Undocumented immigrants represent 3% of the population in the United

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1 May/June 2018 VOLUME 10, NUMBER 4 Guest Contributor Breaking Down Barriers to Treatment Adherence for Dialysis Patients LaVarne A. Burton highlights survey results from the American Kidney Fund. 9 News Pharmacist Intervention Reduces Cardiovascular Risk in Patients with CKD Pharmacists are well positioned to identify patients with CKD, determine cardiovascular risk, and assist in disease management. 14 Focus on Transplantation Immediate-Release versus Extended-Release Tacrolimus in African Americans Results from an open-label, prospective randomized, 2-sequence, 3-period crossover, pharmacogenetics study. 21 PLUS... From the Field Tips for Contract Negotiations Payer contract terms that providers should avoid. 34 Health Insurance Status Affects Dialysis Modality Choice Each year, approximately 60,000 individuals <65 years of age develop end-stage renal disease (ESRD), requiring treatment with dialysis or kidney transplantation. Many patients are uninsured or covered by state-sponsored Medicaid at the onset of ESRD. While patients who are uninsured or covered by Medicaid may experience limited access to healthcare, access to dialysis care is generally available. Federal law provides Medicare coverage to patients with ESRD regardless of age, and most patients with ESRD qualify for Medicare by the fourth month of dialysis therapy. Following confirmation of qualification for Medicare, most patients are accepted for treatment at dialysis facilities. Most patients receiving renal replacement therapy do not have access to a kidney donor and thus initiate either in-center hemodialysis or peritoneal dialysis; a third option at some centers is home dialysis. There are no data favoring outcomes with one modality over another; however, dialysis modality has a significant effect on a patient s quality of life and overall treatment satisfaction. Younger patients with limited insurance may be particularly interested in peritoneal dialysis, which eliminates the need to travel to a hemodialysis center at least three times per week. Peritoneal dialysis is also less costly than in-center hemodialysis and patients receiving peritoneal dialysis are more likely to continued on page 8 Policy Forum Perspective: Healthcare for Undocumented Immigrants with CKD Undocumented immigrants represent 3% of the population in the United States and 27% of the uninsured, despite passage of the Affordable Care Act (ACA) and expansion of state-based insurance coverage. There is a need for countries to re-examine policies regarding healthcare for noncitizens with chronic illnesses, including chronic kidney disease (CKD). The issue centers on the question of providing equal access to healthcare for all persons within a country s border, regardless of immigration status. continued on page 6 Location and Use of Vascular Access Models Vary Widely by International Region A functional vascular access is crucial to the successful delivery of maintenance hemodialysis therapy. National organizations agree that a well-functioning arteriovenous (AV) fistula (AVF) is the preferred access for patients on hemodialysis, while also agreeing that vascular access should be tailored to an individual patient s health status and other considerations. DOPPS (Dialysis Outcomes and Practice Patterns Study), an international prospective cohort study of hemodialysis practices and patient outcomes, has been ongoing since In each participating country, patients 18 years of age and hemodialysis facilities are randomly selected to be representative of all hemodialysis patients and facilities. There were variations in outcomes from DOPPS phase 5 ( ) across 21 countries. Use of an AVF varied from 49% to 92%, use of an AV graft (AVG) varied from 2% to 18%, and use of a central venous catheter varied from 2% to 49%. There were also differences in survival of AVFs following successful first use (cumulative functional survival) across the three continental DOPPS regions; Japan reported longer AVF survival than Europe, Australia, New Zealand (Europe/ ANZ), and North America. Both dialysis and practitioner practices may affect AVF survival. In light of these international variations in vascular access type as well as continued on page 7

2 Only one calcimimetic lowers and maintains key shpt lab values with IV administration you control 1 Not an actual Parsabiv vial. The displayed vial is for illustrative purposes only. Indication Parsabiv (etelcalcetide) is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis. Limitations of Use: Parsabiv has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with CKD who are not on hemodialysis and is not recommended for use in these populations. Important Safety Information Contraindication: Parsabiv is contraindicated in patients with known hypersensitivity to etelcalcetide or any of its excipients. Hypersensitivity reactions, including pruritic rash, urticaria, and face edema, have occurred. Hypocalcemia: Parsabiv lowers serum calcium and can lead to hypocalcemia, sometimes severe. Significant lowering of serum calcium can cause QT interval prolongation and ventricular arrhythmia. Patients with conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to Parsabiv. Closely monitor corrected serum calcium and QT interval in patients at risk on Parsabiv. Significant reductions in corrected serum calcium may lower the threshold for seizures. Patients with a history of seizure disorder may be at increased risk for seizures if they develop hypocalcemia due to Parsabiv. Monitor corrected serum calcium in patients with seizure disorders on Parsabiv. Concurrent administration of Parsabiv with another oral calcimimetic could result in severe, life-threatening hypocalcemia. Patients switching from cinacalcet to Parsabiv should discontinue cinacalcet for at least 7 days prior to initiating Parsabiv. Closely monitor corrected serum calcium in patients receiving Parsabiv and concomitant therapies known to lower serum calcium. Measure corrected serum calcium prior to initiation of Parsabiv. Do not initiate in patients if the corrected serum calcium is less than the lower limit of normal. Monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment with Parsabiv. Measure PTH 4 weeks after initiation or dose adjustment of Parsabiv. Once the maintenance dose has been established, measure PTH per clinical practice. Worsening Heart Failure: In Parsabiv clinical studies, cases of hypotension, congestive heart failure, and decreased myocardial performance have been reported. Closely monitor patients treated with Parsabiv for worsening signs and symptoms of heart failure. Upper Gastrointestinal Bleeding: In clinical studies, 2 patients treated with Parsabiv in 1253 patient years of exposure had upper gastrointestinal (GI) bleeding at the time of death. The exact cause of GI bleeding in these patients is unknown and there were too few cases to determine whether these cases were related to Parsabiv. Patients with risk factors for upper GI bleeding, such as known gastritis, esophagitis, ulcers or severe vomiting, may be at increased risk for GI bleeding with Parsabiv. Monitor patients for worsening of common Parsabiv GI adverse reactions and for signs and symptoms of GI bleeding and ulcerations during Parsabiv therapy. Adynamic Bone: Adynamic bone may develop if PTH levels are chronically suppressed. Adverse Reactions: In clinical trials of patients with secondary HPT comparing Parsabiv to placebo, the most common adverse reactions were blood calcium decreased (64% vs. 10%), muscle spasms (12% vs. 7%), diarrhea (11% vs. 9%), nausea (11% vs. 6%), vomiting (9% vs. 5%), headache (8% vs. 6%), hypocalcemia (7% vs. 0.2%), and paresthesia (6% vs. 1%). Please see Brief Summary of full Prescribing Information on adjacent page. IV = intravenous; shpt = secondary hyperparathyroidism; PTH = parathyroid hormone; P = phosphate; cca = corrected calcium. Reference: 1. Parsabiv (etelcalcetide) prescribing information, Amgen Amgen Inc. All rights reserved. Not for Reproduction. USA Visit ParsabivHCP.com for more information.

