Alan Cass

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.

Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

BACKGROUND The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients

BACKGROUND The optimal intensity of continuous renal-replacement therapy remains unclear. We conducted a multicenter, randomized trial to compare the effect of this therapy, delivered at two different levels of intensity, on 90-day mortality among critically ill patients with acute kidney injury. METHODS We randomly assigned critically ill adults with acute kidney injury to continuous renal-replacement therapy in the form of postdilution continuous venovenous hemodiafiltration with an effluent flow of either 40 ml per kilogram of body weight per hour (higher intensity) or 25 ml per kilogram per hour (lower intensity). The primary outcome measure was death within 90 days after randomization. RESULTS Of the 1508 enrolled patients, 747 were randomly assigned to higher-intensity therapy, and 761 to lower-intensity therapy with continuous venovenous hemodiafiltration. Data on primary outcomes were available for 1464 patients (97.1%): 721 in the higher-intensity group and 743 in the lower-intensity group. The two study groups had similar baseline characteristics and received the study treatment for an average of 6.3 and 5.9 days, respectively (P=0.35). At 90 days after randomization, 322 deaths had occurred in the higher-intensity group and 332 deaths in the lower-intensity group, for a mortality of 44.7% in each group (odds ratio, 1.00; 95% confidence interval [CI], 0.81 to 1.23; P=0.99). At 90 days, 6.8% of survivors in the higher-intensity group (27 of 399), as compared with 4.4% of survivors in the lower-intensity group (18 of 411), were still receiving renal-replacement therapy (odds ratio, 1.59; 95% CI, 0.86 to 2.92; P=0.14). Hypophosphatemia was more common in the higher-intensity group than in the lower-intensity group (65% vs. 54%, P<0.001). CONCLUSIONS In critically ill patients with acute kidney injury, treatment with higher-intensity continuous renal-replacement therapy did not reduce mortality at 90 days. (ClinicalTrials.gov number, NCT00221013.)

Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis

BACKGROUND Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes. METHODS We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, 2010. We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. FINDINGS We identified 18 trials providing data for 45 058 participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0-18) for major cardiovascular events (p=0.048) and a 13% RR reduction (7-19) for coronary events (p<0.0001), but had no benefit on stroke (-3%, -16 to 9; p=0.69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, -8 to 7; p=0.92), cardiovascular mortality (3%, -7 to 12; p=0.59), sudden death (11%, -6 to 26; p=0.19), or non-vascular mortality (-10%, -21 to 0.5; p=0.063). Fibrates reduced the risk of albuminuria progression by 14% (2-25; p=0.028). Serious drug-related adverse events were not significantly increased by fibrates (17 413 participants, 225 events; RR 1.21, 0.91-1.61; p=0.19), although increases in serum creatinine concentrations were common (1.99, 1.46-2.70; p<0.0001). INTERPRETATION Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia. FUNDING National Health and Medical Research Council of Australia.

Albuminuria and Kidney Function Independently Predict Cardiovascular and Renal Outcomes in Diabetes

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Effect of lowering blood pressure on cardiovascular events and mortality in patients on dialysis: a systematic review and meta-analysis of randomised controlled trials

Summary Background Patients undergoing dialysis have a substantially increased risk of cardiovascular mortality and morbidity. Although several trials have shown the cardiovascular benefits of lowering blood pressure in the general population, there is uncertainty about the efficacy and tolerability of reducing blood pressure in patients on dialysis. We did a systematic review and meta-analysis to assess the effect of blood pressure lowering in patients on dialysis. Methods We systematically searched Medline, Embase, and the Cochrane Library database for trials reported between 1950 and November, 2008, without language restriction. We extracted a standardised dataset from randomised controlled trials of blood pressure lowering in patients on dialysis that reported cardiovascular outcomes. Meta-analysis was done with a random effects model. Findings We identified eight relevant trials, which provided data for 1679 patients and 495 cardiovascular events. Weighted mean systolic blood pressure was 4·5 mm Hg lower and diastolic blood pressure 2·3 mm Hg lower in actively treated patients than in controls. Blood pressure lowering treatment was associated with lower risks of cardiovascular events (RR 0·71, 95% CI 0·55–0·92; p=0·009), all-cause mortality (RR 0·80, 0·66–0·96; p=0·014), and cardiovascular mortality (RR 0·71, 0·50–0·99; p=0·044) than control regimens. The effects seem to be consistent across a range of patient groups included in the studies. Interpretation Treatment with agents that lower blood pressure should routinely be considered for individuals undergoing dialysis to reduce the very high cardiovascular morbidity and mortality rate in this population. Funding National Health and Medical Research Council of Australia Program.

