Empagliflozin lowers serum uric acid in chronic kidney disease: exploratory analyses from the EMPA-KIDNEY trial.

BACKGROUND AND HYPOTHESIS: Hyperuricaemia and gout are common in chronic kidney disease (CKD). We aimed to assess the effects of sodium-glucose co-transporter-2 (SGLT2) inhibition on uric acid (urate) and gout in patients with CKD. METHODS: The EMPA-KIDNEY trial randomised 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20 and <90 mL/min/1.73m2) to receive either empagliflozin 10 mg daily or matching placebo over a median of two years follow-up. Serum uric acid was measured at randomisation then 2 and 18 months of follow-up and the effects of empagliflozin were analysed using a pre-specified mixed model repeated measures approach. Participant-reported gout events were analysed in Cox regression models (first events) with the Andersen-Gill extension (total events). A post-hoc composite outcome included new initiation of uric acid lowering therapy or colchicine. EMPA-KIDNEY primary and kidney disease progression outcomes were also assessed in subgroups of baseline serum uric acid. RESULTS: Baseline mean ± SD serum uric acid concentration was 431±114 µmol/L. Allocation to empagliflozin resulted in a study-average between-group difference in serum uric acid of -25.6 (95%CI -30.3,-21.0) µmol/L with larger effects in those with higher eGFR (trend P < 0.001) and without diabetes (heterogeneity P < 0.001). Compared to placebo, empagliflozin did not significantly reduce first or total gout events (HR 0.87, 95%CI 0.74-1.02 for the 595 first events, and 0.86, 0.72-1.03 for the 869 total events) with similar hazard ratios for the post-hoc composite and across subgroups, including by diabetes and eGFR. The effect of empagliflozin on the primary outcome and kidney disease progression outcomes were similar irrespective of baseline level of uric acid. CONCLUSION: SGLT2 inhibition reduces serum uric acid in patients with CKD with larger effects at higher eGFR and in the absence of diabetes. However, the effect on uric acid is modest and did not translate into reduced risk of gout in EMPA-KIDNEY.

Frailty, multimorbidity and polypharmacy: exploratory analyses of the effects of empagliflozin from the EMPA-KIDNEY trial.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England.

BACKGROUND: Several countries affected by the COVID-19 pandemic have reported a substantial drop in the number of patients attending the emergency department with acute coronary syndromes and a reduced number of cardiac procedures. We aimed to understand the scale, nature, and duration of changes to admissions for different types of acute coronary syndrome in England and to evaluate whether in-hospital management of patients has been affected as a result of the COVID-19 pandemic. METHODS: We analysed data on hospital admissions in England for types of acute coronary syndrome from Jan 1, 2019, to May 24, 2020, that were recorded in the Secondary Uses Service Admitted Patient Care database. Admissions were classified as ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), myocardial infarction of unknown type, or other acute coronary syndromes (including unstable angina). We identified revascularisation procedures undertaken during these admissions (ie, coronary angiography without percutaneous coronary intervention [PCI], PCI, and coronary artery bypass graft surgery). We calculated the numbers of weekly admissions and procedures undertaken; percentage reductions in weekly admissions and across subgroups were also calculated, with 95% CIs. FINDINGS: Hospital admissions for acute coronary syndrome declined from mid-February, 2020, falling from a 2019 baseline rate of 3017 admissions per week to 1813 per week by the end of March, 2020, a reduction of 40% (95% CI 37-43). This decline was partly reversed during April and May, 2020, such that by the last week of May, 2020, there were 2522 admissions, representing a 16% (95% CI 13-20) reduction from baseline. During the period of declining admissions, there were reductions in the numbers of admissions for all types of acute coronary syndrome, including both STEMI and NSTEMI, but relative and absolute reductions were larger for NSTEMI, with 1267 admissions per week in 2019 and 733 per week by the end of March, 2020, a percent reduction of 42% (95% CI 38-46). In parallel, reductions were recorded in the number of PCI procedures for patients with both STEMI (438 PCI procedures per week in 2019 vs 346 by the end of March, 2020; percent reduction 21%, 95% CI 12-29) and NSTEMI (383 PCI procedures per week in 2019 vs 240 by the end of March, 2020; percent reduction 37%, 29-45). The median length of stay among patients with acute coronary syndrome fell from 4 days (IQR 2-9) in 2019 to 3 days (1-5) by the end of March, 2020. INTERPRETATION: Compared with the weekly average in 2019, there was a substantial reduction in the weekly numbers of patients with acute coronary syndrome who were admitted to hospital in England by the end of March, 2020, which had been partly reversed by the end of May, 2020. The reduced number of admissions during this period is likely to have resulted in increases in out-of-hospital deaths and long-term complications of myocardial infarction and missed opportunities to offer secondary prevention treatment for patients with coronary heart disease. The full extent of the effect of COVID-19 on the management of patients with acute coronary syndrome will continue to be assessed by updating these analyses. FUNDING: UK Medical Research Council, British Heart Foundation, Public Health England, Health Data Research UK, and the National Institute for Health Research Oxford Biomedical Research Centre.

Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom.

AIMS: Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom. METHODS AND RESULTS: An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73-92.69, P across thirds = 9·1 × 10-48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms. CONCLUSIONS: The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms.

Impact of CKD on Household Income.

INTRODUCTION: The impact of chronic kidney disease (CKD) on income is unclear. We sought to determine whether CKD severity, serious adverse events, and CKD progression affected household income. METHODS: Analyses were undertaken in a prospective cohort of adults with moderate-to-severe CKD in the Study of Heart and Renal Protection (SHARP), with household income information available at baseline screening and study end. Logistic regressions, adjusted for sociodemographic characteristics, smoking, and prior diseases at baseline, estimated associations during the 5-year follow-up, among (i) baseline CKD severity, (ii) incident nonfatal serious adverse events (vascular or cancer), and (iii) CKD treatment modality (predialysis, dialysis, or transplanted) at study end and the outcome "fall into relative poverty." This was defined as household income <50% of country median income. RESULTS: A total of 2914 SHARP participants from 14 countries were included in the main analysis. Of these, 933 (32%) were in relative poverty at screening; of the remaining 1981, 436 (22%) fell into relative poverty by study end. Compared with participants with stage 3 CKD at baseline, the odds of falling into poverty were 51% higher for those with stage 4 (odds ratio [OR]: 1.51; 95% confidence interval [CI]: 1.09-2.10), 66% higher for those with stage 5 (OR: 1.66; 95% CI: 1.11-2.47), and 78% higher for those on dialysis at baseline (OR: 1.78, 95% CI: 1.22-2.60). Participants with kidney transplant at study end had approximately half the risk of those on dialysis or those with CKD stages 3 to 5. CONCLUSION: More advanced CKD is associated with increased odds of falling into poverty. Kidney transplantation may have a role in reducing this risk.

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease.

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .).

Use of Causal Diagrams to Inform the Design and Interpretation of Observational Studies: An Example from the Study of Heart and Renal Protection (SHARP).

Observational studies often seek to estimate the causal relevance of an exposure to an outcome of interest. However, many possible biases can arise when estimating such relationships, in particular bias because of confounding. To control for confounding properly, careful consideration of the nature of the assumed relationships between the exposure, the outcome, and other characteristics is required. Causal diagrams provide a simple graphic means of displaying such relationships, describing the assumptions made, and allowing for the identification of a set of characteristics that should be taken into account (i.e., adjusted for) in any analysis. Furthermore, causal diagrams can be used to identify other possible sources of bias (such as selection bias), which if understood from the outset, can inform the planning of appropriate analyses. In this article, we review the basic theory of causal diagrams and describe some of the methods available to identify which characteristics need to be taken into account when estimating the total effect of an exposure on an outcome. In doing so, we review the concept of collider bias and show how it is inappropriate to adjust for characteristics that may be influenced, directly or indirectly, by both the exposure and the outcome of interest. A motivating example is taken from the Study of Heart and Renal Protection, in which the relevance of smoking to progression to ESRD is considered.

Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP).

BACKGROUND: The absolute and relative importance of smoking to vascular and nonvascular outcomes in people with chronic kidney disease (CKD), as well its relevance to kidney disease progression, is uncertain. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 9,270 participants with CKD enrolled in SHARP. PREDICTOR: Baseline smoking status (current, former, and never). OUTCOMES: Vascular events, site-specific cancer, ESRD, rate of change in estimated glomerular filtration rate (eGFR), and cause-specific mortality. RESULTS: At baseline, 1,243 (13%) participants were current smokers (median consumption, 10 cigarettes/day); 3,272 (35%), former smokers; and 4,755 (51%), never smokers. Median follow-up was 4.9 years. Vascular event rates were 36% higher for current than never smokers (2,317 events; relative risk [RR], 1.36; 95% CI, 1.19-1.55), reflecting increases in both atherosclerotic (RR, 1.49; 95% CI, 1.26-1.76) and nonatherosclerotic (RR, 1.25; 95% CI, 1.05-1.50) events. Cancer was 37% higher among current smokers (632 events; RR, 1.37; 95% CI, 1.07-1.76), with the biggest RRs for lung (RR, 9.31; 95% CI, 4.37-19.83) and upper aerodigestive tract (RR, 4.87; 95% CI, 2.10-11.32) cancers. For 6,245 patients not receiving dialysis at baseline, ESRD incidence did not differ significantly between current and never smokers (2,141 events; RR, 1.02; 95% CI, 0.89-1.17), nor did estimated rate of change in eGFR (current smokers, -1.77±0.14 [SE]; never smokers, -1.70±0.07mL/min/1.73m(2) per year). All-cause mortality was 48% higher among current smokers (2,257 events; RR, 1.48; 95% CI, 1.30-1.70), with significant increases in vascular (RR, 1.35; 95% CI, 1.07-1.69) and nonvascular (RR, 1.60; 95% CI, 1.34-1.91) causes of death, especially cancer (RR, 2.32; 95% CI, 1.58-3.40) and respiratory (RR, 2.25; 95% CI, 1.51-3.35) mortality. LIMITATIONS: Smoking status not assessed during follow-up. CONCLUSIONS: In this study of patients with CKD, smoking significantly increased the risks for vascular and nonvascular morbidity and mortality, but was not associated with kidney disease progression. The associations with vascular and neoplastic disease are in keeping with those observed in the general population and are likely modifiable by cessation.

Neprilysin inhibition in chronic kidney disease.

Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin-angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.

Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial.

BACKGROUND: Calcineurin inhibitors (CNIs) reduce short-term kidney transplant failure, but might contribute to transplant failure in the long-term. The role of alemtuzumab (a potent lymphocyte-depleting antibody) as an induction treatment followed by an early reduction in CNI and mycophenolate exposure and steroid avoidance, after kidney transplantation is uncertain. We aimed to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. METHODS: For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone). Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat. The study is registered at ClinicalTrials.gov, number NCT01120028, and isrctn.org, number ISRCTN88894088. FINDINGS: Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumab-based treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment (31 [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42, 95% CI 0·28-0·64; log-rank p<0·0001). We detected no between-group difference in treatment effect on transplant failure during the first 6 months (16 [4%] patients vs 13 [3%] patients; HR 1·23, 0·59-2·55; p=0·58) or serious infection (135 [32%] patients vs 136 [32%] patients; HR 1·02, 0·80-1·29; p=0·88). During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66-4·83; p=0·25). INTERPRETATION: Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival. FUNDING: UK National Health Service Blood and Transplant Research and Development Programme, Pfizer, and Novartis UK.

