Todd A. Conner

Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy

BACKGROUND Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Prevention of Contrast-Induced AKI: A Review of Published Trials and the Design of the Prevention of Serious Adverse Events following Angiography (PRESERVE) Trial

Contrast-induced AKI (CI-AKI) is a common condition associated with serious, adverse outcomes. CI-AKI may be preventable because its risk factors are well characterized and the timing of renal insult is commonly known in advance. Intravenous (IV) fluids and N-acetylcysteine (NAC) are two of the most widely studied preventive measures for CI-AKI. Despite a multitude of clinical trials and meta-analyses, the most effective type of IV fluid (sodium bicarbonate versus sodium chloride) and the benefit of NAC remain unclear. Careful review of published trials of these interventions reveals design limitations that contributed to their inconclusive findings. Such design limitations include the enrollment of small numbers of patients, increasing the risk for type I and type II statistical errors; the use of surrogate primary endpoints defined by small increments in serum creatinine, which are associated with, but not necessarily causally related to serious, adverse, patient-centered outcomes; and the inclusion of low-risk patients with intact baseline kidney function, yielding low event rates and reduced generalizability to a higher-risk population. The Prevention of Serious Adverse Events following Angiography (PRESERVE) trial is a randomized, double-blind, multicenter trial that will enroll 8680 high-risk patients undergoing coronary or noncoronary angiography to compare the effectiveness of IV isotonic sodium bicarbonate versus IV isotonic sodium chloride and oral NAC versus oral placebo for the prevention of serious, adverse outcomes associated with CI-AKI. This article discusses key methodological issues of past trials investigating IV fluids and NAC and how they informed the design of the PRESERVE trial.

Outcomes after Angiography with Sodium Bicarbonate and Acetylcysteine

Background Intravenous sodium bicarbonate and oral acetylcysteine are widely used to prevent acute kidney injury and associated adverse outcomes after angiography without definitive evidence of their efficacy. Methods Using a 2‐by‐2 factorial design, we randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous 1.26% sodium bicarbonate or intravenous 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention‐to‐treat analysis. The primary end point was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast‐associated acute kidney injury was a secondary end point. Results The sponsor stopped the trial after a prespecified interim analysis. There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary end point (P=0.33). The primary end point occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group as compared with 116 of 2482 (4.7%) in the sodium chloride group (odds ratio, 0.93; 95% confidence interval [CI], 0.72 to 1.22; P=0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group as compared with 112 of 2498 (4.5%) in the placebo group (odds ratio, 1.02; 95% CI, 0.78 to 1.33; P=0.88). There were no significant between‐group differences in the rates of contrast‐associated acute kidney injury. Conclusions Among patients at high risk for renal complications who were undergoing angiography, there was no benefit of intravenous sodium bicarbonate over intravenous sodium chloride or of oral acetylcysteine over placebo for the prevention of death, need for dialysis, or persistent decline in kidney function at 90 days or for the prevention of contrast‐associated acute kidney injury. (Funded by the U.S. Department of Veterans Affairs Office of Research and Development and the National Health and Medical Research Council of Australia; PRESERVE ClinicalTrials.gov number, NCT01467466.)

Therapeutic use of the phosphate binder lanthanum carbonate

Hyperphosphatemia is recognized as a principal mineral disorder in chronic kidney disease (CKD) that leads to the development of secondary hyperparathyroidism. Recent data indicate that hyperphosphatemia is associated with accelerated cardiac calcification and increased mortality in patients with CKD. Control of serum phosphorus is accomplished with phosphate binder therapies that include calcium and aluminum salts. Recently, calcium-based binders have undergone reevaluation because of their association with cardiac calcification. The non-calcium, non-aluminum binder sevelamer hydrochloride has been associated with slower progression of cardiac calcification in clinical trials. Lanthanum carbonate is a newer phosphate binder with phosphate binding activity similar to aluminum salts making this agent a compelling alternative; however, more data are needed to evaluate long-term safety and effects on cardiovascular end points.

Rationale and design of the Drug‐Eluting Stents vs Bare‐Metal Stents in Saphenous Vein Graft Angioplasty (DIVA) Trial

VA Cooperative Studies Program #571 (DIVA) was designed to evaluate the efficacy of drug‐eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure when compared with bare‐metal stents (BMS) in participants undergoing stenting of de novo SVG lesions. Participants undergoing clinically indicated stenting of de novo SVG lesions were randomized in a 1:1 ratio to DES or BMS. Randomization was stratified by presence/absence of diabetes mellitus and the number of target SVG lesions (1 vs ≥2) within each participating site. At sites that did not routinely administer 12‐months of dual antiplatelet therapy after SVG stenting participants without acute coronary syndromes received 1 month of open‐label clopidogrel, followed by 11 months of clopidogrel for those assigned to DES and 11 months of placebo for those assigned to BMS. The primary endpoint was the 12‐month incidence of target‐vessel failure (defined as the composite of cardiac death, target‐vessel myocardial infarction, or target‐vessel revascularization). Secondary endpoints included the incidence of other clinical endpoints and the incremental cost‐effectiveness of DES relative to BMS. Due to lower‐than‐anticipated target‐vessel failure rates, target enrollment was increased from 519 to 762. The study had randomized 599 participants when recruitment ended in December 2015. The DIVA trial will provide clarity on the appropriate stent type for de novo SVG lesions.

Oxidative Stress and Inflammation in Chronic Kidney Disease: Role of Intravenous Iron and Vitamin D

Cardiovascular disease (CVD) is the leading cause of death among chronic kidney disease patients (CKD). The etiology of CVD in CKD is multifactorial and increasing evidence points to the important contribution of “nontraditional” risk factors including oxidative stress and inflammation. CKD is associated with a chronic imbalance of prooxidant and antioxidant factors that results in a state of chronic inflammation. Intravenous iron supplementation has been shown to induce oxidative stress and has been associated with lipid peroxidation and DNA damage. Conversely, treatment with vitamin D analogs has been associated with improved mortality in hemodialysis patients in 2 recent large cohort studies. These data suggest that vitamin D analogs may exert effects beyond their pharmacologic role in parathyroid hormone suppression. This article addresses the current data regarding the relative contributions of intravenous iron supplementation and vitamin D analog therapy on oxidative stress and inflammation in CKD patients.

Correlation between the renal quality of life profile and short form‐36 in a United States hemodialysis population

To the Editor: The Renal Quality of Life Profile (RQLP) is an end-stage renal disease-specific questionnaire used to assess healthrelated quality of life (HRQOL). It was constructed from a survey examining what hemodialysis (HD) patients consider important and is dialysis modality independent. The construct validity of the RQLP was explored with the short form (SF)-36 in the United Kingdom and good correlation between the questionnaires was demonstrated. There are currently no data exploring the validity of the RQLP in a US HD population. The SF-36 was designed to be a health status index that distinguishes among different strata of HRQOL, but is not disease specific. A recent study demonstrated that the RQLP was superior to the SF-36 in identifying specific items that affected overall quality of life in peritoneal dialysis patients. The purpose of this study was to assess the correlation of the RQLP compared with the SF-36 in a US HD population. It is expected that RQLP and SF-36 subscales measuring similar concepts should show higher correlation than subscales measuring dissimilar concepts.