3 BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE PARSABIV is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis. Limitations of Use: PARSABIV has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with chronic kidney disease who are not on hemodialysis and is not recommended for use in these populations. CONTRAINDICATIONS Hypersensitivity PARSABIV is contraindicated in patients with known hypersensitivity to etelcalcetide or any of its excipients. Hypersensitivity reactions, including pruritic rash, urticaria, and face edema, have occurred with PARSABIV [see Adverse Reactions (6.1) in PARSABIV full prescribing information]. WARNINGS AND PRECAUTIONS Hypocalcemia PARSABIV lowers serum calcium [see Adverse Reactions (6.1) in PARSABIV full prescribing information] and can lead to hypocalcemia, sometimes severe. Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, seizures, QT interval prolongation, and ventricular arrhythmia. QT Interval Prolongation and Ventricular Arrhythmia In the combined placebo-controlled studies, more patients treated with PARSABIV experienced a maximum increase from baseline of greater than 60 msec in the QTcF interval (0% placebo versus 1.2% PARSABIV). In these studies, the incidence of a maximum post-baseline predialysis QTcF > 500 msec in the placebo and PARSABIV groups was 1.9% and 4.8%, respectively [see Adverse Reactions (6.1) in PARSABIV full prescribing information]. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to PARSABIV. Closely monitor corrected serum calcium and QT interval in patients at risk receiving PARSABIV. Seizures Significant reductions in corrected serum calcium may lower the threshold for seizures. Patients with a history of seizure disorder may be at increased risk for seizures if they develop hypocalcemia due to PARSABIV. Monitor corrected serum calcium in patients with seizure disorders receiving PARSABIV. Concurrent administration of PARSABIV with another oral calcium-sensing receptor agonist could result in severe, life-threatening hypocalcemia. Patients switching from cinacalcet to PARSABIV should discontinue cinacalcet for at least 7 days prior to initiating PARSABIV [see Dosage and Administration (2.4) in PARSABIV full prescribing information]. Closely monitor corrected serum calcium in patients receiving PARSABIV and concomitant therapies known to lower serum calcium. Measure corrected serum calcium prior to initiation of PARSABIV. Do not initiate in patients if the corrected serum calcium is less than the lower limit of normal. Monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment with PARSABIV [see Dosage and Administration (2.2) in PARSABIV full prescribing information]. Educate patients on the symptoms of hypocalcemia, and advise them to contact a healthcare provider if they occur. If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration). PARSABIV dose reduction or discontinuation of PARSABIV may be necessary [see Dosage and Administration (2.2) in PARSABIV full prescribing information]. Worsening Heart Failure In clinical studies with PARSABIV, cases of hypotension, congestive heart failure, and decreased myocardial performance have been reported. In clinical studies, heart failure requiring hospitalization occurred in 2% of PARSABIV-treated patients and 1% of placebo-treated patients. Reductions in corrected serum calcium may be associated with congestive heart failure, however, a causal relationship to PARSABIV could not be completely excluded. Closely monitor patients treated with PARSABIV for worsening signs and symptoms of heart failure. Upper Gastrointestinal Bleeding In clinical studies, two patients treated with PARSABIV in 1253 patient-years of exposure had upper gastrointestinal (GI) bleeding noted at the time of death while no patient in the control groups in 384 patient-years of exposure had upper GI bleeding noted at the time of death. The exact cause of GI bleeding in these patients is unknown, and there were too few cases to determine whether these cases were related to PARSABIV. Patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers, or severe vomiting) may be at increased risk for GI bleeding while receiving PARSABIV treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with PARSABIV [see Adverse Reactions (6.1) in PARSABIV full prescribing information] and for signs and symptoms of GI bleeding and ulcerations during PARSABIV therapy. Promptly evaluate and treat any suspected GI bleeding. Adynamic Bone Adynamic bone may develop if PTH levels are chronically suppressed. If PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or PARSABIV should be reduced or therapy discontinued. After discontinuation, resume therapy at a lower dose to maintain PTH levels in the target range [see Dosage and Administration (2.1) in PARSABIV full prescribing information]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hypocalcemia [see Warnings and Precautions (5.1) in PARSABIV full prescribing information] Worsening Heart Failure [see Warnings and Precautions (5.2) in PARSABIV full prescribing information] Upper Gastrointestinal Bleeding [see Warnings and Precautions (5.3) in PARSABIV full prescribing information] Adynamic Bone [see Warnings and Precautions (5.4) in PARSABIV full prescribing information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in Table 2 are derived from two placebo-controlled clinical studies in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. The data reflect exposure of 503 patients to PARSABIV with a mean duration of exposure to PARSABIV of 23.6 weeks. The mean age of patients was approximately 58 years, and 60% of the patients were male. Of the total patients, 67% were Caucasian, 28% were Black or African American, 2.6% were Asian, 1.2% were Native Hawaiian or Other Pacific Islander, and 1.6% were categorized as Other. Table 2 shows common adverse reactions associated with the use of PARSABIV in the pool of placebo-controlled studies. These adverse reactions occurred more commonly on PARSABIV than on placebo and were reported in at least 5% of patients treated with PARSABIV. Table 2: Adverse Reactions Reported in 5% of PARSABIV-Treated Patients Adverse Reaction* Placebo (N = 513) PARSABIV (N = 503) Blood calcium decreased a 10% 64% Muscle spasms 7% 12% Diarrhea 9% 11% Nausea 6% 11% Vomiting 5% 9% Headache 6% 8% Hypocalcemia b 0.2% 7% Paresthesia c 1% 6% * Included adverse reactions reported with at least 1% greater incidence in the PARSABIV group compared to the placebo group a Asymptomatic reductions in calcium below 7.5 mg/dl or clinically significant asymptomatic reductions in corrected serum calcium between 7.5 and < 8.3 mg/dl (that required medical management) b Symptomatic reductions in corrected serum calcium < 8.3 mg/dl c Paresthesia includes preferred terms of paresthesia and hypoesthesia

