Heat Stroke as a Cause of Liver Failure and Evaluation of Liver Transplant.

Heat stroke is a multiple organ dysfunction syndrome of poorly understood pathogenesis. Exertional heat stroke with acute liver failure is a rarely reported condition. Liver transplant has been recommended as treatment in cases of severe liver dysfunction; however, there are only 5 described cases of long-term survival after this procedure in patients with heat stroke. Here, we present 2 cases of young athletes who developed heat stroke. Both patients developed acute liver failure and were listed for liver transplant. Liver function tests of one patient improved, and he was discharged on postoperative day 13. The other patient showed no signs of improvement and liver biopsy showed massive necrosis. The patient underwent combined kidney-liver transplant and was discharged on postoperative day 17. After a follow-up of longer than 6 years, both patients are doing well with normal liver function and no neurologic sequelae. We also reviewed all published cases of hepatic failure associated with heat stroke and found 9 published cases of liver transplant for heat stroke in the English literature. Conservative management appears to be justified in heat stroke-associated liver failure, even in the presence of accepted criteria for emergency liver transplant. If the liver does not show signs of recovery and hepatic decompensation progresses, liver transplant should be performed.

Application of Enhanced Recovery After Surgery in Patients Undergoing Kidney Transplant: the Belfast Protocol.

BACKGROUND: The aim of this study was to assess the impact of the Belfast Protocol for enhanced recovery after surgery on hospital length of stay (LOS) after kidney transplant. METHODS: A prospectively collected database was analyzed for all consecutive renal transplant recipients in 2010 and compared with consecutive renal transplant recipients in 2018 before and immediately after the full implementation of the Belfast Protocol. RESULTS: There were 73 renal transplants in 2010 and 115 in 2018. Between 2010 and 2018 there was a significant decrease in LOS from 12 to 7 days (P < .0001). Compared with 2010, in 2018 there was a significant increase in donor age (47 vs 54 years, P < .0001) and kidney transplant from donation after circulatory death donors (0% vs 9%, P < .0001). Although there was no change in the proportion of living donors (59% vs 50%, P = .32), in 2018 there were more blood group incompatible living donors (0% vs 7%, P = .21). Compared with 2010, in 2018 there was a significant increase in recipient age (43 vs 54 years, P = .0002), diabetic nephropathy (5% vs 16%, P = .03), and recipient body mass index >35 kg/m2 (0% vs 9%, P = .02). CONCLUSIONS: Implementation of the Belfast Protocol has decreased LOS in renal transplant recipients despite increasingly complex donor and recipient profiles.

Hyperamylasemia Post Living Donor Nephrectomy Does Not Relate to Pain.

Introduction The aetiology of pain after laparoscopic donor nephrectomy remains unclear. Given the proximity of the left kidney to the tail of the pancreas, we aimed to assess whether mobilisation and retrieval of the left kidney might inflame the pancreas, leading to pain and hyperamylasaemia in the post-operative period. Patient and methods In the present study, 16 consecutive live kidney donors were analysed in the same three months period. Amylase levels were measured on days 1 and 2. For each 24-hour period post-operatively analgesia consumption was recorded, as well as pain scores at rest on a visual analogue scale (VAS). Results Three out of 16 donors presented hyperamylasemia. A multiple regression analysis found levobupivacaine dose, propofol dose, transversus abdominis plane block and day 1 amylase did not significantly predict pain scores. Interestingly, body mass index significantly correlated with increased pain scores (p = 0.041). Also, increasing CO2 insufflation pressure and use of local anaesthetic infusion catheters predicted a decreased deep pain score (p = 0.036 and p = 0.037). Conclusion There was no correlation of amylase levels and pain scores. Pancreatitis is a rare complication of nephrectomy and no overt cases were seen in the case of donor nephrectomy.

Long-Term Outcomes of Renal Transplant in Recipients With Lower Urinary Tract Dysfunction.

