Kieran McCafferty

Ischemic Conditioning Protects the Uremic Heart in a Rodent Model of Myocardial Infarction

Background— Outcomes after acute myocardial infarction in patients with chronic kidney disease are extremely poor. Ischemic conditioning techniques are among the most powerful cytoprotective strategies discovered to date. However, experimental data suggest that comorbidity may attenuate the protective effects of ischemic conditioning. Methods and Results— We conducted investigations into the effects of chronic uremia on myocardial infarct size and the protective effects of ischemic preconditioning (IPC), remote ischemic preconditioning, and ischemic postconditioning in 2 rodent models of chronic uremia. In addition, a limited investigation into the signaling mechanisms involved in cardioprotection after IPC was performed in both uremic and nonuremic animals. Myocardial infarct size was increased in uremic animals, but all 3 conditioning strategies (IPC, remote IPC, ischemic postconditioning) proved highly efficacious in reducing myocardial infarct size (relative reduction, 86%, 39%, and 65% [P<0.005, P<0.05, and P<0.05], respectively). Moreover, some protocols (IPC and ischemic postconditioning) appeared to be more effective in uremic than in sham (nonuremic) animals. Analysis of the signaling mechanisms revealed that components of both the reperfusion injury salvage kinase and survivor activating factor enhancement pathways were similarly upregulated in both uremic and nonuremic animals after an IPC stimulus. Conclusion— Conditioning strategies may present the best opportunity to improve outcomes for patients with chronic kidney disease after an acute coronary syndrome.

Extracellular volume expansion, measured by multifrequency bioimpedance, does not help preserve residual renal function in peritoneal dialysis patients

Residual renal function is a major survival determinant for peritoneal dialysis patients. Hypovolemia can cause acute kidney injury and loss of residual renal function, and it has been suggested that patients receiving peritoneal dialysis should preferably be maintained hypervolemic to preserve residual renal function. Here we determined whether hydration status predicted long-term changes in residual renal function. Changes in residual renal function and extracellular water (ECW) to total body water (TBW) measured by multifrequency bioimpedance in 237 adult patients who had paired baseline and serial 12 monthly measurements were examined. Baseline hydration status (ECW/TBW) was not significantly associated with preservation of residual renal function, unlike baseline and follow-up mean arterial blood pressure. When the cohort was split into tertiles according to baseline hydration status, there was no significant correlation seen between change in hydration status and subsequent loss in residual renal function. Increased ECW/TBW in peritoneal dialysis patients was not associated with preservation of residual renal function. Similarly, increments and decrements in ECW/TBW were not associated with preservation or reduction in residual renal function. Thus, our study does not support the view that overhydration preserves residual renal function and such a policy risks the consequences of persistent hypervolemia.

The challenge of translating ischemic conditioning from animal models to humans: the role of comorbidities

Following a period of ischemia (local restriction of blood supply to a tissue), the restoration of blood supply to the affected area causes significant tissue damage. This is known as ischemia-reperfusion injury (IRI) and is a central pathological mechanism contributing to many common disease states. The medical complications caused by IRI in individuals with cerebrovascular or heart disease are a leading cause of death in developed countries. IRI is also of crucial importance in fields as diverse as solid organ transplantation, acute kidney injury and following major surgery, where post-operative organ dysfunction is a major cause of morbidity and mortality. Given its clinical impact, novel interventions are urgently needed to minimize the effects of IRI, not least to save lives but also to reduce healthcare costs. In this Review, we examine the experimental technique of ischemic conditioning, which entails exposing organs or tissues to brief sub-lethal episodes of ischemia and reperfusion, before, during or after a lethal ischemic insult. This approach has been found to confer profound tissue protection against IRI. We discuss the translation of ischemic conditioning strategies from bench to bedside, and highlight where transition into human clinical studies has been less successful than in animal models, reviewing potential reasons for this. We explore the challenges that preclude more extensive clinical translation of these strategies and emphasize the role that underlying comorbidities have in altering the efficacy of these strategies in improving patient outcomes.