4 Other adverse reactions associated with the use of PARSABIV but reported in < 5% of patients in the PARSABIV group in the two placebo-controlled clinical studies were: Hyperkalemia: 3% and 4% for placebo and PARSABIV, respectively. Hospitalization for Heart Failure: 1% and 2% for placebo and PARSABIV, respectively. Myalgia: 0.2% and 2% for placebo and PARSABIV, respectively. Hypophosphatemia: 0.2% and 1% for placebo and PARSABIV, respectively. Description of Selected Adverse Reactions Hypocalcemia In the combined placebo-controlled studies, a higher proportion of patients on PARSABIV developed at least one corrected serum calcium value below 7.0 mg/dl (7.6% PARSABIV, 3.1% placebo), below 7.5 mg/dl (27% PARSABIV, 5.5% placebo), and below 8.3 mg/dl (79% PARSABIV, 19% placebo). In the combined placebocontrolled studies, 1% of patients in the PARSABIV group and 0% of patients in the placebo group discontinued treatment due to an adverse reaction attributed to a low corrected serum calcium. Hypophosphatemia In the combined placebo-controlled studies, 18% of patients treated with PARSABIV and 8.2% of patients treated with placebo had at least one measured phosphorus level below the lower normal limit (i.e., 2.2 mg/dl). QTc Interval Prolongation Secondary to Hypocalcemia In the combined placebo-controlled studies, more patients treated with PARSABIV experienced a maximum increase from baseline of greater than 60 msec in the QTcF interval (0% placebo versus 1.2% PARSABIV). The patient incidence of maximum post-baseline predialysis QTcF > 500 msec in the placebo and PARSABIV groups was 1.9% and 4.8%, respectively. Hypersensitivity In the combined placebo-controlled studies, the subject incidence of adverse reactions potentially related to hypersensitivity was 4.4% in the PARSABIV group and 3.7% in the placebo group. Hypersensitivity reactions in the PARSABIV group were pruritic rash, urticaria, and face edema. Immunogenicity As with all peptide therapeutics, there is potential for immunogenicity. The detection of anti-drug binding antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to etelcalcetide with the incidence of antibodies to other products may be misleading. In clinical studies, 7.1% (71 out of 995) of patients with secondary hyperparathyroidism treated with PARSABIV for up to 6 months tested positive for binding anti-etelcalcetide antibodies. Fifty-seven out of 71 had pre-existing anti-etelcalcetide antibodies. No evidence of altered pharmacokinetic profile, clinical response, or safety profile was associated with pre-existing or developing anti-etelcalcetide antibodies. If formation of anti-etelcalcetide binding antibodies with a clinically significant effect is suspected, contact Amgen at AMGEN ( ) to discuss antibody testing. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no available data on the use of PARSABIV in pregnant women. In animal reproduction studies, effects were seen at doses associated with maternal toxicity that included hypocalcemia. In a pre- and post-natal study in rats administered etelcalcetide during organogenesis through delivery and weaning, there was a slight increase in perinatal pup mortality, delay in parturition, and transient effects on pup growth at exposures 1.8 times the human exposure for the clinical dose of 15 mg three times per week. There was no effect on sexual maturation, neurobehavioral, or reproductive function in the rat offspring. In embryo-fetal studies, when rats and rabbits were administered etelcalcetide during organogenesis, reduced fetal growth was observed at exposures 2.7 and 7 times exposures for the clinical dose, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data There were no effects on embryo-fetal development in Sprague-Dawley rats when etelcalcetide was dosed at 0.75, 1.5, and 3 mg/kg/day by the intravenous route during organogenesis (pre-mating to gestation day 17) at exposures up to 1.8 times human exposures at the clinical dose of 15 mg three times per week based on AUC. No effects on embryo-fetal development were observed in New Zealand White rabbits at doses of etelcalcetide of 0.375, 0.75, and 1.5 mg/kg by the intravenous route (gestation day 7 to 19), representing up to 4.3 times human exposures based on AUC. In separate studies at higher doses of 4.5 mg/kg in rats (gestation days 6 to 17) and 2.25 mg/kg in rabbits (gestation days 7 to 20), representing 2.7 and 7 fold clinical exposures, respectively, there was reduced fetal growth associated with maternal toxicities of hypocalcemia, tremoring, and reductions in body weight and food consumption. In a pre- and post-natal development study in Sprague-Dawley rats administered etelcalcetide at 0.75, 1.5, and 3 mg/kg/day by the intravenous route (gestation day 7 to lactation day 20), there was a slight increase in perinatal pup mortality, delay in parturition, and transient reductions in post-natal growth at 3 mg/kg/day (representing 1.8-fold human exposures at the clinical dose of 15 mg three times per week based on AUC), associated with maternal toxicities of hypocalcemia, tremoring, and reductions in body weight and food consumption. There were no effects on sexual maturation, neurobehavioral, or reproductive function at up to 3 mg/kg/day, representing exposures up to 1.8-fold human exposure based on AUC. Lactation Risk Summary There are no data regarding the presence of PARSABIV in human milk or effects on the breastfed infant or on milk production. Studies in rats showed [ 14 C]-etelcalcetide was present in the milk at concentrations similar to plasma. Because of the potential for PARSABIV to cause adverse effects in breastfed infants including hypocalcemia, advise women that use of PARSABIV is not recommended while breastfeeding. Data Presence in milk was assessed following a single intravenous dose of [ 14 C]- etelcalcetide in lactating rats at maternal exposures similar to the exposure at the human clinical dose of 15 mg three times per week. [ 14 C]-etelcalcetide-derived radioactivity was present in milk at levels similar to plasma. Pediatric Use The safety and efficacy of PARSABIV have not been established in pediatric patients. Geriatric Use Of the 503 patients in placebo-controlled studies who received PARSABIV, 177 patients (35.2%) were 65 years old and 72 patients (14%) were 75 years old. No clinically significant differences in safety or efficacy were observed between patients 65 years and younger patients ( 18 and < 65 years old). No differences in plasma concentrations of etelcalcetide were observed between patients 65 years and younger patients ( 18 and < 65 years old). OVERDOSAGE There is no clinical experience with PARSABIV overdosage. Overdosage of PARSABIV may lead to hypocalcemia with or without clinical symptoms and may require treatment. Although PARSABIV is cleared by dialysis, hemodialysis has not been studied as a treatment for PARSABIV overdosage. In the event of overdosage, corrected serum calcium should be checked and patients should be monitored for symptoms of hypocalcemia, and appropriate measures should be taken [see Warnings and Precautions (5.1) in PARSABIV full prescribing information]. PARSABIV (etelcalcetide) Manufactured for: KAI Pharmaceuticals, Inc., a wholly owned subsidiary of Amgen, Inc. One Amgen Center Drive Thousand Oaks, California Patent: Amgen, Inc. All rights reserved.