Worldwide access to treatment for end-stage kidney disease: a systematic review

BACKGROUND End-stage kidney disease is a leading cause of morbidity and mortality worldwide. Prevalence of the disease and worldwide use of renal replacement therapy (RRT) are expected to rise sharply in the next decade. We aimed to quantify estimates of this burden. METHODS We systematically searched Medline for observational studies and renal registries, and contacted national experts to obtain RRT prevalence data. We used Poisson regression to estimate the prevalence of RRT for countries without reported data. We estimated the gap between needed and actual RRT, and projected needs to 2030. FINDINGS In 2010, 2·618 million people received RRT worldwide. We estimated the number of patients needing RRT to be between 4·902 million (95% CI 4·438-5·431 million) in our conservative model and 9·701 million (8·544-11·021 million) in our high-estimate model, suggesting that at least 2·284 million people might have died prematurely because RRT could not be accessed. We noted the largest treatment gaps in low-income countries, particularly Asia (1·907 million people needing but not receiving RRT; conservative model) and Africa (432,000 people; conservative model). Worldwide use of RRT is projected to more than double to 5·439 million (3·899-7·640 million) people by 2030, with the most growth in Asia (0·968 million to a projected 2·162 million [1·571-3·014 million]). INTERPRETATION The large number of people receiving RRT and the substantial number without access to it show the need to both develop low-cost treatments and implement effective population-based prevention strategies. FUNDING Australian National Health and Medical Research Council.

Is Low Birth Weight an Antecedent of CKD in Later Life? A Systematic Review of Observational Studies

BACKGROUND There has been considerable interest in the hypothesis that low birth weight may be a marker of impaired nephrogenesis and that this is causally related to chronic kidney disease (CKD). STUDY DESIGN Systematic review and meta-analysis of observational studies. SETTING & POPULATION Studies of the relationship between birth weight and CKD published before February 1, 2008, were identified by using electronic searches. SELECTION CRITERIA All studies that had collected data for birth weight and kidney function at greater than 12 months of age were eligible for inclusion, except for studies of extremely low-birth-weight infants, very premature infants, or toxic exposure in utero. STUDY FACTOR: Birth weight. OUTCOMES CKD defined as albuminuria, low estimated glomerular filtration rate (<60 mL/min/1.73 m(2) or < 10th centile for age/sex), or end-stage renal disease. RESULTS We analyzed 31 relevant cohort or case-control studies with data for 49,376 individuals and data for 2,183,317 individuals from a single record-linkage study. Overall, 16 studies reported a significant association between low birth weight and risk of CKD and 16 observed a null result. The combination of weighted estimates from the 18 studies for which risk estimates were available (n = 46,249 plus 2,183,317 from the record linkage study) gave an overall odds ratio (OR) of 1.73 (95% confidence interval [CI], 1.44 to 2.08). Combined ORs were consistent in magnitude and direction for risks of albuminuria (OR, 1.81; 95% CI, 1.19 to 2.77), end-stage renal disease (OR, 1.58; 95% CI, 1.33 to 1.88), or low estimated glomerular filtration rate (OR, 1.79; 95% CI, 1.31 to 2.45). LIMITATIONS A reliance on published estimates and estimates provided on request rather than individual patient data and the possibility of reporting bias. CONCLUSIONS Existing data indicate that low birth weight is associated with subsequent risk of CKD, although there is scope for additional well-designed population-based studies with accurate assessment of birth weight and kidney function and consideration of important confounders, including maternal and socioeconomic factors.

Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes

BP is an important determinant of kidney disease among patients with diabetes. The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy, respectively. We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. Patients were randomly assigned to fixed combination perindopril-indapamide or placebo, regardless of their BP at entry. During a mean follow-up of 4.3 yr, active treatment reduced the risk for renal events by 21% (P < 0.0001), which was driven by reduced risks for developing microalbuminuria and macroalbuminuria (both P < 0.003). Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP. Lower systolic BP levels during follow-up, even to <110 mmHg, was associated with progressively lower rates of renal events. In conclusion, BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection, even among those with initial BP <120/70 mmHg. We could not identify a BP threshold below which renal benefit is lost.

How can we achieve global equity in provision of renal replacement therapy

There is a significant emerging burden of chronic and end-stage kidney disease in low- and middle-income countries, driven by population ageing and the global epidemic of type 2 diabetes. Sufferers of end-stage kidney disease require ongoing dialysis or kidney transplantation to survive; however, in many low- and middle-income countries, treatment options are strictly limited or unaffordable. Low numbers of maintenance dialysis patients and transplant recipients reflect profound economic and service provision challenges for health-care systems in low- and middle-income countries in sustaining renal replacement therapy programmes. Underdeveloped organ donor and transplant programmes, health system and financing issues, ethical regulation of transplantation and the cost of pharmaceuticals commonly pose additional barriers to the delivery of efficient and cost-effective renal replacement therapy. Development of locally appropriate transplant programmes, effective use of nongovernmental sources of funding, service planning and cost containment, use of generic drugs and local manufacture of dialysis consumables have the potential to make life-saving renal replacement therapy available to many more in need. Select low- and middle-income countries demonstrate more equitable provision of renal replacement therapy is possible outside high-income countries. For other low- and middle-income countries, education, the development of good public policy and a supportive international environment are critical. Prevention of end-stage kidney disease, ideally as part of an integrated approach to chronic vascular diseases, must also be a key objective.