metabolism Correlate With an Athero-Protective Phenotype.

Hepatic macrophages play an essential role in the granulomatous response to infection with the parasitic helminth Schistosoma mansoni, but the transcriptional changes that underlie this effect are poorly understood. To explore this, we sorted the two previously recognized hepatic macrophage populations (perivascular and Kupffer cells) from naïve and S. mansoni-infected male mice and performed microarray analysis as part of the Immunological Genome Project. The two hepatic macrophage populations exhibited remarkably different genomic profiles. However, this diversity was substantially reduced following infection with S. mansoni, and in fact, both populations demonstrated increases in transcripts of the monocyte lineage, suggesting that both populations may be replenished by monocytes following infection. Pathway analysis showed a profound alteration in global metabolic pathways, including changes to phospholipid and cholesterol metabolism, as well as amino acid biosynthesis and glucagon signaling. These changes suggest a possible mechanism for the previously reported athero-protective effects of S. mansoni infection. Indeed, we find that male ApoE null mice fed a high-fat diet in combination with S. mansoni infection have reduced plaque area and increased glucose tolerance as compared to control mice. Transcript analysis of infected and control high-fat diet fed ApoE-/- mice confirm that ApoC1, Psat1, and Gys1 are all altered by infection, suggesting that altered hepatic macrophage metabolism is associated with S. mansoni- induced protection from hyperlipidemia, atherosclerosis, and glucose intolerance. These results suggest a previously unknown and unreported role of hepatic macrophages in the modulation of whole body lipid and glucose metabolism during infection and provide a template for examining the role of immunomodulation on the long-term metabolism of the host.

Recipient Outcomes From Nondirected Live Kidney Donors: A UK-based Cohort Study.

BACKGROUND: Increasing numbers of patients with end-stage renal failure are receiving kidneys from nondirected kidney donors (NKDs), also known as altruistic donors. Transplant outcomes for recipients of such kidneys are largely inferred from studies on specified kidney donors (SKDs), which may be inaccurate due to differences in donor, recipient and transplant specific factors. We report the outcomes for recipients of NKD in the United Kingdom. METHODS: Outcomes for 6861 patients receiving a living donor kidney transplant between January 2007 and December 2014 were analyzed using both the National Health Service Blood and Transplant and the UK Renal Registry datasets. Graft and patient outcomes were compared for patients receiving NKD and SKD organs using univariable and multivariable analyses. RESULTS: There was significant discordance between the NKD and SKD donors and recipients. These included increased donor age (median, 58 years vs 47 years; P < 0.001) and higher rates of hemodialysis and previous transplants in the NKD group (both P < 0.001). Despite such markers of increased risk among both donors and recipients of NKD kidneys, there was no difference in graft survival on univariable (hazard ratio, 1.20; 95% confidence interval, 0.77-1.86; P = 0.419) or multivariable analysis (hazard ratio, 1.13; 95% confidence interval, 0.65-1.95; P = 0.665). CONCLUSIONS: Despite some markers of transplant complexity, nondirected kidney donor organs are an excellent source of organs for transplantation.

Serial changes in the expression of CXCR3 and CCR5 on peripheral blood lymphocytes following human renal transplantation.

OBJECTIVES: In animal models of transplantation, chemokine receptors have been shown to direct the infiltration of T cells in immune responses and inflammation and to be critical in cellular recruitment. Although the chemokine receptors CXCR3 and CCR5 and their ligands have been found during acute rejection in transplanted human kidneys, the kinetics of expression on peripheral blood lymphocytes is unknown. MATERIALS AND METHODS: Using a whole-blood red-cell lysis fluorescence-activated cell sorter, serial expressions of CXCR3 and CCR5 on T-cell subsets were analyzed in 19 human renal transplant recipients following transplant. RESULTS: In patients developing allograft rejection (n=6), increased expression of CXCR3 occurred on the surface of CD4+ T cells by the third day after transplant. In patients remaining rejection free (n=13), decreased expression was seen. In patients experiencing allograft rejection and in those remaining rejection free, levels of CXCR3 on CD8+ T cells and CCR5 on CD4+ and CD8+ cells remained stable throughout the study. CONCLUSIONS: During allograft rejection, expression of CXCR3, but not CCR5, increases on peripheral CD4+ T cells prior to clinical evidence of allograft rejection and remains elevated for more than 2 weeks following transplantation. This may represent a specific molecular target for identifying and preventing allograft rejection.

(13)C glucose labelling studies using 2D NMR are a useful tool for determining ex vivo whole organ metabolism during hypothermic machine perfusion of kidneys.

BACKGROUND: The aim of this study is to determine the feasibility of using nuclear magnetic resonance (NMR) tracer studies ((13)C-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 (13)C ([U-(13)C] glucose), was incorporated into KPS-1-like perfusion fluid at a concentration of 10 mM. Analysis of perfusate was performed using both 1D (1)H and 2D (1)H,(13)C heteronuclear single quantum coherence (HSQC) NMR spectroscopy. The metabolic activity was then studied by quantifying the proportion of key metabolites containing (13)C in both perfusate and tissue samples. RESULTS: There was significant enrichment of (13)C 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 < 0.01). The total amount of enriched alanine increased in a similar fashion (1.73 ± 0.89 nmol at 6 h vs 6.80 ± 2.56 nmol at 24 h p < 0.05). In addition, small amounts of enriched acetate and glutamic acid were evident in some samples. CONCLUSIONS: This study conclusively demonstrates that de novo metabolism occurs during HMP and highlights active metabolic pathways in this hypothermic, hypoxic environment. Whilst the majority of the (13)C-enriched glucose is metabolised into glycolytic endpoint metabolites such as lactate, the presence of non-glycolytic pathway derivatives suggests that metabolism during HMP is more complex than previously thought. Isotopic labelled ex vivo organ perfusion studies using 2D NMR are feasible and informative.

Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation.

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.

Hypothermic machine perfusion permits extended cold ischemia times with improved early graft function.

OBJECTIVES: The logistics of deceased-donor renal transplants are largely affected by cold ischemia time. However, to attain successful outcomes, other issues must be considered. Extending cold ischemia time to accommodate these issues would be valuable. We investigated the role of hypothermic machine perfusion to extend cold ischaemia time. MATERIALS AND METHODS: Deceased-donor kidneys were allocated to a storage method, depending on predicted time to operation. Kidneys to be transplanted from 8:00 AM to 8:00 PM in the transplant room remained in static cold storage. If predicted operating time was out of hours, the kidney was transferred to hypothermic machine perfusion and transplanted at the earliest opportunity on the dedicated transplant list. RESULTS: There were 74 kidneys transplanted from hypothermic machine perfusion and 101 kidneys from static cold storage. Median cold ischemia time was 23.85 hours in the hypothermic machine perfusion group, compared with 13 hours in the static cold storage group (P ≤ .0001). There were 20 kidneys (27%) from hypothermic machine perfusion that had delayed graft function, compared with 47 kidneys (47%) in the static cold storage group (P = .012). There were no other significant differences in graft or postoperative complications. CONCLUSIONS: This study demonstrated that improved early graft outcomes can be achieved following longer cold ischemia time by using hypothermic machine perfusion rather than static cold storage. This effect is likely multifactorial including the inherent effects of hypothermic machine perfusion, improved recipient preparation, and possibly better perioperative conditions.