Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients.

It is unclear whether warfarin is protective or harmful in patients with ESRD and atrial fibrillation. This state of equipoise raises the question of whether alternative anticoagulants may have a therapeutic role. We aimed to determine apixaban pharmacokinetics at steady state in patients on hemodialysis. Seven patients received apixaban 2.5 mg twice daily for 8 days. Blood samples were collected before and after apixaban administration on days 1 and 8 (nondialysis days). Significant accumulation of the drug was observed between days 1 and 8 with the 2.5-mg dose. The area under the concentration-time curve from 0 to 24 hours increased from 628 to 2054 ng h/ml (P<0.001). Trough levels increased from 45 to 132 ng/ml (P<0.001). On day 9, after a 2.5-mg dose, apixaban levels were monitored hourly during dialysis. Only 4% of the drug was removed. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days. The area under the concentration-time curve further increased to 6045 ng h/ml (P=0.03), and trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

Effects of recombinant human erythropoietin on resistance artery endothelial function in stage 4 chronic kidney disease.

BACKGROUND: Recent studies have raised concern about the safety of erythropoiesis-stimulating agents because of evidence of increased risk of hypertension and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. In the present study, we investigated the effects of recombinant human erythropoietin (EPO) on endothelial function of gluteal subcutaneous resistance arteries isolated from 17 stage 4 patients (estimated glomerular filtration rate 21.9±7.4 mL/min per 1.73 m(2)) aged 63±13 years. METHODS AND RESULTS: Arteries were mounted on a pressurized myograph. EPO impaired endothelium-dependent relaxation in a concentration-dependent manner. The maximal response to acetylcholine with EPO at 1, 10, and 20 IU/mL was reduced by 12%, 34%, and 43%, respectively, compared with the absence of EPO (P<0.001). EPO-induced endothelial dysfunction was significantly associated with carotid stiffness and history of cardiovascular events. EPO had no effect on norepinephrine-induced vasoconstriction or sodium nitroprusside-induced relaxation. ABT-627, an endothelin type A receptor antagonist, and tempol, a superoxide dismutase mimetic, partially reversed the altered endothelial function in the presence of EPO (P<0.01). Increased expression of endothelin-1 was found in the vessel wall after incubation with EPO. CONCLUSIONS: EPO alters endothelial function of resistance arteries in CKD patients via a mechanism involving in part oxidative stress and signaling through an endothelin type A receptor. EPO-induced endothelial dysfunction could contribute to deleterious effects of EPO described in large interventional trials.

Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Up to 40% progress to end-stage renal disease (ESRD) over 10-20 years. Currently, treatment is limited. We studied the use of mycophenolate mofetil (MMF) vs placebo in a group of North American IgAN patients at high risk for progressive disease. METHODS: Included were 32 patients aged 18-75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors: (i) male sex; (ii) hypertension >150/90 mmHg or requiring antihypertensive medications; (iii) creatinine clearance, measured by 24 h urine collection, <80 and >20 ml/min at time of enrolment; and (iv) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy. Patients were randomized to either 1 year of MMF, titrated up to a dose of 1000 mg bid, or placebo. Total follow-up was 2 years. All patients received angiotensin inhibition medication. The primary outcome was a 50% increase in baseline serum creatinine (SCr). Secondary outcomes were an increase of 0.5 mg/dl SCr, ESRD and a 50% reduction in proteinuria. RESULTS: The mean baseline SCr was 2.4 mg/dl. No statistically significant differences were observed for any outcome. Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50% increase in SCr (P = 0.4). In both groups, all patients who reached the primary outcome also reached ESRD. Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr (P = 0.7) Only three MMF and two placebo patients had a 50% reduction in 24 h proteinuria. No serious adverse events occurred in either group. CONCLUSION: No benefit was seen in patients who received MMF in this high risk group, probably reflecting the relatively advanced stage of disease of our population. We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency.

Awareness of kidney disease in the US population: findings from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2000.

BACKGROUND: The prevalence of end-stage renal disease (ESRD) in the US population has been predicted to increase by 48% during the next decade and will pose a significant health cost burden. Early identification and treatment of chronic kidney disease (CKD) is necessary to delay progression from CKD to ESRD. CKD awareness among patients is crucial to early intervention programs, but its prevalence and characteristics in the noninstitutionalized US population are unknown. METHODS: The National Health and Nutrition Examination Survey 1999 to 2000 was used to determine prevalence estimates of kidney disease awareness, as well as demographics, health care access, and comorbid characteristics, of participants with CKD. RESULTS: In participants with CKD, 40.5% of patients with stage 1, 29.3% of patients with stage 2, 22.0% of patients with stage 3, and 44.5% of patients with stage 4 CKD were aware of their kidney disease, respectively. The aware and unaware groups did not differ by health care access. In multivariate regression modeling, lack of awareness was significantly associated with sex, race-ethnicity distribution, and hypertension. CONCLUSION: Kidney disease awareness is low among a representative sample of the noninstitutionalized US population. Groups at greater risk for kidney disease, such as non-Hispanic blacks, patients with hypertension, and men, were more likely to be unaware of having kidney disease, even with health care access similar to that of the aware group. Increased efforts to promote kidney disease awareness are needed and probably should target primary care providers involved in the screening process.