5 From the Board Contrast This! Kenneth A. Liss, DO Hypertension and Nephrology Associates EATONTOWN, NEW JERSEY Just when I think I am going to contribute to academe and scribe something about the latest nephrologic innovation or controversy, something in real life brings me to my senses and I have to vent. The latest 3 am phone call from an even more exhausted sounding surgical resident was the impetus this time. Apparently, the local neighborhood skin popper had run out of IV sites to satisfy his cravings. This unseemly behavior brought him to the emergency department (ED) with a rather foul smelling and deeply seeded wound. Doing their due diligence, the ED ran some routine laboratory studies and found that the patient had a serum creatinine of 3.4 mgs/dl. This was confirmed to be a chronic value for at least the past 18 months prior. Being concerned about the possible diagnosis of necrotizing fasciitis and wanting to eschew iodinated contrast, the surgical resident wisely decided to order an MRI study with gadolinium. This brings me to my part in the story. The surgical resident apologized for having to call me but was informed by the department head in radiology that the gadolinium would only be administered if renal gave its blessing. The last time I checked I was not ordained to approve or disapprove of anything. I can make recommendations, but I am not the final arbiter of any medical test or procedure. I am also not a surgeon, but I know that necrotizing fasciitis carries with it tremendously high morbidity and mortality. I am compensated to be concerned about the nephrologic ramifications of contrast agents, but with the exception of anaphylaxis they rarely are lethal. Granted iodinated contrast administered to a volume depleted, septic patient with a GFR of <25 has significant renal risk, but in this immediate case, the risk of not making the proper diagnosis paled in comparison with the contrast risk. More germane, however, was the risk of gadolinium administration in this setting I am not the final arbiter of any medical test or procedure. I am also not a surgeon, but I know that necrotizing fasciitis carries with it tremendously high morbidity and mortality. compared with leaving this potentially fatal disease inappropriately managed. The Yale Registry of reported nephrogenic systemic fibrosis (NSF) cases continues to demonstrate that, although this disease is real and often quite dangerous, it remains exceedingly rare. 1 I will even concede that the onset of this disease likely parallels the use of gadolinium as a medical contrast agent and that the incidence has decreased markedly since our knowledge of gadolinium as a causative agent has grown. 2 Physicians need tools such as chemotherapy, antihypertensives, anti-glycemics, robotic prostatectomies, and renal replacement therapy in order to help our patients. Let s all agree that adriamycin, renal transplantation, renin angiotensin system blocking agents, and even metformin have all been associated with significant patient morbidity and even mortality but I never get awakened at 3 am to give consent to use them. While I advocate continued research to find safer contrast agents, less dangerous chemotherapeutic drugs, more precise surgical techniques, and drugs that are not associated with lactic acidosis, I would never advocate eliminating what is currently a crucial part of our medical therapeutic armamentarium. Until such time that the need for gadolinium has become obsolete, I encourage our radiologic colleagues to formulate a substantive position paper recognizing that the potential benefit of gadolinium, even in patients at risk for NSF, generally outweighs the risk of this rare condition. REFERENCES 1. The International center for Nephrogenic Fibrosing Dermopathy Research Igreja ACdSM, Mesquita KdC, Cowper SE, Costa IMC. Nephrogenic systemic fibrosis: concepts and perspective. An Bras Dermatol. 2012; 87(4): EDITORIAL BOARD CHAIR BOARD Ajay K. Singh, MBBS, MBA Senior Nephrologist Brigham and Women s Hospital Associate Professor of Medicine Harvard Medical School BOSTON, MASSACHUSETTS Mohamed G. Atta, MD, MPH Associate Professor of Medicine Johns Hopkins School of Medicine Division of Nephrology BALTIMORE, MARYLAND Vinod K. Bansal MD, FACP, FASN Professor of Medicine Division of Nephrology and Hypertension Loyola University Medical Center MAYWOOD, ILLINOIS Timothy E. Bunchman, MD Professor & Director Pediatric Nephrology Children s Hospital of Richmond VCU School of Medicine RICHMOND, VIRGINIA Suphamai Bunnapradist, MD, MS Professor of Medicine David Geffen School of Medicine at UCLA Research Director Kidney Transplant Program, UCLA LOS ANGELES, CALIFORNIA Fernando C. Fervenza, MD, PhD Professor of Medicine Division of Nephrology & Hypertension Mayo Clinic ROCHESTER, MINNESOTA Kenneth A. Liss, DO Hypertension and Nephrology Associates EATONTOWN, NEW JERSEY Sayeed K Malek, MD, FACS Clinical Director of Transplant Surgery Brigham and Women s Hospital Instructor in Surgery Harvard Medical School BOSTON, MASSACHUSETTS Alan Salama, MBBS, PhD Reader in Nephrology University College London LONDON, UNITED KINGDOM Lynda A. Szczech, MD, MSCE Associate Professor of Medicine Division of Nephrology Duke University Medical Center DURHAM, NORTH CAROLINA Nephrology Times May/June

6 News TAKEAWAY POINTS Two US national agendas are at the core of the discussion regarding care for undocumented immigrants with chronic kidney disease (CKD): immigration and healthcare. In the face of no uniform national policy, an estimated 30% to 50% of undocumented immigrants with CKD receive treatment only in life-threatening situations (emergent hemodialysis). The rate of kidney transplantation in this patient population is very low due to insurance barriers, a shortage of deceased donors, and the political climate surrounding access to healthcare. Policy Forum Perspective continued from page 1 In the United States, policies for provision of care for undocumented immigrants with kidney failure vary from state to state, resulting in increased costs for hospital systems, reduced quality of life for patients, and frequent ethical dilemmas for clinicians regarding which patients should receive dialysis. Global variation in the care accessible to migrants, refugees, undocumented immigrants, and asylum seekers argues for the need for a framework to transform advocacy into public policy to improve the lives of patients with kidney disease worldwide. Access to non-emergent dialysis is humane and cost effective; it deserves to be espoused and advocated by leading medical organizations. There have been two previous reviews of the care of undocumented immigrants dependent on dialysis. In a recent issue of the American Journal of Kidney Diseases [2-18;71)4): ], Rajeev Raghavan, MD, provides an update to those reviews, discusses changes in US policy, examines global patterns of kidney care for noncitizens, and offers an approach for documentation and improvement in the care of individuals in this patient population. In 2014, the states with the highest proportion of undocumented