OBJECTIVES: Lower urinary tract dysfunction can lead to chronic kidney disease, which, despite surgical intervention, will progress to end-stage renal disease, requiring dialysis. Urologic pathology may damage a transplanted kidney, limiting patient and graft survival. Although smaller studies have suggested that urinary tract dysfunction does not affect graft or patient survival, this is not universally accepted. Northern Ireland has historically had the highest incidence of neural tube defects in Europe, giving rich local experience in caring for patients with lower urinary tract dysfunction. Here, we analyzed outcomes of renal transplant recipients with lower urinary tract dysfunction versus control recipients. MATERIALS AND METHODS: We identified 3 groups of kidney transplant recipients treated between 2001 and 2010; those in group 1 had end-stage renal disease due to lower urinary tract dysfunction with prior intervention (urologic surgery, long-term catheter, or intermittent self-catheterization), group 2 had end-stage renal disease secondary to lower urinary tract dysfunction without intervention, and group 3 had end-stage renal disease due to polycystic kidney disease (chosen as a relatively healthy control cohort without comorbid burden of other causes of end-stage renal disease such as diabetes). The primary outcome measured, graft survival, was death censored, with graft loss defined as requirement for renal replacement therapy or retransplant. Secondary outcomes included patient survival and graft function. RESULTS: In 150 study patients (16 patients in group 1, 64 in group 2, and 70 in group 3), 5-year death-censored graft survival was 93.75%, 90.6%, and 92.9%, respectively, with no significant differences in graft failure among groups (Cox proportional hazards model). Five-year patient survival was 100%, 100%, and 94.3%, respectively. CONCLUSIONS: Individuals with a history of lower urinary tract dysfunction had graft and patient survival rates similar to the control group. When appropriately treated, lower urinary tract dysfunction is not a barrier to successful renal transplant.

Development of transplant immunosuppressive agents - considerations in the use of animal models.

INTRODUCTION: The development of all immunosuppressant agents to date has involved the experimental use of large and small animal models. Over the last half-century, immunosuppressive drugs have extended the lives of transplant patients worldwide. However, the use of animal models in the development of these drugs is not perfect, and this has brought to light a number of issues including idiosyncratic reactions that are found in animal models but not in humans. The 2006 highly publicized case of the 'elephant man' TGN 1412 drug trial highlights the importance of being cogent of the limitations of animal models. Areas covered: This review covers the utility and limitations of the use of animal models for the development of immunosuppressant agents. This includes both large and small animal models, particularly rodent models in the transplant setting. Expert opinion: The use of animal models represents a critical stage in the development of immunosuppressive drugs. Limitations include physiological differences to humans; this is especially true of immunologically naïve lab rodents with small memory cell populations. Toxic drug levels may differ widely between species. Animal models are also costly and raise ethical concerns. However, there is currently no way to recreate the complex environment of the human immune system purely in vitro.

Preoperative radial artery volume flow is predictive of arteriovenous fistula outcomes.

OBJECTIVE: Guidelines recommend the creation of a wrist radiocephalic arteriovenous fistula (RAVF) as initial hemodialysis vascular access. This study explored the potential of preoperative ultrasound vessel measurements to predict AVF failure to mature (FTM) in a cohort of patients with end-stage renal disease in Northern Ireland. METHODS: A retrospective analysis was performed of all patients who had preoperative ultrasound mapping of upper limb blood vessels carried out from August 2011 to December 2014 and whose AVF reached a functional outcome by March 2015. RESULTS: There were 152 patients (97% white) who had ultrasound mapping and an AVF functional outcome recorded; 80 (54%) had an upper arm AVF created, and 69 (46%) had a RAVF formed. Logistic regression revealed that female gender (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.12-5.55; P = .025), minimum venous diameter (OR, 0.6; 95% CI, 0.39-0.95; P = .029), and RAVF (OR, 0.4; 95% CI, 0.18-0.89; P = .026) were associated with FTM. On subgroup analysis of the RAVF group, RAVFs with an arterial volume flow <50 mL/min were seven times as likely to fail as RAVFs with higher volume flows (OR, 7.0; 95% CI, 2.35-20.87; P < .001). CONCLUSIONS: In this cohort, a radial artery flow rate <50 mL/min was associated with a sevenfold increased risk of FTM in RAVF, which to our knowledge has not been previously reported in the literature. Preoperative ultrasound mapping adds objective assessment in the clinical prediction of AVF FTM.

The utility of animal models in developing immunosuppressive agents.

