Charles Tomson

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection) : a randomised placebo-controlled trial

Summary Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients. Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607. Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13). Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease. Funding Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

Increase in Creatinine and Cardiovascular Risk in Patients with Systolic Dysfunction after Myocardial Infarction

Baseline renal function is a potent independent risk factor for adverse events after acute myocardial infarction (MI). Worsening renal function (WRF) has been shown to influence outcomes in the heart failure population, but its impact on cardiovascular risk in the post-MI period has not been well defined. For assessment of the prognostic importance of WRF, 2231 patients who had left ventricular dysfunction and were enrolled in the Survival and Ventricular Enlargement (SAVE) trial were studied. Patients were randomly assigned between 3 and 16 d (average 11 d) after acute MI to receive captopril or placebo; those with a serum creatinine of >2.5 mg/dl were excluded from SAVE. WRF was defined as an increase in creatinine of >0.3 mg/dl measured from baseline to 2 wk after randomization. The predictive value of WRF on cardiovascular morbidity and mortality was examined during 42 mo of follow-up. Paired serum creatinine measurements at baseline and 2 wk were available in 1854 patients. WRF occurred in 223 (12.0%) patients and was a stronger predictor of death (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.05 to 2.02) than baseline creatinine (HR 1.31; 95% CI 1.01 to 1.70). WRF also showed an increased risk for cardiovascular death (HR 1.62; 95% CI 1.14 to 2.30) and the composite end point (HR 1.32; 95% CI 1.03 to 1.70). When stratified by treatment, 104 (5.7%) and 116 (6.4%) patients with WRF in the placebo and captopril groups had no significant association between treatment group and WRF (P = 0.38). The risk for death associated with WRF was HR 1.63 (95% CI 1.05 to 2.52) in the placebo group compared with HR 1.33 (95% CI 0.81 to 2.21) in the captopril group (P = 0.49 for interaction). WRF as early as 2 wk after MI was not uncommon (12.0%) and was associated with increased mortality in patients without renal dysfunction at baseline. Patients who received captopril did not demonstrate more WRF than patients who received placebo. Monitoring serum creatinine in patients during the first few weeks after MI may help to identify those who are at highest risk and guide effective long-term therapeutic choices.

Serum Phosphate as a Risk Factor for Cardiovascular Events in People with and without Chronic Kidney Disease: A Large Community Based Cohort Study

Background Serum phosphate is a known risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD), however data on the association of these outcomes with serum phosphate in the general population are scarce. We investigate this relationship in people with and without CKD in a large community-based population. Methods Three groups from an adult cohort of the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial (ISRCTN56023731) were followed over a period of 2.5 years: people with normal renal function (N = 24,184), people with CKD stages 1–2 (N = 20,356), and people with CKD stages 3–5 (N = 13,292). We used a multilevel logistic regression model to determine the association between serum phosphate, in these groups, and a composite outcome of all-cause mortality, cardiovascular events, and advanced coronary artery disease. We adjusted for known cardiovascular risk factors. Findings Higher phosphate levels were found to correlate with increased cardiovascular risk. In people with normal renal function and CKD stages 1–2, Phosphate levels between 1.25 and 1.50 mmol/l were associated with increased cardiovascular events; odds ratio (OR) 1.36 (95% CI 1.06–1.74; p = 0.016) in people with normal renal function and OR 1.40 (95% CI 1.09–1.81; p = 0.010) in people with CKD stages 1–2. Hypophosphatemia (<0.75 mmol/l) was associated with fewer cardiovascular events in people with normal renal function; OR 0.59 (95% CI 0.36–0.97; p = 0.049). In people with CKD stages 3–5, hyperphosphatemia (>1.50 mmol/l) was associated with increased cardiovascular risk; OR 2.34 (95% CI 1.64–3.32; p<0.001). Other phosphate ranges were not found to have a significant impact on cardiovascular events in people with CKD stages 3–5. Conclusions Serum phosphate is associated with cardiovascular events in people with and without CKD. Further research is required to determine the mechanisms underlying these associations.

