A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease.

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events.

Cardiovascular and renal disease manifestation and healthcare resource utilization in patients on first-line oral therapy for type 2 diabetes: A claims-based observational cohort study.

AIM: To examine incident cardiovascular disease (CVD) and chronic kidney disease (CKD) diagnosis and associated healthcare resource utilization (HCRU) in a real-world population of patients with type 2 diabetes (T2D) initiating first-line oral antidiabetes drug (OAD) therapy. MATERIALS AND METHODS: Adults with T2D without CVD/CKD initiating first-line OAD therapy from 2008 to 2018 IBM MarketScan claims data were included. Incident CVD/CKD diagnoses following OAD initiation and first diagnosis type were assessed. Risk of incident diagnosis of heart failure (HF) among patients with CKD and of CKD among patients with HF was evaluated. HCRU and costs were compared for the 12 months before and after the first CVD/CKD diagnosis. RESULTS: Of 12 286 016 patients, 1 286 287 met all the inclusion criteria. During follow-up (mean 752 days), 205 865 (16.0%) patients had CVD/CKD diagnoses; the most common first diagnosis was the composite cardiorenal outcome of HF and/or CKD (64.6%). Most first diagnoses were within 2 years of OAD initiation. For HF and CKD, diagnosis of one was associated with increased risk of subsequent diagnosis of the other (both P < .001). Average annualized visits per patient increased by 31% after the first CVD/CKD diagnosis and annualized payer and patient costs increased by 75% and 26%, respectively, compared with the 12 months prediagnosis. Costs increased for all diagnosis types. CONCLUSIONS: Most first CVD/CKD diagnoses occurred within 2 years after OAD initiation and were associated with increased HCRU and costs. Reducing CVD/CKD risk with T2D treatments that improve both cardiovascular and renal outcomes may attenuate the burden of illness.

Comparison of Two Manufacturing Processes of Daprodustat for Bioequivalence and Dissolution in Healthy Volunteers: A Randomized Crossover Study.

Daprodustat, an orally bioavailable hypoxia-inducible factor-prolyl hydroxylase enzyme inhibitor, has recently completed phase 3 clinical development for treating anemia of chronic kidney disease. Part A of this 2-part, randomized, double-blind, single-dose, cross-over study (NCT04640311) compared pharmacokinetic properties of a single oral dose of daprodustat 4 mg tablets manufactured via twin-screw wet granulation (process 1) to 2 sets of 4 mg tablets manufactured via high-shear wet granulation (process 2), to assess the impact of different dissolution profiles on pharmacokinetics. Part B assessed the bioequivalence of daprodustat tablets manufactured via process 1 with tablets manufactured via process 2 at 5 different dose strengths (1, 2, 4, 6, and 8 mg). In part A, mean plasma concentrations of daprodustat were comparable over a 24-hour period despite differences in manufacturing processes and dissolution profiles. In part B, the 90% confidence intervals of the ratios of the least squared means for area under the concentration-time curve and maximum observed plasma concentration fell within the 0.8-1.25 bioequivalence range for all doses, except for maximum observed plasma concentration at 8 mg. A prespecified sensitivity analysis jointly assessing all doses showed bioequivalence for all doses tested. No new safety concerns for daprodustat were identified.

Real-World Management of Hyperkalemia in the Emergency Department: An Electronic Medical Record Analysis.

INTRODUCTION: Hyperkalemia is often managed in the emergency department (ED) and it is important to understand how ED management and post-discharge outcomes vary by hyperkalemia severity. This study was conducted to characterize ED management and post-discharge outcomes across hyperkalemia severities. METHODS: Adults with an ED visit with hyperkalemia (at least one serum potassium lab measure above 5.0 mEq/L) were selected from US electronic medical record data (2012-2018). Patient characteristics, potassium levels, treatments, and monitoring prior to and during the ED visit were compared by hyperkalemia severity (mild [> 5.0-5.5 mEq/L], moderate [> 5.5-6.0], severe [> 6.0]) using unadjusted analyses. Death, immediate inpatient admission, 30-day hyperkalemia recurrence, and 30-day inpatient admission were also assessed by severity. RESULTS: Of 6222 patients included, 4432 (71.2%) had mild hyperkalemia, 1085 (17.4%) had moderate, and 705 (11.3%) had severe hyperkalemia. Chronic kidney disease (39.9-50.1%) and heart failure (21.6-24.3%) were common. In the ED, electrocardiograms (mild, 56.5%; moderate, 69.6%; severe, 81.0%) and patients with at least two potassium laboratory values increased with severity (15.0%; 40.4%; 75.5%). Among patients with at least two potassium laboratory values, over half of patients (60.4%) had potassium levels ≤ 5.0 mEq/L prior to discharge. Use of potassium-binding treatments (sodium polystyrene sulfonate: mild = 4.1%; moderate = 17.1%; severe = 27.4%), temporizing agents (5.6%; 15.5%; 31.6%), or dialysis (0.4%; 0.8%; 3.0%) increased with severity; treatment at discharge was not common. Death (1.1%; 3.7%; 10.6%), immediate admission to inpatient care (5.8%; 8.7%; 12.7%), 30-day hyperkalemia recurrence (2.9%; 19.0%; 32.5%), 30-day inpatient admission with hyperkalemia (6.5%; 7.9%; 9.3%) also increased with severity. CONCLUSION: Patients with moderate and severe hyperkalemia experienced elevated risk of hyperkalemia recurrence and hyperkalemia-related inpatient readmission following discharge from the ED from a descriptive analysis. Future research to assess strategies to reduce hyperkalemia recurrence and inpatient admission in this patient population would be beneficial.