immigrants were California (20.9%), Texas (14.7%), Florida (7.5%), New York (6.9%), New Jersey (4.4%), and Illinois (4.0%). The percentage of Mexicans in the US undocumented immigrant population has decreased since 2007, while immigration from Central America has increased. Basic healthcare is available to undocumented uninsured patients at federally qualified health centers or safety net hospitals; care is provided at those centers without regard to citizenship status or ability to pay. The centers may provide culturally oriented care as well as local bilingual staff to overcome common barriers; building trust with the healthcare system is important in undocumented immigrants who are fearful of apprehension and deportation. In the absence of registries or databases, it is not possible to calculate the number of undocumented immigrants with kidney failure. Using the US Renal Data System incidence rate of end-stage renal disease among Hispanics (515 per million) puts the figure at 6500 individuals. There are also few data on the causes of kidney disease in this population; available descriptive analyses suggest that these patients are younger, male, and nondiabetic, and present with small atrophic kidneys. The 1972 End-Stage Renal Disease Amendment to the Social Security Act (Public Law ) provided access to dialysis and transplantation for nearly all citizens. Because undocumented immigrants do not qualify for Medicare, there is a patchwork of options among as well as within states. Approximately 30% of undocumented immigrants who have chronic kidney failure receive emergent hemodialysis only in the presence of life-threatening laboratory abnormalities and volume overload. Patients receiving emergent hemodialysis represent large costs to local healthcare systems: approximately $285,000 per person per year in Houston, Texas, and more than $400,000 per person per year in Denver, Colorado. State (Medicaid) and local funding provide resources for patients receiving emergent hemodialysis. In Houston, 50% of undocumented immigrants receive treatment at an outpatient center funded with city taxes. In California, undocumented immigrants who require dialysis are granted Permanent Residence Under Color of Law (PRUCOL) status, a category created by the US Court of Appeals for the Second Circuit entitling undocumented immigrants residing in the United States with benefits under the Medicaid program. PRUCOL is not an immigration status recognized by the US government. Since 2014, following inception of the ACA, more than 200 undocumented immigrants dependent on dialysis in Texas and Illinois have been able to purchase off-exchange plans covering thrice-weekly dialysis in outpatient clinics. The plans are upheld by one insurance company, they do not require a social security number, and the premium is funded by a third-party payer. The sustainability of this program is in question in light of efforts to repeal, replace, or weaken the ACA. Opponents believe the plan will encourage illegal immigration; however, in California, a state with the largest undocumented immigrant population in the United States and a provision that covers nonemergent dialysis, there has been no significant increase in the population of undocumented immigrants since Insurance barriers and a shortage of deceased organ donors contribute to the low incidence of transplantation in this patient population in spite of being younger, Rajeev Raghavan, MD, FASN having a lower incidence of cardiovascular disease or diabetes, having a desire to keep working, and at least 60% having a potential donor. Living kidney donor transplantation for young undocumented immigrants with no major comorbid conditions has financial benefits to the patients as well as to society. Other benefits include increased life expectancy, the ability to return to work, potential growth of the donor pool, and an alternative to dialysis saves healthcare costs. Only 400 undocumented immigrants underwent kidney transplantation between 1990 and 2011; >70% of those were in California and from living donors. Illinois became the first state to pass legislation in 2014 to allow undocumented immigrants to be listed for kidney transplantation. In 2016, despite some opposition and defunding by the state government, approximately 50 patients underwent transplantation in Illinois. The Gift of Hope, a nonprofit organization, provided funding for posttransplant medication. In some states, including California and Texas, undocumented immigrants with chronic kidney failure have the option of peritoneal dialysis, which is more cost-effective than in-center hemodialysis. However, the need for infrastructure (nephrology nurse and supplies) and the lack of space to store supplies create barriers for safety-net hospitals to offer peritoneal dialysis to this patient population. Currently, there are 39 cities, 364 counties, and four states in the United States that have statutes limiting routine reporting of documentation status of individuals seeking police or health services. The current administration has initiated steps to eliminate sanctuary status, creating the possibility that hospitals and physicians would be made to act as immigration enforcement personnel. The permanent rescinding of DACA (Deferred Action for Childhood Arrivals) would also affect the care of undocumented immigrants. In the review s conclusion, Dr. Raghavan said, Nephrologists provide a life-saving intervention to dialysis-dependent undocumented immigrants, an undertaking fraught with ethical dilemmas, political undertones, and variable barriers. Despite high employment rates, undocumented immigrants face an array of cultural, linguistic, economic, and legal barriers to equitable healthcare. As countries wrestle with immigration and healthcare reform, the prospects for a uniform solution to provide comprehensive care for this population seem bleak. Continued directed research in this field along with adoption of a uniform position statement by representative organizations are key steps of advocacy that would send a worldwide message of equitable care for all community members residing within any border. 6 Nephrology Times May/June 2018

