Approaches to Medication Management in Patients with Kidney Failure Opting for Conservative Management.

After consideration of risks and benefits, some patients with kidney failure choose conservative management. Conservative management of kidney failure (CM-KF) does not include dialysis or transplant and utilizes primarily pharmacologic strategies for symptom management, which can be challenging due to the number and complexity of symptoms. Additionally, there are safety concerns regarding altered pharmacokinetics and the adverse effects induced by some of the therapies that may be selected to treat symptoms. This review describes common kidney failure symptoms and provides recommendations for pharmacologic management in CM-KF. Selection of medication should be individualized to the patient and comorbidities, drug interactions, cost, and adverse effects should be carefully considered. Additional studies specifically focused on CM-KF are needed.

Assessment of literacy and numeracy skills related to medication labels in patients on chronic in-center hemodialysis.

OBJECTIVES: Patients on hemodialysis have complicated medication regimens requiring the ability to accurately interpret medication information. Literacy and numeracy skills have been shown to differ by the types of materials provided to patients. The aims of this study were to determine prescription and over-the-counter medication label understanding and to assess the prevalence of low health literacy regarding medication labeling among in-center hemodialysis patients. DESIGN, SETTING AND PARTICIPANTS: The Medication Literacy and Numeracy in Dialysis (MedLitD) tool is an assessment of a person's ability to read and understand medication labels. A comparison with the Rapid Estimate of Adult Literacy in Medicine Short Form (REALM-SF), an established literacy tool, was conducted to determine if there were differences in the literacy results from the 2 tools that could be leveraged to target education initiatives for this specialized population. RESULTS: A total of 110 patients receiving hemodialysis from 3 dialysis facilities in the Capital Region of upstate New York were enrolled in the study. Most patients (77%) achieved a maximum REALM-SF score, indicating a high level of literacy proficiency; however, their MedLitD scores varied. Patients who were 65 years and older had lower scores on the MedLitD tool compared with younger patients. Gender, education, and the number of medications did not influence the MedLitD scores. Only 16% of all participants correctly answered the question asking for an indication of the phosphate binder (PB), although the most patients were currently taking PBs. CONCLUSION: A continuum of medication literacy levels exists among patients on hemodialysis. Appropriate evaluation of medication literacy should be done to better inform individualized education and counseling.

Lipoteichoic Acid as a Potential Noninvasive Biomarker of Biofilm in Dialysis Access.

Tunneled central venous catheters (TCVCs) are colonized by Gram-positive organisms and form biofilm. Lipoteichoic acid (LTA) is a Gram-positive cell wall component that can be measured in serum. The purpose of this pilot study was to characterize LTA concentrations in hemodialysis (HD) patients with TCVCs compared to other access types and to evaluate biofilm morphology and microbiology in TCVCs removed by clinical decision. The study enrolled patients with TCVCs (18), grafts (19), and fistulas (18). Blood samples were collected before HD, at 30 minutes, 2 hours, and end of HD. Catheters removed by clinical decision were evaluated by scanning electron microscopy (SEM) for biofilm morphology, and portions of the catheter were cultured. LTA was detectable in all samples and concentrations increased significantly in all access types during HD (p < 0.05 for all comparisons). Patients with TCVCs that had a >30% increase in LTA concentration from baseline also had the greatest rate of increase (slope) compared to grafts and fistulas (p = 0.03 and p = 0.04, respectively). Catheters removed by clinical decision (n = 7) and examined by SEM had deposition of fibrin. Cultures revealed polymicrobial colonization. TCVCs had the highest rate of increase of LTA during HD. Further studies to determine the source of LTA in patients with AVG and AVF are warranted.

Hypoxia-inducible factor prolyl hydroxylase inhibitors: a paradigm shift for treatment of anemia in chronic kidney disease?