Acidosis: progression of chronic kidney disease and quality of life.

Metabolic acidosis (MA) is relatively common in patients with chronic kidney disease (CKD) particularly in stages 4 and 5. It is assumed to play a contributory role in the development of several complications including bone disease, skeletal muscle wasting, altered protein synthesis, and degradation. Recent evidence also suggests that even mild acidosis might play a role in progressive glomerular filtration rate loss. Experimental and clinical studies suggest that correction of acidosis by alkali therapy attenuates these complications and improves quality of life. Despite several recent small and single-center studies supporting this notion, more robust evidence is required with regard to the long-term benefits of alkali therapy, type of alkali supplements, and the optimal level of serum bicarbonate.

Intestinal Microbiota Determine Severity of Myocardial Infarction in Rats

We read with great interest the recent paper by Lam et al. (1). This novel paper demonstrated that alteration of the gut microbiome by vancomycin significantly reduced leptin levels and subsequently led to an increased myocardial ischemia tolerance. They confirmed that leptin was directly involved in myocardial ischemia tolerance by demonstrating that pretreatment with leptin abolished the cardioprotection seen with vancomycin treatment. There is, however, conflicting evidence of the role of leptin in myocardial ischemia tolerance, with other groups reporting that leptin may be beneficial (2–4). Receptors for leptin are known to be present on both the myocardium and the kidney (5), which prompted us to examine whether tissue protection induced by vancomycin treatment could be extended to other organs. We replicated the experimental protocol described by Lam et al. (1) in 24 male Wistar rats, which were divided into control and vancomycin (0.5 mg/ml)treated groups. After 1 week, all animals underwent a right nephrectomy and a 45-min left renal artery occlusion, followed by reperfusion for 48 h, at which point, the animals were killed. Serum leptin concentrations and the degree of renal failure were measured. We confirmed the finding by Lam et al. (1)—that 1 week of vancomycin treatment led to a significant reduction in serum leptin levels (Table 1). Despite a 41% reduction in serum leptin levels by vancomycin, no difference in renal injury was seen between the treated and untreated groups, as measured by serum urea, creatinine, phosphate, potassium, or AST. We conclude that this novel effect of leptin-mediated, reduced ischemia tolerance appears to be tissue-specific and currently limited to the myocardium. REFERENCES

Could metformin be used in patients with diabetes and advanced chronic kidney disease

Diabetes is an important cause of end stage renal failure worldwide. As renal impairment progresses, managing hyperglycaemia can prove increasingly challenging, as many medications are contra‐indicated in moderate to severe renal impairment. Whilst evidence for tight glycaemic control reducing progression to renal failure in patients with established renal disease is limited, poor glycaemic control is not desirable, and is likely to lead to progressive complications. Metformin is a first‐line therapy in patients with Type 2 diabetes, as it appears to be effective in reducing diabetes related end points and mortality in overweight patients. Cessation of metformin in patients with progressive renal disease may not only lead to deterioration in glucose control, but also to loss of protection from cardiovascular disease in a cohort of patients at particularly high risk. We advocate the need for further study to determine the role of metformin in patients with severe renal disease (chronic kidney disease stage 4‐5), as well as patients on dialysis, or pre‐/peri‐renal transplantation. We explore possible roles of metformin in these circumstances, and suggest potential key areas for further study.

Is lack of suitable housing a barrier to home-based dialysis therapy for patients with end-stage renal disease? A cohort study

Objective To determine whether inadequate housing is the main barrier to the provision of home dialysis treatment. Design Prospective observational study. Participants All patients attending a predialysis clinic between 2006 and 2009 deemed medically suitable for home dialysis and not active on the preemptive transplant list. Setting A predialysis clinic in a London teaching hospital. Main outcome measure Assessment of patients accommodation for suitability for home-based dialysis using departmental guidelines and the Governments Housing Health and Safety Rating System regulations 2005. Results A lack of adequate housing prohibited the provision of home haemodialysis to all but one of these patients. Moreover, only 29% of homes assessed were suitable for peritoneal dialysis, despite the lower spatial demands of this form of renal replacement therapy. In addition to the specific requirements of dialysis, we also found that only 33% of the homes visited fulfilled the minimum standard of housing as defined in the Governments Decent Homes Standard, with multiple specific hazards identified across the properties. Conclusions This study illustrates that the lack of suitable housing is a major barrier to the provision of home-based dialysis and underscores the need for this to be addressed urgently at both the central government and local authority levels. We suggest that it should be considered as a major priority to rehouse medically suitable patients with a view to enabling home-based therapy.