Evaluating the contribution of the cause of kidney disease to prognosis in CKD: results from the Study of Heart and Renal Protection (SHARP).

BACKGROUND: The relevance of the cause of kidney disease to prognosis among patients with chronic kidney disease is uncertain. STUDY DESIGN: Observational study. SETTINGS & PARTICIPANTS: 6,245 nondialysis participants in the Study of Heart and Renal Protection (SHARP). PREDICTOR: Baseline cause of kidney disease was categorized into 4 groups: cystic kidney disease, diabetic nephropathy, glomerulonephritis, and other recorded diagnoses. OUTCOMES: End-stage renal disease (ESRD; dialysis or transplantation) and death. RESULTS: During an average 4.7 years' follow-up, 2,080 participants progressed to ESRD, including 454 with cystic kidney disease (23% per year), 378 with glomerulonephritis (10% per year), 309 with diabetic nephropathy (12% per year), and 939 with other recorded diagnoses (8% per year). By comparison with patients with cystic kidney disease, other disease groups had substantially lower adjusted risks of ESRD (relative risks of 0.28 [95% CI, 0.24-0.32], 0.40 [95% CI, 0.34-0.47], and 0.29 [95% CI, 0.25-0.32] for glomerulonephritis, diabetic nephropathy, and other recorded diagnoses, respectively). Albuminuria and baseline estimated glomerular filtration rate were associated more weakly with risk of ESRD in patients with cystic kidney disease than the 3 other diagnostic categories (P for interaction, <0.001 and 0.01, respectively). Death before ESRD was uncommon in patients with cystic kidney disease, but was a major competing risk for participants with diabetic nephropathy, whose adjusted risk of death was 2-fold higher than that of the cystic kidney disease group (relative risk, 2.35 [95% CI, 1.73-3.18]). LIMITATIONS: Exclusion of patients with prior myocardial infarction or coronary revascularization. CONCLUSIONS: The cause of kidney disease has substantial prognostic implications. Other things being equal, patients with cystic kidney disease are at much higher risk of ESRD (and much lower risk of death before ESRD) than other patients. Patients with diabetic nephropathy are at particularly high risk of death prior to reaching ESRD.

The effect of lowering LDL cholesterol on vascular access patency: post hoc analysis of the Study of Heart and Renal Protection.

BACKGROUND AND OBJECTIVES: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering LDL-C on vascular access patency is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo. This study aimed to explore the effects of treatment on vascular access occlusive events, defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis access. RESULTS: Among 2353 SHARP participants who had functioning vascular access at randomization, allocation to simvastatin plus ezetimibe resulted in a 13% proportional reduction in vascular access occlusive events (355 [29.7%] for simvastatin/ezetimibe versus 388 [33.5%] for placebo; risk ratio [RR], 0.87; 95% confidence interval [95% CI], 0.75 to 1.00; P=0.05). There was no evidence that the effects of treatment differed for any of the separate components of this outcome. To test the hypothesis raised by SHARP, comparable analyses were performed using the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort. AURORA did not provide independent confirmation (vascular access occlusive events: 352 [28.9%] for rosuvastatin versus 337 [27.6%] for placebo; RR, 1.06, 95% CI, 0.91 to 1.23; P=0.44). After combining the two trials, the overall effect of reducing LDL-C with a statin-based regimen on vascular access occlusive events was not statistically significant (707 [29.3%] with any LDL-C-lowering therapy versus 725 [30.5%] with placebo; RR, 0.95, 95% CI, 0.85 to 1.05; P=0.29). CONCLUSIONS: Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy may improve vascular access patency, but there was no evidence of benefit in AURORA. Taken together, the available evidence suggests that any benefits of lowering LDL-C on vascular access patency are likely to be modest.

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.

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.

Prediction of ESRD and death among people with CKD: the Chronic Renal Impairment in Birmingham (CRIB) prospective cohort study.