INTRODUCTION: The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) pathway is responsible for regulating the biosynthesis of erythropoietin (EPO) and maintaining iron homeostasis. Investigational drugs that target the HIF-PH pathway are promising alternatives for treating anemia in Chronic Kidney Disease (CKD). AREAS COVERED: This review summarizes recent advances focused on the clinical development of HIF-PH inhibitors (HIF-PHIs) as potentially novel therapies in the treatment of anemia in CKD based on publications available on PubMed and restricted Google searches. We provide a comparison between HIF-PHIs regarding their pharmacokinetics, dosing regimens and safety concerns, structure-activity relationships, and alterations in key laboratory parameters observed in animal models and clinical trials. EXPERT OPINION: HIF-PHIs may be advantageous in some aspects compared to the conventional erythropoiesis-stimulating agents (ESAs). While ESAs could increase the risk of cardiovascular events due to rapid rises in ESA blood levels, HIF-PHIs have been reported to maintain EPO concentrations at levels that are closer to the normal physiological ranges. Although HIF-PHIs have been demonstrated to be relatively safe and effective in clinical trials, long-term safety data are needed in order to establish whether these therapeutic agents will lead to a major paradigm change in the treatment of anemia of CKD.

Impact of hemodialysis on the concentrations of sodium and potassium during infusion of sodium thiosulfate using an In Vitro hemodialysis model.

INTRODUCTION: The purpose of this study was to evaluate the impact of hemodialysis on the concentrations of sodium and potassium in the blood when a 25 g dose of sodium thiosulfate injection is infused over 60 minutes in combination with hemodialysis. METHODS: Sodium thiosulfate (25 g) was prepared by diluting 100 mL of 250 mg/mL Sodium Thiosulfate Injection with 800 mL of 5% dextrose. This was added to the circulating blood surrogate solution at a rate of 15 mL/minute using an infusion pump of an in vitro model of dialysis machine. Serial samples were collected before the administration of the sodium thiosulfate solution, after 15 minutes, 30 minutes, and 60 minutes of infusion from pre-and post-dialyzer ports in both the dialysate circuit and the extracorporeal circuit. FINDINGS: The concentration of sodium thiosulfate in pre-dialyzer and post-dialyzer samples of the circulating blood surrogate solution peaked at 30 minutes and 15 minutes, respectively and then remained relatively unchanged during the remainder of the infusion. Mean sodium concentrations (mEq/L) in the circulating blood surrogate solution collected after exposure to a dialyzer were 103.2 ± 12.2, 114.2 ± 18.8, 117.2 ± 7.5, 93.5 ± 5.9 at 0, 15, 30, and 60 minutes, respectively (p = 0.248). Mean potassium concentrations (mEq/L) in the circulating blood surrogate solution collected after exposure to a dialyzer were 1.4 ± 0.3, 1.6 ± 0.3, 1.5 ± 0.1, 1.2 ± 0.1 at 0, 15, 30, and 60 minutes, respectively (p = 0.365). Sodium and potassium concentrations in dialysate increased marginally after exposure to the dialyzer. DISCUSSION: Our study demonstrates that neither potassium nor sodium accumulated in circulating blood surrogate solution when a dose of sodium thiosulfate was infused in conjunction with hemodialysis.

Assessment of literacy and numeracy skills related to non-steroidal anti-inflammatory drug labels.

BACKGROUND: Non-steroidal anti-inflammatory drugs are widely used and have a potential for over-the-counter misuse. Limited health literacy is associated with poor health outcomes. Identification of new strategies to assess literacy and numeracy could be useful in targeting effective education initiatives. OBJECTIVE: To characterize numeracy and literacy skills related to non-steroidal anti-inflammatory drug labels in primary care patients. METHODS: Patients were recruited and consented over an 8-month period after their regular primary care visit. Demographic information was collected and two instruments were administered to assess literacy and numeracy skills: (1) a medication label literacy instrument focused on non-steroidal anti-inflammatory drugs (MedLit-NSAID) and (2) a general healthy literacy-screening tool, the Newest Vital Sign. Two questions on the MedLit-NSAID instrument evaluated understanding of the Food and Drug Administration medication guide for non-steroidal anti-inflammatory drugs and the Food and Drug Administration approved over-the-counter label. RESULTS: A total of 145 patients were enrolled. Mean MedLit-NSAID and Newest Vital Sign scores were 6.8 (scale range 0-8) and 4.2 (scale range 0-6), respectively. Higher education level was associated with higher scores for both tools (p ⩽ 0.05). Total MedLit-NSAID scores on average were higher in females compared with males (6.5 vs 6, p = 0.05). Patients with decreased kidney function (n = 18) had significantly lower MedLit-NSAID scores (p ⩽ 0.05). Test-retest scores were not significantly different for MedLit-NSAID (p = 0.32). The correlation between the tools was 0.54 and internal consistency MedLit-NSAID was 0.61. CONCLUSION: A medication information focused instrument provided specific information to assess health literacy related to non-steroidal anti-inflammatory drug labels. This information could be utilized to develop patient education initiatives for medication label comprehension.