Determinants of Hyperkalemia Progression Among Patients with Mild Hyperkalemia.

INTRODUCTION: The progression of mild hyperkalemia and the predictors of progression have not been well characterized. In this study we aimed to characterize the progression of hyperkalemia and identify the risk factors for hyperkalemia progression. METHODS: Adults with mild hyperkalemia (at least one serum potassium measure > 5.0 and ≤ 5.5 mEq/L) were identified using electronic medical records from the Research Action for Health Network (2012-2018). Progression to moderate-to-severe and progression to severe hyperkalemia were defined as the first occurrences of a serum potassium measure > 5.5 and > 6.0 mEq/L, respectively. Kaplan-Meier analyses were conducted to estimate progression rates for all patients and by pre-specified patient subgroups. Hazard ratios (HR) of moderate-to-severe and severe hyperkalemia progression were estimated using Cox models. RESULTS: Of 35,369 patients with mild hyperkalemia, 16.9% and 8.7% progressed to moderate-to-severe and severe hyperkalemia, respectively. Rates of hyperkalemia progression elevated with the severity of chronic kidney disease (CKD). The highest progression rates were seen in patients with CKD stage 5 (stage 5 vs. no CKD: moderate-to-severe, 50.2% vs. 12.0%; severe, 31.3% vs. 3.9%; p < 0.001). Higher progression rates were also observed in patients with heart failure, hypertension, and type II diabetes compared with patients without those conditions (all p < 0.001). The most prominent risk factors were CKD stage 5 (HR of progression to moderate-to-severe hyperkalemia, 3.32 [95% CI 3.03-3.64]; severe, 4.08 [3.55-4.69]), CKD stage 4 (2.19 [1.97-2.43], 2.28 [1.92-2.71]), CKD stage 3 (1.57 [1.46-1.68], 1.65 [1.46-1.87]), type I diabetes (1.37 [1.18-1.61], 1.54 [1.23-1.93]), and serum potassium (1.12 [1.10-1.15], 1.13 [1.10-1.17] per 0.1 mEq/L increase) (all p values < 0.05). CONCLUSION: Hyperkalemia progression rates increased significantly with CKD stage and were also higher among patients with higher baseline potassium level, heart failure, hypertension, and diabetes.

Inpatient management and post-discharge outcomes of hyperkalemia.

OBJECTIVES: Patients with hyperkalemia are commonly treated in the inpatient setting; however, real-world evidence is limited. The purpose of this study was to describe the inpatient management and post-discharge outcomes among patients with hyperkalemia. METHODS: Electronic medical record data (2012-2018) were used to analyze US adult patients with an inpatient stay with hyperkalemia (≥1 potassium value >5.0mEq/L). Patient characteristics, treatments, and monitoring six months prior to and during the inpatient stay, and hyperkalemia recurrence and inpatient readmissions post-discharge were summarized and compared among patients with mild (>5.0-5.5mEq/L), moderate (>5.5-6.0), and severe (>6.0) hyperkalemia. RESULTS: Of the 21,793 patients, 69.2% had mild, 19.0% had moderate, and 11.8% had severe hyperkalemia during inpatient care. The most common inpatient treatments were temporizing agents (mild: 28.9%; moderate: 46.0%; severe: 73.0%), diuretics (32.7%; 37.1%; 34.6%), and sodium-polystyrene sulfonate (11.7%; 27.8%; 45.3%). Almost no patients (0.1%) received a potassium binder at discharge. Most patients (86.8%) had their potassium levels return to ≤5.0mEq/L during the inpatient stay. Death during the inpatient stay occurred in 12.3% of mild, 15.5% of moderate, and 19.5% of severe hyperkalemic patients. Within 30 days of discharge, hyperkalemia recurred in 13.3%, 15.4%, and 18.4% of patients with mild, moderate, and severe hyperkalemia, respectively. Additionally, 19.7%, 21.5%, and 19.6% of patients were readmitted to inpatient care within 30 days post-discharge. CONCLUSION: Among patients with hyperkalemia in the inpatient setting, treatment and normalization of serum potassium levels were common. However, death, readmission, and hyperkalemia recurrence were also fairly common across all cohorts. Future studies examining measures to reduce inpatient death, readmission, and hyperkalemia recurrence among patients with hyperkalemia in inpatient care are warranted.