FP473DOES PERITONEAL DIALYSIS VINTAGE AFFECT RELATIVE LEUCOCYTE TELOMERE LENGTH; A NOVEL BIOMARKER OF AGEING?

METHODS: This is a post-hoc analysis of a prospective, randomized, controlled double-blind clinical study on a low Na PDF (125 mmol/L Na) compared to a standard Na PDF (134 mmol/L Na) (Rutkowski et al. Am J Kidney Dis 2015). Patients in the per protocol population were divided into subgroups according to glomerular filtration rate (GFR) at baseline (&#8804; /> 6 ml/min/1.73 m). Linear mixed models were used to analyse the interaction between GFR and the effect of the low Na PDF on BP and on further parameters related to the effect of sodium balance after 12 weeks of exposure following the initial analysis of this study. Estimation of the treatment effect was adjusted for baseline levels, country, GFR subgroup and the interaction between treatment and GFR subgroup; clustering of patients within study centres was accounted for by a random centre effect. Treatment effects on antihypertensive medication from baseline to week 12 were analysed by use of a Wilcoxon rank sum test.

Eye and foot checks in patients with diabetes on haemodialysis: Are they done, and who does them?

AIM To determine if retinal and foot checks are carried out on patients with diabetes receiving haemodialysis. METHODS Eighty-four patients with diabetes receiving haemodialysis were asked if they recalled having eye and foot screening in the last year, and if so, by whom was the check done. RESULTS Seventy-seven (91.7%) patients recalled having an eye check in the preceding 12 mo. Of these, 52 (67.5%) did so in an ophthalmology clinic, 17 (22%) in retinal screening, three (3.9%) in an optician clinic. Three patients (3.9%) went to both ophthalmology and retinal screening, and two (2.6%) attended an ophthalmology and optician. Seventy (83.3%) patients recalled having a foot check in the preceding 12 mo. Of these, 33 (47.1%) were done by practice nurse, 14 (20%) by a diabetes nurse, 11 (15.7%) by a general practitioner, eight (11.4%) by a chiropodist, and four (5.7%) were each checked by renal nurse, diabetes consultant, junior doctor, or unknown person at a foot clinic. CONCLUSION Most patients with diabetes on haemodialysis are able to recall having an eye check in the last year, although 8.3% could not. A significant proportion of patients could not recall having a foot check (16.7%) in the last year. This baseline audit suggests that an improvement in the rate of foot screening is important to achieve in patients with diabetes on haemodialysis in our unit.

Ischemic conditioning in solid organ transplantation: is it worth giving your right arm for?

Purpose of review Ischemia reperfusion injury (IRI) is an inevitable complication in solid organ transplantation. Limiting this injury can increase patient and graft survival and can decrease complications associated with transplantation. We provide an extensive literature review analyzing the available evidence for ischemic conditioning in solid organ transplantation, including kidney, liver, heart, and lung. Recent findings Ischemic conditioning strategies are a group of interventions, characterized by episodes of ischemia and reperfusion to an organ which confirm tissue protection. Arguably, transplantation is the ideal setting to use this novel strategy due to the predictable timing and duration of the ischemic insult. Liver transplantation has provided us with the most number of clinical trials, followed by kidney transplantation. Most of these trials have been negative but the methodology has been variable, making comparison difficult. Summary Despite the promising results seen in animal models, translating these results in clinical trials has proved to be difficult. The promising effects of ischemic conditioning are present in some trials with weaker positive signals existing in other trials. We believe that tailoring trials to allow better comparison will provide positive results in the future.