Patient-selected media and knowledge of risk to kidneys of nonsteroidal anti-inflammatory drugs.

OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause community-acquired acute kidney injury, especially in high-risk populations. Both the U.S. Food and Drug Administration (FDA) medication guide and over-the-counter labeling vaguely describe kidney risks of NSAIDs and do not provide information for patients to evaluate their risk for kidney problems. The purpose of this study was to use a mobile application to evaluate the impact of patient choice of media delivering NSAID avoidance education on patient knowledge about kidney risks associated with NSAIDs. DESIGN: Prospective cohort study. The mobile application was used to deliver either a redesigned FDA medication guide or a video focused on NSAID risks (selected by the patient), followed by patient knowledge questions (PKQs) and a kidney risk assessment. SETTING AND PARTICIPANTS: One hundred fifty adult primary care patients in southeast Michigan. MAIN OUTCOME MEASURES: The primary outcome was the score on 5 NSAID PKQs between the media selected. Secondary outcomes included characterization of media choice among different demographic and NSAID kidney risk groups. The relationship between kidney risk assessment and self-reported NSAID avoidance behavior also was evaluated. RESULTS: The majority of participants (72.7%) chose to review print material. Those that chose print had significantly higher PKQ scores (5 total points) compared with participants who selected the video: mean scores 4.2 ± 0.9 with print and 3.8 ± 1.0 with video (P = 0.034). Older patients (>65 years) had significantly lower PKQ scores compared with other age groups. Forty-four percent of individuals (n = 66) reported current NSAID use, and 65% stated that they would avoid NSAIDs after the selected education material. CONCLUSION: Scores for questions related to NSAID kidney risk knowledge were higher among participants who chose print compared with video education material. Education regarding NSAID kidney risks encouraged patients to limit their use. Targeted education may be beneficial in high-risk (e.g., older) patients and should be further studied.

Iron Oxide Nanoparticle Formulations for Supplementation.

Intravenous (IV) iron is widely used to provide supplementation when oral iron is ineffective or not tolerated. All commercially available intravenous iron formulations are comprised of iron oxyhydroxide cores coated with carbohydrates of varying structure and branch characteristics. The diameter of the iron-carbohydrate complexes ranges from 5-100 nm and meets criteria for nanoparticles. Clinical use of IV iron formulations entered clinical practice beginning of the late 1950s, which preceded the nanomedicine exploration frontier. Thus, these agents were approved without full exploration of labile iron release profiles or comprehensive biodistribution studies. The hypothesis for the pathogenesis of acute oxidative stress induced by intravenous iron formulations is the release of iron from the iron-carbohydrate structure, resulting in transient concentrations of labile plasma iron and induction of the Fenton chemistry and the Haber-Weiss reaction promoting formation of highly reactive free radicals such as the hydroxyl radical. Among available IV iron formulations, products with smaller carbohydrate shells are more labile and more likely to release labile iron directly into the plasma (i.e., before metabolism by the reticuloendothelial system). The proposed biologic targets of labile-iron-induced oxidative stress include nearly all systemic cellular components including endothelial cells, myocardium, liver as well as low density lipoprotein and other plasma proteins. Most studies have relied on plasma pharmacokinetic analyses that require many model assumptions to estimate contribution of the iron-carbohydrate complex to elevations in serum iron indices and hemoglobin. Additionally, the commercially available formulations have not been well studied with regard to optimal dosing regimens, long-term safety and comparative efficacy. The IV iron formulations fall into a class defined by the Food and Drug Administration as "Complex Drugs" and thus present considerable challenges for bioequivalence evaluation.

Need for a Judicious Use of Nonsteroidal Anti-inflammatory Drugs to Avoid Community-Acquired Acute Kidney Injury.