Prevalence of Metabolic Acidosis Among Patients with Chronic Kidney Disease and Hyperkalemia.

INTRODUCTION: Although hyperkalemia and metabolic acidosis often co-occur in patients with chronic kidney disease (CKD), the prevalence of metabolic acidosis among patients with CKD and hyperkalemia is understudied. Therefore, we used medical record data from the Research Action for Health Network to estimate this prevalence. METHODS: Adult patients with CKD stage 3-5, ≥ 1 outpatient potassium value > 5.0 mEq/l, and ≥ 1 outpatient bicarbonate value available were identified. Patients with end stage kidney disease (ESKD) in the prior year were excluded. The prevalence of metabolic acidosis in each calendar year from 2014 to 2017 among patients with CKD and hyperkalemia was estimated using two definitions of hyperkalemia (potassium > 5.0 mEq/l and > 5.5 mEq/l) and metabolic acidosis (bicarbonate < 18 mEq/l and < 22 mEq/l). RESULTS: In the 2017 patient cohort and among patients with CKD and hyperkalemia, patients with metabolic acidosis were younger (69 versus 74 years), more likely to have advanced CKD (35% versus 13%), and use oral sodium bicarbonate (21% versus 4%) than patients without metabolic acidosis. The prevalence of metabolic acidosis (< 22 mEq/l) ranged from 25 to 29% when hyperkalemia was defined by potassium > 5.0 mEq/l and ranged from 33 to 39% when hyperkalemia was defined by potassium > 5.5 mEq/l. CONCLUSION: Results demonstrated that prevalence estimates of metabolic acidosis varied based on the definition of hyperkalemia and metabolic acidosis utilized.

Physician characteristics and knowledge of CKD management.

BACKGROUND: Many studies suggest that chronic kidney disease (CKD) care is suboptimal in the United States. However, it is not known whether knowledge of CKD management in primary care physicians (PCPs) might have an important role in the suboptimal care and whether PCP characteristics are associated with having adequate knowledge. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Self-administered questionnaire sent to a random sample of 1,550 US PCPs in February 2007. PREDICTOR OR FACTOR: PCP characteristics, including age, sex, degree (MD versus DO), primary specialty, board certification, patient volume, percentage of time in patient care spent in the inpatient versus outpatient setting, and number of patients referred to nephrologists in a month. OUTCOMES & MEASUREMENTS: Regression analyses of the association between physician characteristics and overall physician knowledge of CKD management, as well as individual subdomains of CKD knowledge related to recognition of CKD and management of hypertension in the setting of CKD. RESULTS: 470 of 1,453 (32.4%) eligible PCPs returned a completed survey. PCPs show significant variation in their ability to recognize CKD stages 2 to 4, but most have appropriate blood pressure goals in patients with CKD and are knowledgeable of the role of angiotensin-converting enzyme inhibitors in managing proteinuria. For each 10-year increase in age, the odds of showing satisfactory knowledge of CKD management decreased by 26% (odds ratio, 0.74; 95% confidence interval, 0.60 to 0.92). PCPs with the primary specialty of internal medicine had a more than 3-fold greater odds of showing a satisfactory level of knowledge compared with family practice specialists (odds ratio, 3.40; 95% confidence interval, 2.17 to 5.32). LIMITATIONS: The study findings are limited by the potential presence of nonresponse bias, information bias, and results suggesting there are multiple knowledge subdomains that perhaps are not additive. CONCLUSION: There is need to improve CKD knowledge in PCPs, especially regarding recognition of CKD at an early stage.

Hemoglobin variability and mortality in ESRD.