ACE inhibitor and angiotensin receptor-II antagonist prescribing and hospital admissions with acute kidney injury: a longitudinal ecological study.

Background ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. Methods and Findings English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio = 1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions. Conclusion In this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level data such as indication for prescribing and patient characteristics.

A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry

C3 glomerulopathy describes glomerular pathology associated with predominant deposition of complement C3 including dense deposit disease and C3 glomerulonephritis. Familial C3 glomerulonephritis has been associated with rearrangements affecting the complement factor H–related (CFHR) genes. These include a hybrid CFHR3-1 gene and an internal duplication within the CFHR5 gene. CFHR5 nephropathy, to date, occurred exclusively in patients with Cypriot ancestry, and is associated with a heterozygous internal duplication of the CFHR5 gene resulting in duplication of the exons encoding the first two domains of the CFHR5 protein. Affected individuals possess both the wild-type nine-domain CFHR5 protein (CFHR512-9) and an abnormally large mutant CFHR5 protein in which the initial two protein domains are duplicated (CFHR51212-9). We found CFHR51212-9 in association with familial C3 glomerulonephritis in a family without Cypriot ancestry. The genomic rearrangement was distinct from that seen in Cypriot CFHR5 nephropathy. Our findings strengthen the association between CFHR51212-9 and familial C3 glomerulonephritis and recommend screening for CFHR51212-9 in patients with C3 glomerulopathy irrespective of ethnicity. Since CFHR51212-9 can result from at least two genomic rearrangements, screening is most readily achieved through analysis of CFHR5 protein.

Social deprivation, ethnicity, and uptake of living kidney donor transplantation in the United Kingdom

Background. Socioeconomic disparities and their contribution to the ethnic differences in living kidney donor transplantation have not been adequately studied. Methods. A total of 12,282 patients aged 18 to 69 years starting renal replacement therapy (January 1, 1997, to December 31, 2004) in the United Kingdom were included. Logistic regression models were used to examine probability of living donor transplantation within 3 years of renal replacement therapy. The effect of area deprivation (Townsend index) was studied among whites only adjusted for patient characteristics and the effect of ethnic origin (South Asians and blacks compared with whites) was then examined among all patients adjusting for area deprivation. Results. Among whites, increasing social deprivation was associated with lower odds of living donor transplantation. In the fully adjusted model, odds ratio (OR) for the most deprived quintile was 0.40 (95% confidence interval [CI] 0.33, 0.49; P trend<0.0001) compared with the least deprived. These gradients were more pronounced among centers performing more live donor transplants (P value for interaction <0.0001). South Asians and blacks had lower odds of living donor transplantation compared with whites, but there was an interaction with age (P<0.0001), so that this disparity was observed only in those younger than 50 years (blacks: OR, 0.31; 95% CI, 0.18, 0.54; South Asians: OR, 0.55; 95% CI, 0.34, 0.90; P value <0.0001). Conclusions. Socially deprived and younger ethnic minority patients have lower probability of living kidney donor transplantation. The extent to which these inequalities reflect modifiable societal healthcare system barriers and donor/recipient factors requires further study.

Association Between Glycemia and Mortality in Diabetic Individuals on Renal Replacement Therapy in the U.K.

