Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.

BACKGROUND: Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis. METHODS: In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events. RESULTS: The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%). CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.

DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC study.

BACKGROUND: Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD). METHODS: We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate. RESULTS: The mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m(2) in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. CONCLUSIONS: Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.

Association between albuminuria, kidney function, and inflammatory biomarker profile in CKD in CRIC.

BACKGROUND AND OBJECTIVES: Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been examined in a large cohort of CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study measured the plasma levels of IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-ß, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1ß, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR). RESULTS: Plasma levels of IL-1ß, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001). CONCLUSIONS: Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.

Renal failure: implications of chronic kidney disease in the management of the diabetic foot.

Foot complications are common in patients with diabetes, however, chronic kidney disease has emerged as an independent risk factor for development of foot lesions in the diabetic population. Apart from peripheral arterial disease, infection, and neuropathy, which are classic factors contributing to development of foot lesions, skin disorders specific to renal failure, impaired wound healing from uremia, and psychosocial issues offer further compounded risk. Consequently, there are high ulceration and amputation rates that are associated with increased morbidity and mortality. In recent studies, foot-care programs with a multidisciplinary approach within dialysis units have demonstrated improved outcomes.

Epidemiology and management of hypertension in the Hispanic population: a review of the available literature.

Hispanics are the fastest growing ethnic minority in the USA. Among Hispanics, lack of hypertension awareness and lack of effective blood pressure (BP) control are problematic, as are higher incidence rates of hypertension-related co-morbidities compared with non-Hispanic populations. Moreover, there are currently no hypertension treatment guidelines that address the unique characteristics of this ethnic group. This article discusses ethnic differences in hypertension and cardiovascular risk factors and reviews the literature on the efficacy of antihypertensive agents in Hispanic patients, with a focus on the role of renin-angiotensin-aldosterone system (RAAS) inhibition in the management of hypertension in these patients. Hypertension in Hispanic patients can be challenging to manage, in part because this population has a higher prevalence of obesity, diabetes, and metabolic syndrome compared with non-Hispanic whites. The presence of these co-morbidities suggests that RAAS-inhibitor-based therapies may be particularly beneficial in this population. However, few studies have evaluated the efficacy of antihypertensive treatments in Hispanic patients. Two outcomes studies in hypertensive patients have shown the benefits of treating Hispanic patients with antihypertensive therapy and included RAAS inhibitors as part of the treatment regimen. In addition, BP-lowering trials have shown the antihypertensive efficacy of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and direct renin inhibitors, although data on the latter are more limited. Additional studies are needed to more thoroughly evaluate the effects of RAAS inhibitors (and other drug classes) on outcomes and BP lowering in the Hispanic hypertensive population.

Challenges associated with the management of gouty arthritis in patients with chronic kidney disease: a systematic review.

OBJECTIVE: As many as half of all patients with gouty arthritis have some degree of renal impairment. The goal of this systematic review is to provide physicians with a comprehensive examination of available data on the risks and benefits of gouty arthritis treatment options when used in patients with chronic kidney disease (CKD). METHODS: We conducted a systematic literature review to determine what information is available to guide treatment decisions in this patient population. PubMed was searched for English-language articles indexed through July 2011 containing the terms "gout" or "hyperuricemia" and synonyms for renal impairment in combination with drug names. Publications were deemed relevant if they reported results from clinical studies, case reports, or prescribing practices of the drug of interest in patients with gouty arthritis and CKD. RESULTS: Nonsteroidal anti-inflammatory drugs and colchicine are oftentimes not considered appropriate in patients with CKD. Corticosteroids may be an effective alternative in this population; however, their efficacy has not been confirmed in randomized controlled trials and these agents can cause serious side effects. Allopurinol can be used for the prophylactic management of chronic hyperuricemia in patients with CKD, but the recommended decreased dosage may limit efficacy and serious hypersensitivity reactions may preclude its use. Febuxostat and pegloticase are new treatment options for chronic urate-lowering prophylaxis; however, the safety of these drugs in patients with advanced CKD has not yet been reported. CONCLUSIONS: There is currently an unmet need for additional treatment options for the management of gouty arthritis in patients with CKD.

Acute renal failure.

Preview An abrupt decrease in the kidneys' ability to excrete waste products is a common cause of severe morbidity and death in critically ill patients. This complication may result from prerenal, renal parenchymal, or postrenal causes. The authors describe the clinical and laboratory evaluation of acute renal failure and offer an approach to prevention and appropriate management.