BACKGROUND: Validated prediction scores are required to assess the risks of end-stage renal disease (ESRD) and death in individuals with chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study with validation in a separate cohort. SETTING & PARTICIPANTS: Cox regression was used to assess the relevance of baseline characteristics to risk of ESRD (mean follow-up, 4.1 years) and death (mean follow-up, 6.0 years) in 382 patients with stages 3-5 CKD not initially on dialysis therapy in the Chronic Renal Impairment in Birmingham (CRIB) Study. Resultant risk prediction equations were tested in a separate cohort of 213 patients with CKD (the East Kent cohort). FACTORS: 44 baseline characteristics (including 30 blood and urine assays). OUTCOMES: ESRD and all-cause mortality. RESULTS: In the CRIB cohort, 190 patients reached ESRD (12.1%/y) and 150 died (6.5%/y). Each 30% lower baseline estimated glomerular filtration rate was associated with a 3-fold higher ESRD rate and a 1.3-fold higher death rate. After adjustment for each other, only baseline creatinine level, serum phosphate level, urinary albumin-creatinine ratio, and female sex remained strongly (P < 0.01) predictive of ESRD. For death, age, N-terminal pro-brain natriuretic peptide, troponin T level, and cigarette smoking remained strongly predictive of risk. Using these factors to predict outcomes in the East Kent cohort yielded an area under the receiver operating characteristic curve (ie, C statistic) of 0.91 (95% CI, 0.87-0.96) for ESRD and 0.82 (95% CI, 0.75-0.89) for death. LIMITATIONS: Other important factors may have been missed because of limited study power. CONCLUSIONS: Simple laboratory measures of kidney and cardiac function plus age, sex, and smoking history can be used to help identify patients with CKD at highest risk of ESRD and death. Larger cohort studies are required to further validate these results.

A practical method of measuring glomerular filtration rate by iohexol clearance using dried capillary blood spots.

BACKGROUND: Exogenous tracer-based methods of measuring glomerular filtration rate (GFR) are difficult to perform, whilst creatinine-based estimation formulae are inaccurate. METHODS: We assessed a new technique of measuring iohexol clearance using timed dried capillary blood spots. A reference GFR was measured in 81 subjects (GFR 15-124 ml/min/1.73 m(2)) by iohexol clearance using three venous samples (2, 3 and 4 h after an intravenous bolus). GFR was estimated by six test methods; iohexol clearance using (i) 3 blood spots (2, 3, 4 h); (ii) 2 blood spots (2, 4 h) and (iii) 1 blood spot (4 h); (iv) the Modification of Diet in Renal Disease (MDRD) formula; (v) the Cockcroft-Gault formula, and (vi) a formula estimating GFR from serum cystatin C concentration. For each test method the bias and precision were calculated as the mean and standard deviation (SD) of the 'GFR differences' (test method GFR - reference GFR). RESULTS: The limits of agreement (bias +/-1.96 x SD; in ml/min/1.73 m(2)) were: (i) 1.1 +/- 15.1 for 3-spot iohexol clearance; (ii) 0.6 +/- 14.9 for 2-spot iohexol clearance; (iii) 4.5 +/- 21.2 for 1-spot iohexol clearance; (iv) -15.7 +/- 33.3 for the MDRD formula; (v) -9.6 +/- 32.9 for the Cockcroft-Gault formula, and (vi) -12.1 +/- 31.7 for the Cystatin C formula. The accuracy of all six test methods was similar among individuals with GFR <60 ml/min/ 1.73 m(2); however, in individuals with GFR > or =60 ml/min/ 1.73 m(2), the MDRD, Cockcroft-Gault and Cystatin C formulae were all imprecise and systematically underestimated GFR. CONCLUSIONS: Blood spot iohexol clearance provides a potentially practical method of estimating GFR accurately in large-scale epidemiological studies especially among individuals without established chronic kidney disease.