7 News PUBLISHER Gene Conselyea NEPHROLOGY TIMES STAFF EDITORIAL MANAGING EDITOR Victoria Socha EDITOR AT LARGE Eric Raible DIGITAL PROJECTS MANAGER Chris Gedikli ART DIRECTOR Ari Mihos ASSISTANT ART DIRECTOR John Salesi ADVERTISING ACCOUNT MANAGERS Jane Liss Jen Callow Recruitment advertising orders can be sent to: DIRECTOR, RECRUITMENT CLASSIFIEDS Lauren Morgan 630 Madison Avenue Manalapan, NJ Nephrology Times (ISSN ) is published monthly by American Medical Communications, at Madison Avenue, Manalapan, NJ Printed in the U.S.A. Copyright 2018 by American Medical Communications. Subscription information and orders: Physicians who are listed with AMA/AOA as having a primary or secondary specialty related to nephrology within the US are eligible for a free subscription. If you are not currently receiving the publication, send an with your name, address, and specialty to Tori Socha at: tsocha@ americanmedicalcomm.com. For customer service on your free subscription, please call Annual subscription rates: US: $99 individual, $200 institution. Postmaster: Send address change to: Nephrology Times, 630 Madison Avenue, 2nd Floor, Manalapan, NJ No part of this publication may be reproduced without the written permission of the publisher. The appearance of advertising in Nephrology Times does not constitute on the part of American Medical Communications a guarantee of endorsement of the quality or value of the advertised product or services or of the claims made for them by their advertisers. Location and Use of Vascular Access Models continued from page 1 outcomes, Ronald L. Pisoni, PhD, MS, and colleagues conducted an analysis designed to examine international differences in (1) AVF creation location, i.e., upper versus lower arm; (2) trends in AVF location from DOPPS phases 1 to 5; and (3) successful use of newly created AVFs and AVGs (together referred to as AV accesses ). Results of the analysis were reported in the American Journal of Kidney Diseases [2018;71(4): ]. Individuals participating in DOPPS and included in the current analysis were from the United States, Japan, and Europe/ANZ [Belgium, France, Germany, Italy, Spain, Sweden, United Kingdom, Australia, and New Zealand]. Of the participants, 3850 received 4247 new AVFs and 842 received 1129 new AVGs in the period 2009 to Location trends for AVFs were calculated based on 38,868 AVFs recorded in cross-sections from DOPPS phases 1 to 5 ( ). In DOPPS phases 1 to 5, >96% of all AVFs were located in an upper-extremity location. There were substantial international differences in the location of arm AVFs: in Japan, 93% were in the lower arm (DOPPS phases 1 to 5); in Europe/ANZ, 77% were in the lower arm (DOPPS phases 1 to 2, declining to ~65% in DOPPS phases 4 to 5); in the United States, 70% were in the lower arm in DOPPS phase 1 while only 32% were in the lower arm in DOPPS phase 5. When the analysis was restricted to patients of dialysis vintage <90 days, similar international trends were seen. Facility variation in percentage of lowerarm AVFs in DOPPS phases 4 to 5 indicated a tight distribution within Japan, with 95% of AVFs in the lower arm in the median facility; broad variation across facilities in the 11 Europe/ANZ countries, with 67% of arm AVFs located in the lower arm in the median facility; and large variation across facilities in the United States, with 38% of arm AVFs located in the lower arm in the median facility. Additional aspects of location placement of AV access were examined in DOPPS phases 4 and 5; most patients (86%) contributed only one AV access to those analyses. Lower-arm location among AVFs was highest in Japan (89%), compared with 60% in Europe/ANZ, and 34% in the United States. The lower figure in the United States was seen despite US patients having the lowest mean age. US patients had the highest prevalence of diabetes, and there was little difference among patients in the United States having lower- versus upperarm AVF placement. In DOPPS phases 4 to 5, 12% to 13% of all created AV access in Europe/ANZ and Japan was AVGs, compared with 25% in the United States. Compared with patients with a newly created AVF, those with a newly created AVG had longer median dialysis vintage and lower percentage of males in all three regions; mean age was slightly older in the United States and Europe/ANZ, and higher in Japan. DOPPS phases 4 to 5 defined successful AV access use as a newly created AV access being used for 30 continuous days (for typical thrice-weekly hemodialysis) during follow-up. In analyses without follow-up time requirement beyond 30 days, successful AVF use was 87% in Japan, 67% in Europe/ANZ, and 64% in the United States. Results of a secondary calculation allowing AVFs to have up to 7 months after creation to demonstrate successful AVF use, the proportions of successful use were 89% in Japan, 76% in Europe/ANZ, and 77% in the United States. Successful use of AVGs created in DOPPS phases 4 and 5 were assessed in each international region. In analyses without time requirements, successful AVG use was 86% in Japan, 75% in Europe/ANZ, and 78% in the United States. In alternative calculations that allowed AVGs up to 3 months following creation to demonstrate successful use, the proportions of successful use were 89% in Japan, 78% in Europe/ANZ, and 83% in the United States. In Europe/ANZ and the United States, 3% to 6% of newly created AVGs failed within 30 days of first use. There was wide variation by international region in time until the first day of successful AVF use among newly created AVFs that were successfully used for 30 days in DOPPS phases 4 to 5: Japan, median of 10 days; Europe/ANZ, median of 46 days; and United States, median 82 days. Among newly created AVGs, median time until first day of successful AVG use was 6 days in Japan, 24 days in Europe/ANZ, and 29 days in the United States. A limitation to the analyses cited by the authors was dependence on accurate reporting of vascular access data from each study site. In conclusion, the authors said, Large international differences exist in the percentage of arm AVFs created in the lower arm, predictors of lower- versus upper-arm AVF location, successful use of newly created AVFs, and time to first use of newly created AVFs and AVGs. These findings, coupled with large differences in AVF survival across these international regions, raise important questions regarding what is best practice and how it is best achieved to optimize vascular access outcomes. Importantly, the large shift in predominantly lower- to upper-arm AVF creation in the United States, even in ideal young patients for AVF creation, raises the question of whether this practice shift may place patients at greater risk for exhausting available sites for future AVF creation when needed. This could have substantial health implications for patients and economic implications for healthcare systems. TAKEAWAY POINTS There is wide international variation in the use of arteriovenous fistulas (AVFs) and arteriovenous grafts (AVGs), and in maturation time and location for AVFs. Analyses of data from DOPPS (Dialysis Outcomes and Practice Patterns Study) included dialysis patients from 21 countries; 3850 patients who received new AVFs and 842 patients who received new AVGs in 2009 to The international variations seen in the analyses challenge what constitutes best practice, the researchers said. Nephrology Times May/June