Millions of Americans use over-the-counter analgesics on a daily basis, and nearly 100 million nonsteroidal anti-inflammatory drug (NSAID) prescriptions are filled per year. In high-risk patients, these medications can disrupt kidney hemodynamics and precipitate community-acquired acute kidney injury (CA-AKI). The risk of NSAID-associated CA-AKI increases 3- to 5-fold in patients taking renin-angiotensin system inhibitors and diuretics concurrently. CA-AKI increases the risk of developing chronic kidney disease (CKD) or accelerating progression of pre-existing CKD. Importantly, many cases of NSAID-induced CA-AKI may be avoided by identifying high-risk patients and providing patient and provider education on when to avoid these medications and minimize risk.

Fostering Innovation in Symptom Management among Hemodialysis Patients: Paths Forward for Insomnia, Muscle Cramps, and Fatigue.

Individuals receiving in-center maintenance hemodialysis bear a high burden of both physical and mood symptoms. More than half of patients on hemodialysis report sleep disturbance, muscle cramps, and fatigue. Patients describe symptoms as having a deleterious effect on their quality of life, suggesting that symptom alleviation may meaningfully improve patient-reported outcomes. Moreover, patients on hemodialysis have identified symptom management as a key area for research and innovation, prioritizing symptom alleviation over other health outcomes such as mortality and biochemical indices. Despite the importance of symptoms to patients, there has been little research explicitly geared toward improving patient symptoms, and therefore minimal innovation in symptom management. In general, the physiologic underpinnings of symptoms are poorly understood, hampering the development of targeted therapies. In fact, there have been few drugs or devices approved by the US Food and Drug Administration for the indication of improving any patient-reported outcomes for patients on hemodialysis. Recognizing this gap in innovation, the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration, convened a workgroup to first prioritize symptoms for the development of therapeutic interventions, and then identify near-term actionable research goals for the prioritized physical symptoms of insomnia, muscle cramps, and fatigue. This paper summarizes the pathophysiology of the three prioritized symptoms, identifies key knowledge gaps, acknowledges factors that challenge development of new therapies, and offers the nephrology community actionable research goals for insomnia, muscle cramps, and fatigue.

In vitro and in vivo DFO-chelatable labile iron release profiles among commercially available intravenous iron nanoparticle formulations.

Intravenous (IV) iron formulations are complex colloidal suspensions of iron oxide nanoparticles. Small changes in formulation can allow more labile iron to be released after injection causing toxicity. Thus, bioequivalence (BE) evaluation of generic IV iron formulations remains challenging. We evaluated labile iron release in vitro and in vivo using a high performance liquid chromatography chelatable iron assay to develop a relational model to support BE. In vitro labile iron release and in vivo labile iron pharmacokinetics were evaluated for Venofer®, Ferrlecit®, generic sodium ferric gluconate complex, InFeD®, Feraheme® and a pre-clinical formulation GE121333. Labile iron release profiles were studied in vitro in 150 mM saline and a biorelevant matrix (rat serum) at 0.952 mgFe/mL. In vivo plasma labile iron concentration-time profiles (t0-240 min) were studied in rats after a 40 mgFe/kg IV dose. In vitro labile iron release in saline was significantly higher compared to rat serum, especially with InFeD®. An in vitro release constant (iKr) was calculated which correlated well with maximal plasma concentrations in the in vivo rat PK model (R2 = 0.711). These data suggest an in vitro to in vivo correlation model of labile iron release kinetics could be applied to BE. Other generic IV iron formulations need to be studied to validate this model.

Symptom Prioritization among Adults Receiving In-Center Hemodialysis: A Mixed Methods Study.

