Magdi Yaqoob

Mechanisms of Disease: cell death in acute renal failure and emerging evidence for a protective role of erythropoietin

Acute renal failure—characterized by a sudden loss of the ability of the kidneys to excrete nitrogenous waste, and to maintain electrolyte homeostasis and fluid balance—is a frequently encountered clinical problem, particularly in the intensive care unit. Unfortunately, advances in supportive interventions have done little to reduce the high mortality associated with this condition. Might erythropoietin (EPO) have utility as a therapeutic agent in acute renal failure? This hormone mediates anti-apoptotic effects in the bone marrow, facilitating maturation and differentiation of erythroid progenitors. New evidence indicates that EPO also exerts anti-apoptotic effects in the brain, heart and vasculature, which can limit the degree of organ damage. Here, we review the emerging biological role of EPO in the kidney and the pathophysiology of ischemia–reperfusion injury in an attempt to understand the therapeutic potential of EPO in acute renal failure.

Long term outcome of patients with autosomal dominant polycystic kidney diseases receiving peritoneal dialysis

There is a general perception that patients with polycystic kidney disease on peritoneal dialysis have poor long-term technique survival. In order to test this opinion, we performed a retrospective analysis comparing results of 56 consecutive patients with polycystic kidney disease to 56 non-diabetic patients with bilateral small kidneys. The patient groups were all initiated on peritoneal dialysis over a 12 year period and matched for age, gender and years of end stage renal failure. After a mean follow-up period of 37 months the two groups were statistically indistinguishable in terms of mortality, kidney transplantation-censored technique survival, median death-censored technique survival, the number of patients switched permanently to hemodialysis due to technique failure and the rate of peritonitis. On Cox regression (multivariate) analysis, only the baseline serum albumin level was a significant and independent risk factor of death-censored technique failure. Our study found no difference in long term outcome of peritoneal dialysis therapy in patients with polycystic kidney disease compared to a non-diabetic matched control group.

A survey to determine the views of renal transplant patients on generic substitution in the UK

Rising healthcare costs promote the generic substitution among patients because it is identifiable costs. A key concern is that patients should be involved in the decision of switching. The aim of this study was to examine renal transplant patients’ views on generic substitution in the UK. A total of 163 renal patients were surveyed using 36 multiple‐choice questions at Barts and The London Renal Transplant Clinic, in the UK. Transplant recipients over 18 years, able to read and write English and willing to fill in the questionnaire were targeted; 84% of patients were conscious of the availability of generic medicines, 70% understood the terms “generic” and “branded” in relation to medicines and 54% were aware of generic substitution practice. However, 75% did not know if they were taking generics and 84% felt that generics are not equivalent or only equivalent sometimes and they were uncertain that generics had the same quality as branded medicines. Moreover, many patients admitted that they would not accept the generic substitution of ciclosporin when become available in the UK. A number of factors such as patients’ education, knowledge, severity of the disease, efficacy of generic medicines and patients’ involvement in decisions regarding their health appear to drive patients’ attitudes towards generic substitution.

Managing diabetes in dialysis patients

Burgeoning levels of diabetes are a major concern for dialysis services, as diabetes is now the most common cause of end-stage renal disease in most developed nations. With the rapid rise in diabetes prevalence in developing countries, the burden of end stage renal failure due to diabetes is also expected to rise in such countries. Diabetic patients on dialysis have a high burden of morbidity and mortality, particularly from cardiovascular disease, and a higher societal and economic cost compared to non-diabetic subjects on dialysis. Tight glycaemic and blood pressure control in diabetic patients has an important impact in reducing risk of progression to end stage renal disease. The evidence for improving glycaemic control in patients on dialysis having an impact on mortality or morbidity is sparse. Indeed, many factors make improving glycaemic control in patients on dialysis very challenging, including therapeutic difficulties with hypoglycaemic agents, monitoring difficulties, dialysis strategies that exacerbate hyperglycaemia or hypoglycaemia, and possibly a degree of therapeutic nihilism or inertia on the part of clinical diabetologists and nephrologists. Standard drug therapy for hyperglycaemia (eg, metformin) is clearly not possible in patients on dialysis. Thus, sulphonylureas and insulin have been the mainstay of treatment. Newer therapies for hyperglycaemia, such as gliptins and glucagon-like peptide-1 analogues have become available, but until recently, renal failure has precluded their use. Newer gliptins, however, are now licensed for use in ‘severe renal failure’, although they have yet to be trialled in dialysis patients. Diabetic patients on dialysis have special needs, as they have a much greater burden of complications (cardiac, retinal and foot). They may be best managed in a multidisciplinary diabetic–renal clinic setting, using the skills of diabetologists, nephrologists, clinical nurse specialists in nephrology and diabetes, along with dietitians and podiatrists.

Palisaded neutrophilic granulomatous dermatitis associated with systemic lupus erythematosus presenting with the burning rope sign

Palisaded neutrophilic granulomatous dermatitis is a rare but increasingly recognized cutaneous manifestation of connective tissue disorders. It is reported most commonly with rheumatoid arthritis but also occasionally in association with systemic lupus erythematosus, inflammatory bowel disease, lymphoproliferative disorders, and systemic vasculitides. The clinicopathological presentation is highly variable, which has led to suggestions that it encompasses a number of distinct diseases. Most previous cases have reported only a single clinical and histologic manifestation of the condition within an individual. Here, we present a case of systemic lupus erythematosus-associated palisaded neutrophilic granulomatous dermatitis in which a striking evolution of both clinical and histologic features was observed during the course of 7 years, providing compelling evidence for the proposal that palisaded neutrophilic granulomatous dermatitis represents a disease spectrum rather than separate disease entities.

