Browsing by Author "Sarnak, Mark J."

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    Chronic kidney disease and peripheral nerve function in the Health, Aging and Body Composition Study
    (Oxford University Press, 2019-04) Moorthi, Ranjani N.; Doshi, Simit; Fried, Linda F.; Moe, Sharon M.; Sarnak, Mark J.; Satterfield, Suzanne; Schwartz, Ann V.; Shlipak, Michael; Lange-Maia, Brittney S.; Harris, Tamara B.; Newman, Anne B.; Strotmeyer, Elsa S.; Medicine, School of Medicine
    BACKGROUND: Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. METHODS: Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999-2000) and nerve function measurements at Year 4 (2000-01) were analyzed (n = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as ≤60 (CKD) or >60 mL/min/1.73 m2 (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. RESULTS: Participants with CKD (n = 476) were older (77 ± 3 versus 75 ± 3 years; P < 0.05) and had a higher prevalence of diabetes (20.6% versus 13.1%; P < 0.001). CKD was associated with higher odds for vibration detection threshold {odds ratio [OR] 1.7 [95% confidence interval (CI) 1.1-2.7]} and light touch insensitivity [OR 1.4 (95% CI 1.1-1.7)]. CMAPs and NCVs were not significantly different between CKD and non-CKD patients. In adjusted analyses, participants with CKD had higher odds of an abnormal heart rate response [OR 1.6 (95% CI 1.1-2.2)] and poor heart rate recovery [OR 1.5 (95% CI 1.1-2.0)]. CONCLUSIONS: CKD is associated with changes in sensory and autonomic nerve function, even after adjustment for demographics and comorbidities, including diabetes. Longitudinal studies in CKD are needed to determine the contribution of nerve impairments to clinically important outcomes.
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    Global Phase 3 programme of vadadustat for treatment of anaemia of chronic kidney disease: rationale, study design and baseline characteristics of dialysis-dependent patients in the INNO2VATE trials
    (Oxford University Press, 2021-11-09) Eckardt, Kai-Uwe; Agarwal, Rajiv; Farag, Youssef Mk; Jardine, Alan G.; Khawaja, Zeeshan; Koury, Mark J.; Luo, Wenli; Matsushita, Kunihiro; McCullough, Peter A.; Parfrey, Patrick; Ross, Geoffrey; Sarnak, Mark J.; Vargo, Dennis; Winkelmayer, Wolfgang C.; Chertow, Glenn M.; Medicine, School of Medicine
    Background: Erythropoiesis-stimulating agents (ESAs) are currently the mainstay of treatment for anaemia of chronic kidney disease (CKD). Vadadustat is an investigational oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that stimulates endogenous erythropoietin formation. The INNO2VATE programme comprises two studies designed to evaluate the safety and efficacy of vadadustat versus the ESA darbepoetin alfa in ameliorating anaemia in patients with dialysis-dependent CKD (DD-CKD). Here we describe the trial design along with patient demographics and baseline characteristics. Methods: Two Phase 3, open-label, sponsor-blind, active-controlled trials enrolled adults with anaemia of CKD who recently initiated dialysis and had limited ESA exposure (incident DD-CKD trial) or were receiving maintenance dialysis with ESA treatment (prevalent DD-CKD trial). Study periods include correction/conversion (Weeks 0-23), maintenance (Weeks 24-52), long-term treatment (Weeks 53 to end of treatment) and safety follow-up. The primary safety endpoint is the time to the first major adverse cardiovascular event and the primary efficacy endpoint is the change in haemoglobin (baseline to Weeks 24-36). Results: A total of 369 and 3554 patients were randomized in the incident DD-CKD and prevalent DD-CKD trials, respectively. Demographics and baseline characteristics were similar among patients in both trials and comparable to those typically observed in DD-CKD. Conclusions: The two INNO2VATE trials will provide important information on the safety and efficacy of a novel approach for anaemia management in a diverse DD-CKD population. Demographics and baseline characteristics of enrolled patients suggest that study results will be representative for a large proportion of the DD-CKD population.
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    Overall Adverse Event Profile of Vadadustat versus Darbepoetin Alfa for the Treatment of Anemia Associated with Chronic Kidney Disease in Phase 3 Trials
    (Karger, 2022) Agarwal, Rajiv; Anand, Sanjeev; Eckardt, Kai-Uwe; Luo, Wenli; Parfrey, Patrick S.; Sarnak, Mark J.; Solinsky, Christine M.; Vargo, Dennis L.; Winkelmayer, Wolfgang C.; Chertow, Glenn M.; Medicine, School of Medicine
    Introduction: Anemia frequently occurs in chronic kidney disease (CKD), is associated with poor quality of life and cardiovascular outcomes, and its treatment represents a considerable economic burden to the healthcare system. Although effective, the current standard of care for the treatment of anemia in chronic kidney disease patients with erythropoiesis-stimulating agents requires chronic/ongoing injections, making the treatment less accessible or desirable to patients not treated by in-center maintenance hemodialysis. Furthermore, safety concerns, including an increased risk of cardiovascular events and mortality, have emerged from their use in studies targeting hemoglobin concentrations in the normal or near-normal range. The orally active hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat may offer advantages over erythropoiesis-stimulating agents by correcting anemia via pathways activating endogenous erythropoietin production. Methods: To comprehensively analyze the safety profile of vadadustat in patients with dialysis-dependent and non-dialysis-dependent CKD-related anemia, we pooled the safety populations from each of the four trials in the phase 3 clinical program (n = 7,373) and compared the risk of treatment-emergent adverse events (TEAEs) for each treatment arm. Results: In patients randomized to vadadustat versus darbepoetin alfa, rates of TEAEs (88.9% vs. 89.3%), treatment-emergent serious adverse events (58.0% vs. 59.3%), and TEAEs leading to death (16.1% vs. 16.2%) were similar, as were rates of adverse events of special interest, including cardiovascular-, hepatic-, and neoplasm-related adverse events. Discussion/conclusion: Among patients with CKD-related anemia treated with vadadustat, we observed similar rates of adverse events relative to those treated with darbepoetin alfa.
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    Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis
    (Oxford University Press, 2023) Sarnak, Mark J.; Agarwal, Rajiv; Boudville, Neil; Chowdhury, Pradip C. P.; Eckardt, Kai-Uwe; Gonzalez, Carlos R.; Kooienga, Laura A.; Koury, Mark J.; Ntoso, Kwabena A.; Luo, Wenli; Parfrey, Patrick S.; Vargo, Dennis L.; Winkelmayer, Wolfgang C.; Zhang, Zhiqun; Chertow, Glenn M.; Medicine, School of Medicine
    Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. Methods: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). Results: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. Conclusions: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.