Hemoglobin levels vary substantially over time in hemodialysis patients, and this variability may portend poor outcomes. For a given patient, hemoglobin concentration over time can be described by absolute levels, rate of change, or by the difference between observed level and expected level based on the preceding trend (i.e., seemingly random variability). We investigated the independent associations of these different methods of describing hemoglobin over time with mortality in a retrospective cohort of 34,963 hemodialysis patients. Hemoglobin concentration over time was modeled with linear regression for each subject, and the model was then used to define the subject's absolute level of hemoglobin (intercept), temporal trend in hemoglobin (slope), and hemoglobin variability (residual standard deviation). Survival analyses indicated that each 1g/dl increase in the residual standard deviation was associated with a 33% increase in rate of death, even after adjusting for multiple covariates. Patient characteristics accounted for very little of the variation in our hemoglobin variability metric (R2 = 0.019). We conclude that greater hemoglobin variability is independently associated with higher mortality.

History-adjusted marginal structural analysis of the association between hemoglobin variability and mortality among chronic hemodialysis patients.

BACKGROUND AND OBJECTIVES: Hemoglobin variability is common among dialysis patients, and has been associated with increased mortality. The causal nature of this association has been difficult to ascertain because of potential time-dependent confounding, for which traditional statistical methods do not control. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort of 34,963 Fresenius Medical care dialysis patients from 1996 was assembled. Hemoglobin variability, absolute hemoglobin level, and temporal hemoglobin trend were measured over rolling 6-mo exposure windows. Their association with mortality was estimated using history-adjusted marginal structural analysis that adjusts for time-dependent confounding by applying weights to observations inversely related to the predictability of observed levels of hemoglobin. RESULTS: In the primary analysis, each g/dl increase in hemoglobin variability was associated with an adjusted hazard ratio (HR) [95% confidence interval (CI)] for all-cause mortality of 1.93 (1.20 to 3.10). Neither higher absolute hemoglobin level nor increasing hemoglobin trend were significantly associated with mortality; adjusted HR (95% CI) 0.85 (0.64 to 1.11) and 0.60 (0.25 to 1.45), respectively. CONCLUSIONS: Marginal structural analysis demonstrates that hemoglobin variability is associated with increased mortality among chronic hemodialysis patients, and that this effect is more pronounced than appreciated using standard statistical techniques that do not take time-dependent confounding into account.

Use of antiepileptic drugs in patients with kidney disease.

The number of medications used to treat different types of seizures has increased over the last 10-15 years. Most of the newer antiepileptic drugs (AEDs) are likely to be unfamiliar to many nephrologists. For both the older and newer AEDs, basic pharmacokinetic information, recommendations for drug dosing in patients with reduced kidney function or who are on dialysis, and adverse renal and fluid-electrolyte effects are reviewed. Newer AEDs are less likely to have significant drug-drug interactions than older agents, but are more likely to need dosage adjustment in patients with reduced kidney function. The most common renal toxicities of these drugs include metabolic acidosis, hyponatremia, and nephrolithiasis; interstitial nephritis and other adverse effects are less common. Little is known about the clearance of most of the newer AEDs with high-efficiency hemodialyzers or with peritoneal dialysis. Monitoring of drug levels when available, careful clinical assessment of patients taking AEDs, and close collaboration with neurologists is essential to the management of patients taking AEDs.

Willingness of dialysis patients to participate in a randomized controlled trial of daily dialysis.

BACKGROUND: The National Institutes of Health (NIH) has proposed conducting randomized controlled trials comparing short, daily, in-center hemodialysis with conventional hemodialysis. However, there is concern that difficulties recruiting patients may prevent the successful completion of such trials if patients believe the inconveniences of daily dialysis outweigh any potential health benefits. METHODS: To gauge willingness to participate in a daily dialysis trial, we described a hypothetical, randomized controlled trial comparing conventional to daily hemodialysis to 209 chronic hemodialysis patients, and assessed their motivations for and concerns about participating. RESULTS: We found that 85 patients (41%) of 209 patients who agreed to be interviewed expressed some willingness to participate in the hypothetical trial. Patients who expressed greater willingness to participate were younger (OR for participating = 0.96 per year, 95% CI = 0.94 to 0.98, P= 0.001), less likely to smoke (OR = 0.38, 95% CI = 0.17 to 0.84, P= 0.017), more likely to have been hospitalized during the last 12 months (OR = 2.8, 95% CI = 1.5 to 5.5, P= 0.002), less likely to have reactive airway disease (OR = 0.21, 95% CI = 0.06 to 0.69, P= 0.01) or coronary artery disease (OR = 0.20, 95% CI = 0.08 to 0.53, P= 0.001), and less likely to be on the waiting list for a kidney transplant (OR = 0.23, 95% CI = 0.10 to 0.50, P < 0.0001). CONCLUSION: The study suggests that less than half of eligible patients would be willing to participate in the randomized controlled trial. Differing willingness to participate across patient subgroups suggests that certain subgroups (i.e., older patients and those with coronary artery disease) will need to be targeted to ensure that results are generalizable to most hemodialysis patients.