The immune system comprises an integrated network of cellular interactions. Some responses are predictable, while others are more stochastic. While in vitro the outcome of stimulating a single type of cell may be stereotyped and reproducible, in vivo this is often not the case. This phenomenon often merits the use of animal models in predicting the impact of immunosuppressant drugs. A heavy burden of responsibility lies on the shoulders of the investigator when using animal models to study immunosuppressive agents. The principles of the three R׳s: refine (less suffering,), reduce (lower animal numbers) and replace (alternative in vitro assays) must be applied, as described elsewhere in this issue. Well designed animal model experiments have allowed us to develop all the immunosuppressive agents currently available for treating autoimmune disease and transplant recipients. In this review, we examine the common animal models used in developing immunosuppressive agents, focusing on drugs used in transplant surgery. Autoimmune diseases, such as multiple sclerosis, are covered elsewhere in this issue. We look at the utility and limitations of small and large animal models in measuring potency and toxicity of immunosuppressive therapies.

Sickle cell and renal transplant: a national survey and literature review.

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.

Diverticular fistulation is associated with nicorandil usage.

INTRODUCTION: We observed that a number of patients presenting to our clinic with diverticular fistulation were taking nicorandil for angina. Recognised side effects of nicorandil include gastrointestinal and genital ulceration. The aim of our study was to determine whether nicorandil is an aetiological agent in diverticular fistulation. PATIENTS AND METHODS: We conducted a case-control study of patients with diverticular disease related enteric fistulae. Two patient groups were identified: a study group of patients with diverticular fistulae, and a control group with uncomplicated diverticular disease. The proportion of patients who had ever used nicorandil was compared between the two groups. RESULTS: A total of 153 case notes were analysed, 69 patients with fistulae and 84 control patients with uncomplicated diverticular disease. Female to male ratio in both groups was 2:1. The mean age was 71 years in the fistula group and 69 years in the control diverticular disease group (P = ns). Of those with colonic fistulae, 16% were taking nicorandil compared with 2% of the control group (odds ratio 7.8; 95% confidence interval 1.5-39.1; P = 0.008). There was no significant difference in rates of ischaemic heart disease between fistula and control groups. CONCLUSIONS: Nicorandil is associated with fistula formation in diverticular disease.

Heme oxygenase-1 is essential for and promotes tolerance to transplanted organs.

This investigation focused on obtaining a further understanding of the role of heme oxygenase-1 (HO-1) in tolerance induction. Hearts from C57BL/6 (H-2b) mice survived long-term when transplanted into BALB/c (H-2d) recipients treated with the tolerance-inducing regimen of anti-CD40L antibody (MR-1) plus donor-specific transfusion (DST). Grafts did not, however, survive long-term in (HO-1-/-) recipients given the same treatment. Similarly, long-term survival induced by DST was ablated when HO-1 activity was blocked by zinc protoporphyrin IX (ZnPPIX). We further asked whether modulation of HO-1 expression/activity could be used to promote the induction of graft tolerance. DST alone (day 0) failed to promote any prolongation of survival of DBA/2 (H-2d) hearts transplanted into B6AF1 (H-2(b,k/d)) recipients. However, long-term survival and (dominant peripheral) tolerance were readily induced when DST was combined with induction of HO-1 expression by cobalt protoporphyrin IX (CoPPIX). HO-1 induction plus DST led to a significant up-regulation of Foxp3, TGF-beta, IL-10, and CTLA4, which suggests a prominent role for CD4+CD25+ regulatory T cells (Tregs). In fact, the tolerogenic effect of HO-1 plus DST was dependent on CD4+CD25+ Tregs as suggested by adoptively transferring these cells into irradiated recipients under various regimens. Taken together, these findings show that expression of HO-1 in a graft recipient can be essential for long-term graft survival and for induction of tolerance and that modulation of HO-1 expression/activity can be used therapeutically to synergize in the generation of graft tolerance.

Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation.

BACKGROUND: Bilirubin, a natural product of heme catabolism by heme oxygenases, was considered a toxic waste product until 1987, when its antioxidant potential was recognized. On the basis of observations that oxidative stress is a potent trigger in vascular proliferative responses, that heme oxygenase-1 is antiatherogenic, and that several studies now show that individuals with high-normal or supranormal levels of plasma bilirubin have a lesser incidence of atherosclerosis-related diseases, we hypothesized that bilirubin would have salutary effects on preventing intimal hyperplasia after balloon injury. METHODS AND RESULTS: We found less balloon injury-induced neointima formation in hyperbilirubinemic Gunn rats and in wild-type rats treated with biliverdin, the precursor of bilirubin, than in controls. In vitro, bilirubin and biliverdin inhibited serum-driven smooth muscle cell cycle progression at the G1 phase via inhibition of the mitogen-activated protein kinase signal transduction pathways and inhibition of phosphorylation of the retinoblastoma tumor suppressor protein. CONCLUSIONS: Bilirubin and biliverdin might be potential therapeutics in vascular proliferative disorders.