8 News TAKEAWAY POINTS Researchers conducted a retrospective cohort analysis to examine whether health insurance limitations affected the use of peritoneal dialysis among patients initiating dialysis therapy. Patients with limited insurance (no insurance or Medicaid) were compared with patients with Medicare at onset of end-stage renal disease. Following adjustments, patients with limited insurance had a 2.4% lower probability of peritoneal dialysis use by the fourth month of dialysis compared with patients with Medicare coverage at dialysis initiation. Health Insurance Status continued from page 1 remain employed than those on in-center hemodialysis. Rates of peritoneal dialysis in the United States are lower than in other countries. Barriers to use of peritoneal dialysis included inadequate patient education and financial disincentives. In addition, peritoneal dialysis requires surgical placement of a peritoneal dialysis catheter prior to therapy initiation, making choosing peritoneal dialysis difficult for patients who are uninsured or covered by Medicaid. It is not known whether insurance status at ESRD onset influences choice of dialysis modality. Jose J. Perez, MD, and colleagues recently conducted a retrospective cohort analysis to examine whether use of peritoneal dialysis early in dialysis is affected by health insurance status and whether the effect of health insurance coverage changed following enactment of the ESRD Prospective Payment System (PPS) in Results of the analysis were reported in the American Journal of Kidney Diseases [2018;71(4): ]. The researchers utilized data from the US Renal Data System registry to select patients with incident ESRD who initiated in-center hemodialysis or peritoneal dialysis as their first modality in 2006 through Patients who died, recovered kidney function, or underwent kidney transplantation in the first 90 days of dialysis therapy were excluded. Patients were selected based on insurance criteria and age at initiation of dialysis therapy. Patients with limited insurance (i.e., uninsured or Medicaid only) were compared with patients with Medicare at onset of ESRD. Included patients with limited insurance were 60 to 64 years of age and entered Medicare s 90-day waiting period at ESRD onset. Included patients covered by Medicare at ESRD onset were 66 to 70 years of age. There were 18,346 patients in the study cohort; of those, 45% had limited insurance. By the fourth month of dialysis, 2.7% of patients with limited insurance used peritoneal dialysis, compared with 4.3% of patients with Medicare (P<.001). Compared with patients covered by Medicare, patients in the limited insurance cohort were less likely to have received nephrology care prior to initiation of dialysis, were less likely to be women, and were less likely to have coronary artery disease, heart failure, cerebrovascular disease, peripheral vascular disease, lung disease, and immobility. They also had lower concentrations of serum hemoglobin and were less likely to be white. There were 17,289 patients receiving in-center hemodialysis at the start of their fourth dialysis month; of those, 3.7% with limited insurance switched to peritoneal dialysis for the remainder of their first year of dialysis therapy, compared with 1.2% of patients with Medicare coverage at initiation of dialysis (P<.001). The analysis censored 23% and 33% of patients with limited insurance and Medicare, respectively, for death between days 90 and 365. The researchers also censored 0.6% and 0.3% of patients with limited insurance and Medicare, respectively, for kidney transplantation. Results of multivariable analyses showed that patients with limited insurance at ESRD onset were less likely to receive peritoneal dialysis by their fourth dialysis month, compared with patients with Medicare (odds ratio [OR], 0.48; 95% confidence interval [CI], ). This was an average predicted decrease of 2.4% (95% CI, 1.1%-3.7%) in the absolute adjusted probability of peritoneal use among patients with limited insurance. Following adjustment for differences in pre-esrd nephrology care, the results were only slightly changed (OR, 0.52; 95% CI, ). When patients acquired Medicare after the third month of dialysis, those with limited insurance at onset of ESRD were significantly more likely to switch to peritoneal dialysis (hazard ratio, 2.9; 95% CI, ). There were no substantial changes in those findings when analyses were conducted using patients first dialysis modality rather than dialysis modality at the start of the fourth dialysis month. Regression analysis that included post-pps interactions estimated that prior to enactment of the PPS, the odds of peritoneal use by the fourth dialysis month were 58% (95% CI, 37%- 72%) lower among patients with limited insurance compared with patients with Medicare coverage at dialysis initiation. Following enactment of the PPS, the magnitude of reduction in odds became less pronounced (38%; 95% CI, 4%-60%) (P for interaction=.03). The researchers cited some limitations to the study, including the observational design that created the possibility of selection bias, and the inability to use Medical Evidence Report to determine patient comorbid conditions. In summary, we found evidence that the use of peritoneal dialysis early in dialysis can be limited by insurance coverage that patients have when initiating dialysis therapy. Programs designed to educate physicians, patients, and other healthcare providers about home dialysis therapy and policies directed toward increasing patients access to providers involved in preparing patients for peritoneal dialysis therapy may give more patients the option to initiate peritoneal dialysis as their first kidney replacement modality. NKF Spring Clinical Meetings Female Sex Protective Mortality Related to AKI Austin Patients who experience acute kidney injury (AKI) are at increased risk for short- and long-term mortality. Results of previous studies have revealed a higher risk of mortality among males with AKI; female sex has been shown to be protective in both the development of AKI and the AKI-related mortality risk. The majority of those studies utilize univariate analyses, without consideration of the effects of confounding factors. In animal models of ischemic AKI, female sex has also been shown to be protective. Robert Adrah, MD, and Ladan Golestaneh, MD, conducted an analysis to test the hypothesis that female sex is protective against mortality related to AKI. They reported results of the analysis during a poster session at the NKF Spring Clinical Meetings in a poster titled Female Sex Protects against Mortality after an Episode of Acute Kidney Injury (AKI). The researchers utilized Montefiore s clinical database, Looking Glass, to define a cohort of all hospitalized patients from January 2009 to November 2011, and selected patients without chronic kidney disease with a >10% difference in estimated glomerular filtration rate (egfr) measured within the previous 6 months and upon admission. Community-acquired AKI was defined using the two egfr measurements according to criteria from the Acute Kidney Injury Network (AKIN). Bivariate analysis and log-rank testing were used to examine the associations between gender, community-acquired AKI, and 2-year mortality. The researchers examined the robustness of the association of gender and AKI-related mortality with Cox regression (stepwise forward selection). The total cohort included 19,571 patients. Of those, 33% had AKIN stage 1 AKI, 6.5% had AKIN stage 2 AKI, and 2.5% had AKIN stage 3 AKI. Compared with the men in the cohort, women in the cohort were older, more commonly black, had lower socioeconomic status, lower Charlson scores, and had lower length of stay during the index hospitalization. Women also tended to have less severe illness during hospitalization. Log-rank testing showed the association between female sex and mortality to be significant. The hazard ratio for mortality was 0.89 (95% confidence interval, ) for women compared with men. The strength of the protective effect of female sex on mortality was attenuated by the Charlson score and the severity of illness. In conclusion, the researchers said, In patients with community-acquired AKI, female gender was protective against mortality after an episode of AKI. Cox modeling showed that females have less severe disease with their diagnosis of community-acquired AKI, which explains some, but not all, of this protective effect, the researchers said. Source: Adrah R, Golestaneh L. Female sex protects against mortality after an episode of acute kidney injury (AKI). Abstract of a poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April 10-14, 2018, Austin, Texas. 8 Nephrology Times May/June 2018

