Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study.

BACKGROUND: Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. STUDY DESIGN: Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. SETTING & PARTICIPANTS: Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. PREDICTOR: Uric acid concentration. OUTCOMES: The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. RESULTS: 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models (P=0.5 for CV events; P=0.09 for death, and P=0.1 for transplant failure). LIMITATIONS: Unknown use of uric acid-lowering agents among study participants. CONCLUSIONS: Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation.

The safety of achieved iron stores and their effect on IV iron and ESA use: post-hoc results from a randomized trial of ferric citrate as a phosphate binder in dialysis
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Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p < 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p < 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations > 34% are safe and provide maximal efficacy.
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Pyridorin in type 2 diabetic nephropathy.

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

Design of the Dialysis Access Consortium (DAC) Aggrenox Prevention Of Access Stenosis Trial.

BACKGROUND: Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis. RESULTS: This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial.

BACKGROUND: The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery. PURPOSE: The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure. METHODS: This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1,284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis. RESULTS: This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention. CONCLUSIONS: This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

Total plasma homocysteine and arteriosclerotic outcomes in type 2 diabetes with nephropathy.

Total serum homocysteine (tHcy) has been shown to predict de novo and recurrent cardiovascular events in many studies. However, results in diabetic populations with minimal nephropathy are mixed. The independent relationship between tHcy and arteriosclerotic outcomes and congestive heart failure (CHF) events in a population with high cardiovascular risk and diabetic nephropathy was examined. A total of 1575 individuals were enrolled in the international Irbesartan Diabetic Nephropathy Trial (IDNT) and followed for 2.6 yr. All participants had baseline diabetic nephropathy, overt proteinuria, and hypertension and were recruited between 1996 and 1999. A total of 492 total arteriosclerotic outcomes (primary outcome) and 317 CHF events (secondary outcome) were tallied. Established cardiovascular risk factors were highly prevalent, as were high tHcy levels (quintiles [microM]: first 4.5 to 11; second >11 to 13; third >13 to 15; fourth >15 to 19; fifth >19). No association between tHcy and arteriosclerotic outcomes was observed in a univariate model or after adjustment for study randomization and established cardiovascular risk factors. The strongest outcome predictor was the presence of baseline cardiovascular disease, followed by an inverse relationship to diastolic BP. The significant univariate association between tHcy and CHF events disappeared when serum creatinine alone was added to the model. These findings question the utility of tHcy in predicting de novo or recurrent cardiovascular events in individuals with diabetic nephropathy. Further studies are needed to confirm whether these negative results apply to other populations with heavy cardiovascular risk burdens. Previous positive findings can potentially be explained through tHcy's role as a sensitive surrogate marker for kidney disease, itself a recognized cardiovascular risk factor.