Donor treatment with carbon monoxide can yield islet allograft survival and tolerance.

Treatment of animals or certain cells with carbon monoxide (CO), a product of heme degradation by heme oxygenase-1 (HO-1), has potent anti-inflammatory and antiapoptotic effects that contribute to the survival of transplanted organs. We report here that inducing HO-1 in, or administering CO to, only the donor can be used in a therapeutic manner to sustain the survival of transplanted allogeneic islets. Similar treatments of only the islets or only the recipient are also salutary. Administering CO only to the donor frequently leads to long-term survival of those islets in untreated allogeneic recipients, which are then antigen-specifically tolerant. Several proinflammatory and proapoptotic genes that are strongly induced in islets after transplantation in the untreated situation were significantly suppressed after administering CO to the donor without further treatment. These included tumor necrosis factor-alpha, inducible nitric oxide synthase, monocyte chemoattractant protein-1, granzyme B, and Fas/Fas ligand, all of which contribute to the pathogenesis of the rejection of transplanted islets. This correlated with a lesser infiltration of recipient macrophages into the transplanted islets. Our present findings show that induction of HO-1 in, or administration of CO to, only the donor, islets, or the recipient or combinations of such treatments improve allogeneic islet survival.

Heme oxygenase-1 modulates the allo-immune response by promoting activation-induced cell death of T cells.

Heme oxygenase-1 (HO-1), which degrades heme into three products (carbon monoxide, free iron, and biliverdin), plays a protective role in many models of disease via its anti-inflammatory, anti-apoptotic, and anti-proliferative actions. Overexpression of HO-1 has been shown to suppress immune responses and prolong the survival of allografts; however, the underlying mechanism is not clear. We demonstrate two "new" properties of HO-1 that mediate activation induced cell death (AICD) of allo-antigen-responsive murine CD4+ T cells, resulting in immunomodulation. First, it functions in vivo and in vitro to "boost" the proliferative response of CD4+ T cells to allo-antigens in the early phase of allo-antigen-driven immune responses. This "boosting" effect is accompanied with a significant increase of activation markers and IL-2 production. Second, it exerts a pro-apoptotic effect in those activated T cells after the initial burst of proliferation. We further show that the AICD effect is mediated through the Fas/CD95-FasL signal transduction pathway. Correlating with the above-mentioned findings is the observed prolongation of mouse heart graft survival when HO-1 is expressed in vivo in both donor and recipient. In conclusion, induction of HO-1 expression accelerates clonal deletion of peripheral alloreactive CD4+ T cells by promoting AICD, which is presumably a key mechanism for its immunomodulatory effects such as in prolonging the survival of transplanted organs.

Biliverdin, a natural product of heme catabolism, induces tolerance to cardiac allografts.

Biliverdin, a product of heme oxygenase-1 (HO-1) enzymatic action, is converted into bilirubin, which has been considered a waste product in the past. We now show that administration of biliverdin has a salutary effect in organ transplantation. A brief course of treatment with biliverdin leads to long-term survival of H-2 incompatible heart allografts. Furthermore, those recipients harboring long-surviving (>100 days) allografts were tolerant to donor antigens indicated by the acceptance of second donor strain hearts but not third-party grafts. Treatment with biliverdin decreased intragraft leukocyte infiltration and inhibited T cell proliferation. Likely related to tolerance induction, biliverdin interferes with T cell signaling by inhibiting activation of nuclear factor of activated T cells (NFAT) and nuclear factor kappaB (NF-kappaB), two transcription factors involved in interleukin-2 (IL-2) transcription and T cell proliferation, as well as suppressing Th1 interferon-gamma (IFN-gamma) production in vitro. These findings support the potential use of biliverdin, a natural product, in transplantation and other T cell mediated immune disorders.