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Rationale & Objective: The risk of developing colorectal cancer in patients with chronic kidney disease (CKD) is twice that of the general population, but the factors associated with colorectal cancer are poorly understood. The aim of this study was to identify factors associated with advanced colorectal neoplasia in patients with CKD., Study Design: Prospective cohort study., Setting & Participants: Patients with CKD stages 3-5, including those treated with maintenance dialysis or transplantation across 11 sites in Australia, New Zealand, Canada, and Spain, were screened for colorectal neoplasia using a fecal immunochemical test (FIT) as part of the Detecting Bowel Cancer in CKD (DETECT) Study., Exposure: Baseline characteristics for patients at the time of study enrollment were ascertained, including duration of CKD, comorbidities, and medications., Outcome: Advanced colorectal neoplasia was identified through a 2-step verification process with colonoscopy following positive FIT and 2-year clinical follow-up for all patients., Analytical Approach: Potential factors associated with advanced colorectal neoplasia were explored using multivariable logistic regression. Sensitivity analyses were performed using grouped LASSO (least absolute shrinkage and selection operator) logistic regression., Results: Among 1,706 patients who received FIT-based screening-791 with CKD stages 3-5 not receiving kidney replacement therapy (KRT), 418 receiving dialysis, and 497 patients with a functioning kidney transplant-117 patients (6.9%) were detected to have advanced colorectal neoplasia (54 with CKD stages 3-5 without KRT, 34 receiving dialysis, and 29 transplant recipients), including 9 colorectal cancers. The factors found to be associated with advanced colorectal neoplasia included older age (OR per year older, 1.05 [95% CI, 1.03-1.07], P<0.001), male sex (OR, 2.27 [95% CI, 1.45-3.54], P<0.001), azathioprine use (OR, 2.99 [95% CI, 1.40-6.37], P=0.005), and erythropoiesis-stimulating agent use (OR, 1.92 [95% CI, 1.22-3.03], P=0.005). Grouped LASSO logistic regression revealed similar associations between these factors and advanced colorectal neoplasia., Limitations: Unmeasured confounding factors., Conclusions: Older age, male sex, erythropoiesis-stimulating agents, and azathioprine were found to be significantly associated with advanced colorectal neoplasia in patients with CKD., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Anemia associated with chronic kidney disease (CKD) often requires treatment with recombinant human erythropoietin (EPO). Hypoxia-inducible factor-prolyl hydroxylase inhibitors (PHIs) stimulate endogenous EPO synthesis and induce effective erythropoiesis by non-EPO effects. GSK1278863 is an orally administered small-molecule PHI., Study Design: Multicenter, single-blind, randomized, placebo-controlled, parallel-group study., Setting & Participants: Anemic non-dialysis-dependent patients with CKD stages 3-5 (CKD-3/4/5 group; n=70) and anemic hemodialysis patients with CKD stage 5D (CKD-5D group; n=37)., Interventions: Patients with CKD-3/4/5 received placebo or GSK1278863 (10, 25, 50, or 100mg), and patients with CKD-5D received placebo or GSK1278863 (10 or 25mg) once daily for 28 days., Outcomes & Measurements: Primary pharmacokinetic and pharmacodynamic (increase and response rates in achieving the target hemoglobin [Hb] concentration, plasma EPO concentrations, reticulocyte count, and others]) and safety and tolerability end points were obtained., Results: Both CKD-3/4/5 and CKD-5D populations showed a dose-dependent increase in EPO concentrations and consequent increases in reticulocytes and Hb levels. Percentages of GSK1278863 participants with an Hb level increase > 1.0g/dL (CKD-3/4/5) and >0.5g/dL (CKD-5D) were 63% to 91% and 71% to 89%, respectively. Per-protocol-defined criteria, high rate of increase in Hb level, or high absolute Hb value was the main cause for withdrawal (CKD-3/4/5, 30%; CKD-5D, 22%). A dose-dependent decrease in hepcidin levels and increase in total and unsaturated iron binding were observed in all GSK1278863-treated patients., Limitations: Sparse pharmacokinetic sampling may have limited covariate characterization. EPO concentrations at the last pharmacodynamic sample (5-6 hours) postdose may not represent peak concentrations, which occurred 8 to 10 hours postdose in previous studies. Patients were not stratified by diabetes status, potentially confounding vascular endothelial growth factor and glucose analyses., Conclusions: GSK1278863 induced an effective EPO response and stimulated non-EPO mechanisms for erythropoiesis in anemic non-dialysis-dependent and dialysis-dependent patients with CKD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Secondary hyperparathyroidism is observed in patients with early chronic kidney disease (CKD). This study investigated the safety and efficacy of cinacalcet for secondary hyperparathyroidism in participants with CKD not receiving dialysis., Study Design: Double-blind, randomized, 32-week, phase 3 study., Setting & Participants: 404 participants with stage 3 or 4 CKD from 73 centers in 9 countries., Interventions: Cinacalcet:placebo (3:1 ratio)., Outcomes & Measurements: Proportion of participants with a mean decrease of 30% or greater