OBJECTIVE In the U.K., one-third of patients receiving treatment with dialysis have diabetes. Guidelines from organizations representing patients with renal disease or diabetes advocate tight glycemic control in patients with end-stage renal disease, despite glucose-lowering trials having excluded these patients. RESEARCH DESIGN AND METHODS Using national UK Renal Registry data, we tested whether glycemia as measured by hemoglobin (Hb) A1c (HbA1c) level is associated with death in adults with diabetes starting hemodialysis or peritoneal dialysis between 1997 and 2006, and observed for at least 6 months. Of 7,814 patients, we excluded those who had died within 6 months; had received transplants; were lost/recovered; or lacked measures of HbA1c, ethnicity, or Hb. Categorizing HbA1c measured in the first 6 months of starting dialysis as <6.5% (<48 mmol/mol), 6.5–7.4% (48–57 mmol/mol) (reference value), 7.5–8.4% (58–68 mmol/mol), and ≥8.5% (≥69 mmol/mol), we adjusted in proportional hazards models for age, sex, ethnicity, deprivation, year, dialysis type, and Hb, and tested for interactions. RESULTS Of 3,157 patients observed for a median time of 2.7 years, 1,688 died. For patients ≥60 years of age, we found no association between HbA1c and death; among younger patients, relative to those with HbA1c values 6.5–7.4%, the hazard ratio for HbA1c level 7.5–8.4% was 1.2 (95% CI 0.9–1.5), and for HbA1c level >8.5% was 1.5 (1.2–1.9). The projected difference in median survival time between younger patients with a reference HbA1c value versus >8.5% was 1 year. CONCLUSIONS In the absence of trials, and confounding notwithstanding, these observational data support improved glycemic control in younger patients prior to and during dialysis.

The accuracy of diagnostic coding for acute kidney injury in England – a single centre study

BackgroundAcute kidney injury (AKI) is an independent risk factor for mortality and is responsible for a significant burden of healthcare expenditure, so accurate measurement of its incidence is important. Administrative coding data has been used for assessing AKI incidence, and shows an increasing proportion of hospital bed days attributable to AKI. However, the accuracy of coding for AKI and changes in coding over time have not been studied in England.MethodsWe studied a random sample of admissions from 2005 and 2010 where ICD-10 code N17 (acute renal failure) was recorded in the administrative coding data at one acute NHS Foundation Trust in England. Using the medical notes and computerised records we examined the demographic and clinical details of these admissions.ResultsAgainst a 6.3% (95% CI 4.8-7.9%) increase in all non-elective admissions, we found a 64% increase in acute renal failure admissions (95% CI 41%-92%, p < 0.001) in 2010 compared to 2005. Median age was 78 years (IQR 72–87), 11-25% had a relevant pre-admission co-morbidity and 64% (55-73%) were taking drugs known to be associated with AKI. Over both years, 95% (91-99%) of cases examined met the Kidney Disease: Improving Global Outcomes criteria for AKI.ConclusionsPatients with hospital admissions where AKI has been coded are elderly with multiple co-morbidities. Our results demonstrate a high positive predictive value of coding data for a clinical diagnosis of AKI, with no suggestion of marked changes in coding of AKI between 2005 and 2010.

The 'centre effect' in nephrology: what do differences between nephrology centres tell us about clinical performance in patient management?

Improving the quality of care provided by nephrology centres to patients with kidney disease requires a clear understanding of how to compare performance after adjustment for case mix, combined with a detailed understanding of the structure and processes that are associated with the achievement of good clinical results. In this review, we discuss how to measure quality of care (using process or outcome measures), how to take case mix into account, how best to display comparisons between nephrology centres, and how to study the causes of real variations in quality between centres. This is a narrative review; we include examples from other fields in which the centre effect has been studied, including education.

From potential donor to actual donation: does socioeconomic position affect living kidney donation? A systematic review of the evidence.

Evidence from Europe, Australia and the United States demonstrates that socioeconomically deprived individuals with advanced chronic kidney disease are less likely to receive a living kidney transplant compared with less deprived individuals. This systematic review focuses on how socioeconomic position (SEP) may influence hypothetical and actual living kidney donors and where appropriate, summarizes the quantitative evidence. In the general population, a higher SEP appears to be associated with an increased ‘hypothetical’ willingness to be a living kidney donor but with marked heterogeneity in the absolute differences (I2 = 95.9%, P < 0.001). In a commercial setting, lower SEP motivates people to donate. Outside of this setting, there is no evidence of discordance in the SEP of donors and recipients that would suggest undisclosed financial exchange. There is evidence for a complex interaction between SEP and other variables, such as ethnicity, sex, and the national economic climate. Some evidence suggests that measures to remove financial disincentives to donation are associated with an increase in living donation rates. Future research needs to study how SEP impacts the potential donor population from willingness to donate, progression through donor assessment to actual donor nephrectomy.