Characteristics and Outcomes of Dialysis Patients with Infective Endocarditis

Background: The incidence of infective endocarditis (IE) in dialysis patients is higher than the general population. Dialysis patients who develop endocarditis are thought to have a poorer prognosis than other patients with IE. Aim: To examine the risk profiles, clinical features, and outcomes of patients on dialysis who developed IE in a large cohort. Design and Methods: A retrospective analysis of all patients developing IE on dialysis (using the modified Duke criteria) was undertaken between 1998 and 2011. Patients were identified from a prospectively collected clinical database. Results: 42 patients developed IE out of a total incident dialysis population of 1,500 over 13 years. 95% of the patients (40/42) were on long-term haemodialysis (HD) and 5% (2/42) on peritoneal dialysis. Mean patient age was 55.2 years (IQR: 43-69), and mean duration of HD prior to IE was 57.4 months. Primary HD access at the time of diagnosis was an arteriovenous fistula in 35% (14/40), a dual-lumen tunnelled catheter in 55% (22/40), and a dual-lumen non-tunnelled catheter in 10% (4/40). Staphylococcus aureus (including methicillin-resistant S. aureus) was present in 57.1% (24/42). The aortic valve was affected in 42.8% of the patients (18/42), the mitral valve in 30.9% (13/42), and both valves in 9.5% (4/42). 33.3% of the patients had an abnormal valve before the episode of IE. In 21.4% (9/42), valve surgery was performed and mortality was lower in the surgical group compared to the group managed medically during hospitalisation (11.1 vs. 15.2%, p = 0.892), at 3 months (13.1 vs. 19.6%, p = 0.501), and during follow-up (p = 0.207), but this difference did not reach statistical significance. Age >60 years, septic emboli, and methicillin-resistant S. aureus were all adverse prognostic factors. Patients receiving surgery were younger (mean 47.1 ± 14.4 years vs. 57.4 ± 14.3, p = 0.049) and less likely to be infected with S. aureus (surgery 33.3% vs. antibiotics 63.6%, p = 0.046). Conclusion: This is one of the largest reported series of IE in dialysis patients. The incidence of IE remains high and the prognosis poor in dialysis patients, although patients selected for early valve surgery have good 1-year survival.

Prevalence of cognitive impairment in patients attending pre-dialysis clinic.

Approximately 20-30% of patients on renal replacement therapy (RRT) have cognitive impairment. Less is known about the prevalence of cognitive impairment in patients with advanced kidney disease awaiting the initiation of dialysis. Routine cognitive assessment was implemented in the pre-dialysis clinic, which enabled the Nephrologist and Pre-dialysis Nurse to identify those patients with impaired cognitive function and utilise this information to assess the suitability for self-care treatments, such as peritoneal dialysis, as well as to adapt information to meet their needs. Subsequently, a cross-sectional single-centre audit was undertaken to identify the prevalence of cognitive impairment in 132 consecutive new referrals to the pre-dialysis clinic using the Mini-mental State Examination (MMSE). Twenty percent (95% CI = 0.13, 0.27) were classified as cognitively impaired. Those with cognitive impairment were significantly older, and had lower eGFR and higher serum creatinine. It can be concluded that approximately 1 in 5 patients attending the pre-dialysis clinic has cognitive impairment, which may not be apparent on a routine clinical history. Cognitive function assessment is recommended for all, but particularly to the older patient, before advising on choice of dialysis modality or opting for conservative treatment.

Human papillomavirus is detected in transitional cell carcinoma arising in renal transplant recipients

Aims: We investigated the role of human papillomavirus (HPV) in the development of transitional cell carcinoma (TCC) arising in renal transplant recipients. Methods: Genomic DNA was extracted from 10 µm paraffin embedded sections of five TCCs arising in five renal transplant recipients using the QIAamp DNA mini kit according to the manufacturers instructions. β‐globin PCR was performed to test DNA adequacy. Samples were tested for the presence of HPV DNA by broad spectrum HPV PCR method using non‐biotinylated SPF10 primers (SPF1A, SPF1B, SPF1C, SPF1D, SPF2B, SPF2D) which amplify a short 65 bp fragment. Positive bands were identified on a 3% gel. Positive samples underwent a second HPV PCR and were amplified using biotinylated SPF10 primer set, which amplifies the same 65 bp region of the L1 open reading frame. INNO‐LiPA line probe assay was then performed to genotype the samples which uses a reverse hybridisation principle. Results: Four of five TCCs examined were positive for HPV. The high risk HPV16 was detected in three cases whereas in the fourth case an unclassifiable HPV genotype was present. In all DNA samples, β‐globin amplification was successful. Conclusions: Our results indicate that HPV and in particular HPV16 may play an aetiological role in the development of TCC in renal transplant patients.

Using metformin in the presence of renal disease

Current guidelines are too restrictive, and many patients who could benefit are missing out

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