in intact parathyroid hormone (iPTH) level, proportion with iPTH level of 70 or less or 110 or less pg/mL (stage 3 and 4 CKD, respectively), and mean percentage of iPTH change from baseline, all during the efficacy-assessment phase., Results: A greater proportion of cinacalcet than placebo participants achieved a 30% or greater decrease in iPTH level (74% versus 28%; P < 0.001), corresponding to a 43.1% decrease in iPTH level from baseline (cinacalcet) compared with a 1.1% increase (placebo). At week 32, serum calcium levels were 8.9 +/- 0.8 mg/dL (-8.9%; cinacalcet) and 9.9 +/- 0.6 mg/dL (+0.8%; placebo), phosphorus levels were 4.5 +/- 1.0 mg/dL (+21.4%) and 4.0 +/- 0.7 mg/dL (+6.8%), and calcium-phosphorus product values were 40.1 +/- 8.3 mg(2)/dL(2) (+18.9%) and 38.9 +/- 6.9 mg(2)/dL(2) (+17.1%), respectively. During the study course, 62% (cinacalcet) and 1% (placebo) of participants experienced 2 consecutive serum calcium concentrations less than 8.4 mg/dL. They generally were asymptomatic and without significant clinical consequences. Treatment generally was well tolerated, and most adverse events were mild to moderate in severity., Limitations: The study was not designed to assess the effects of cinacalcet on vascular calcification, bone histomorphometric parameters, or other clinical outcomes. It is not known whether the observed differences in changes in iPTH levels are clinically more important than observed differences in changes in serum calcium or phosphorus levels or dosages of vitamin D sterols and phosphate binders., Conclusions: These data show that cinacalcet treatment in patients with CKD not receiving dialysis can decrease plasma iPTH levels, but with frequent (albeit generally asymptomatic) serum calcium levels less than 8.4 mg/dL and increases in serum phosphorus levels.

Background: This study is designed to assess the effect of early and complete correction of anemia by using recombinant human erythropoietin (epoetin) alfa on the progression of chronic kidney disease (CKD)., Methods: Patients were randomly assigned to achieve high (13 to 15 g/dL [130 to 150 g/L]) or low (11 to 12 g/dL [110 to 120 g/L]) hemoglobin-level targets during 4 months of stabilization, followed by 36 months of maintenance. Glomerular filtration rate (GFR) decrease was measured by using iohexol clearance. Quality of life, nutrition, and safety also were monitored., Results: Because of labeling changes for subcutaneous administration of epoetin alfa (Eprex; Johnson and Johnson, Schaffhausen, Switzerland), the study was terminated prematurely. There were 195 patients enrolled in each group; 108 high-hemoglobin and 133 low-hemoglobin patients entered the maintenance phase. Mean maintenance duration was 7.4 months for the high-hemoglobin group and 8.3 months for the low-hemoglobin group. GFR decrease was numerically, but not statistically significantly, lower with the high-hemoglobin group (0.058 versus 0.081 mL/min/1.73 m2/mo [< 0.01 mL/s/1.73 m2/mo]). Physical quality-of-life measures showed trends (Role-Physical, P = 0.055; Physical Function, P = 0.083) or statistically significant improvement (Vitality, P = 0.042) with high hemoglobin levels at the end of the stabilization phase. Adverse events were similar between groups. Cardiovascular adverse events occurred in 25% of the high-hemoglobin and 18% of the low-hemoglobin patients (P = 0.137). Neither epoetin dosage nor hemoglobin level was associated with cardiovascular adverse events or death., Conclusion: These data suggest that normalization of hemoglobin levels in patients with CKD is safe. Longer duration studies are needed to clarify efficacy benefits with high hemoglobin levels.

Increased blood pressure (BP) has been the most commonly reported side effect in trials of treatment of the anemia of chronic renal failure with recombinant human erythropoietin (rHuEPO). An increase in BP develops in one third of patients, in most cases necessitating initiation or increase of antihypertensive therapy. Elevated BP is not related to dose of rHuEPO, nor to the final hematocrit level achieved or the rate of increase of hematocrit. Increases in BP arise particularly during the first 4 months of therapy, and BP usually stabilizes thereafter. rHuEPO therapy does not appear to affect BP in patients with normal renal function. The mechanism of hypertension related to rHuEPO remains uncertain. An increase in systemic vascular resistance occurs in all patients, whether or not BP increases. This is due largely to increased blood viscosity and reversal of hypoxic vasodilatation, but other factors may also contribute. A lack of adequate reduction in cardiac output distinguishes patients in whom BP increases, and this in turn may be due to abnormal cardiovascular autoregulation in these patients. Acute elevation in BP during rHuEPO therapy occasionally results in hypertensive encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit, but is associated with a rapid increase in BP, and may occur in previously normotensive patients. Hypertension developing during rHuEPO therapy should be controlled by conventional antihypertensive therapy. If hypertension persists, the rHuEPO dose should be reduced or therapy temporarily discontinued. Frequent BP monitoring during the first 4 months of treatment is mandatory.(ABSTRACT TRUNCATED AT 250 WORDS)