BACKGROUND AND OBJECTIVES: Individuals receiving in-center hemodialysis experience a high symptom burden that detrimentally affects their quality of life. There are few evidence-based interventions for symptom relief in this population. To stimulate innovation in symptom management, data on patient symptom prioritization and treatment preferences are needed. We undertook this study to (1) identify patient-prioritized symptoms for the development of symptom relief therapies and (2) elicit preferences for treatments among individuals receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a mixed methods study that included focus groups in Carrboro, North Carolina; Tucson, Arizona; and Seattle, Washington and a nationally distributed online survey. Focus group transcripts were analyzed for patterns, and the highest priority symptoms were determined on the basis of frequency and report severity. We used focus group findings to inform survey items. Focus group and survey results were crossvalidated and synthesized for final symptom prioritization. RESULTS: There were 32 participants across three focus groups and 87 survey respondents from 27 states in the United States. The physical symptoms of insomnia, fatigue, muscle cramping, and nausea/vomiting and the mood symptoms of anxiety and depressed mood were reported by participants in all focus groups. Among survey respondents, fatigue (94%), cramping (79%), and body aches (76%) were the most common physical symptoms, and feeling depressed (66%), worried (64%), and frustrated (63%) were the most common mood symptoms. The top-prioritized symptoms were consistent across focus group and survey participants and included the physical symptoms insomnia, fatigue, and cramping and the mood symptoms anxiety, depression, and frustration. Participants indicated that symptom frequency, duration, unpredictability, and social and financial effects factored most heavily into symptom prioritization. CONCLUSIONS: Patients prioritized the physical symptoms of insomnia, fatigue, and cramping and the mood symptoms of anxiety, depression, and frustration as the top symptoms for which to find new therapies.

Complexity of intravenous iron nanoparticle formulations: implications for bioequivalence evaluation.

Intravenous iron formulations are a class of complex drugs that are commonly used to treat a wide variety of disease states associated with iron deficiency and anemia. Venofer® (iron-sucrose) is one of the most frequently used formulations, with more than 90% of dialysis patients in the United States receiving this formulation. Emerging data from global markets outside the United States, where many iron-sucrose similars or copies are available, have shown that these formulations may have safety and efficacy profiles that differ from the reference listed drug. This may be attributable to uncharacterized differences in physicochemical characteristics and/or differences in labile iron release. As bioequivalence evaluation guidance evolves, clinicians should be educated on these potential clinical issues before a switch to the generic formulation is made in the clinical setting.

Drug Transporter Function--Implications in CKD.

Drug transporters typically move substrates, including drugs, in an intracellular to extracellular direction and thus are efflux transporters. There is a small subset of transporters that move substrates in the opposite direction and are classified as influx transporters. Collectively, drug transporters contribute to the pharmacokinetic profile of a wide variety of drugs and other molecules including xenobiotics, metabolites, and endogenous solutes. Identification of genetic variants in the genes that encode these transporters is an emerging area of pharmacogenomics. Many polymorphisms of the multitude of genes that code for the transporters within the 2 major superfamilies (ATP-binding cassette transporters and solute carrier transporters) have been identified. Studies have shown that many single-nucleotide polymorphisms are associated with changes in protein expression, functionality, and drug exposure; however, there are limited data for most single-nucleotide polymorphisms and impact on clinical end points. Preliminary data suggest that patients with CKD may have reduced transporter function that may have effects on exposure and toxicity profiles. Additional research translating the functional significance of polymorphisms on clinical pharmacokinetics and relevant disease-specific end points will provide further understanding of the role of genetic variations in transporter genes.

Iron-based phosphate binders--a new element in management of hyperphosphatemia.

INTRODUCTION: Management of serum phosphorus in patients with chronic kidney disease remains a significant clinical challenge. A pivotal component of the clinical approach to maintaining serum phosphorus concentrations towards the normal range is the use of phosphate binding agents in addition to comprehensive dietary counseling. The available agents work similarly by capitalizing on a cation within the agent to bind negatively charged phosphorus, forming an insoluble complex and reducing ingested phosphorus absorption. Despite several effective options for phosphate binder therapies, patient adherence remains an issue, mainly due to adverse effect profiles and large daily pill burdens. AREAS COVERED: Two new iron-based phosphate binder therapies have recently become available in the United States, sucroferric oxyhydroxide and ferric citrate. These agents have both been shown to effectively reduce serum phosphorus comparably to widely used calcium-based binders and sevelamer salts. EXPERT OPINION: The two new iron-based binders differ substantially with regard to phosphate binding chemistry and iron absorption profiles. Their place in therapy is still evolving and the impact of pill burden, gastrointestinal adverse effect profiles, potential cost reduction of anemia therapies and physiologic effects of long-term iron exposure need to be further evaluated.