9 Guest Contributor Breaking Down Barriers to Treatment Adherence for Dialysis Patients LaVarne A. Burton President and CEO, American Kidney Fund Living with kidney failure is incredibly challenging for patients and their loved ones. Dialysis is a complex, demanding process that requires individuals to stick closely to treatment for the best possible outcomes. Unfortunately, there are often unforeseen roadblocks standing in the way of adherence when adjusting to a rigorous new routine that requires a specific diet, critical medication, and intensive treatment. The risks posed by missed dialysis sessions are grave: nonadherence can lead to adverse health effects, hospitalization, and even death. Understanding why treatment regimens are so tough to follow and what makes it difficult for patients to stick with them are important first steps in helping patients with treatment self-management. Recently, the American Kidney Fund (AKF) released a new survey report that sheds light on the challenges kidney patients face in treating this chronic illness. Nearly 1200 dialysis patients and 400 renal professionals shared their experiences via the survey. Some of the key findings confirm what we already knew about treatment adherence; others caught us by surprise. Overall, we see clear patterns in lack of adherence related to age, mental health status, and communication between patients and providers. The findings are just a piece of the nonadherence puzzle to solve; it is important for the renal community to work together to address these issues at every stage of the care process so that we can help patients live fuller, more complete lives despite their diagnosis of kidney failure. The full survey report is available on AKF s website. YOUNGER PATIENTS ARE MORE LIKELY TO STRUGGLE WITH PRESCRIBED TREATMENT. Patients aged 18 to 39 reported lower adherence to nearly all treatment recommendations, including medication and diet regimens, compared with patients in any other age group. Many left dialysis sessions early and were more likely to skip sessions altogether. They also indicated feeling depressed nearly twice as often as older patients. Though living with kidney failure is difficult regardless of age, it is important that we consider tailored support for different age groups to meet their unique needs. DEPRESSION IS A LEADING CONTRIBUTING FACTOR TO TREATMENT NON- ADHERENCE REGARDLESS OF AGE. The National Institute of Mental Health classifies depression as a common but serious mood disorder that causes symptoms that can severely impact one s feelings, thoughts, sleep, appetite, employment, and participation in common daily activities. 1 More than 40% of survey respondents reported that depression, nervousness, or fear had held them back from required treatments in the previous month they were more likely to skip dialysis sessions and medication and were less likely to follow recommendations for fluid intake and exercise. Some patients who reported feelings of depression noted discomfort talking to their healthcare teams. It is clear there is a great need for better interventions, including screening, counseling, and treatment, to help patients manage depression. All of us in the renal community can use these insights to help address challenges patients encounter every day. That means increasing awareness of how patient moods, attitudes, and beliefs affect treatment and identifying ways to help address lifestyle changes and empower patients to become more fully invested in their treatment planning. Finding ways to adjust to a demanding dialysis schedule while still maintaining the things patients love and need to do requires support from family, friends, and caregivers. With careful planning to ensure dialysis sessions, medication, diet, and other key aspects of treatment are balanced, we can help patients prepare for and, ideally, avoid the depression, nervousness, and fear that can keep them from their treatments. AKF will continue to use the insights from this survey to provide the best possible support for patients with kidney disease. We have used these findings to develop programs, educational tools, and new materials that shed light on the treatment process and equip patients and providers with information they need to make confident care decisions. We should all keep these insights in mind as we continue to explore the questions posed by nonadherence. It is the responsibility of all of us within the renal community to help make positive changes in the lives of patients with kidney disease starting with encouragement and education around the importance of adherence to treatment so that patients are better able to lead fulfilling, balanced lives. REFERENCE Nephrology Times May/June

10 Conference Coverage NKF Spring Clinical Meetings Austin, Texas April 10-14, 2018 The National Kidney Foundation held its 2018 Spring Clinical Meetings in Austin, Texas, from April 10 to 14. We have selected a few posters and presentations to highlight here, as well as a recap of the 2018 awards recipients honored at the meeting. We will cover additional NKF posters in upcoming issues of Nephrology Times. 10 Nephrology Times May/June 2018

11 Patients May Only Partially Report Symptom Burden of Hemodialysis Austin, Texas Patients on maintenance dialysis experience substantial burden of symptoms that are associated with impaired quality of life. Symptom control is cited as a top research priority by patients, but results of previous studies suggest that providers may underestimate the burden on patients. Researchers at the University of North Carolina, Chapel Hill, led by Adeline Dorough, BS, conducted a qualitative study designed to characterize patient beliefs regarding hemodialysis-related symptoms and symptom reporting. The researchers utilized exploratory analyses to examine dialysis nurse and patient care technician (PCT) perspective on symptoms. Results of the current study were reported during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Perspectives on Hemodialysis-Related Symptoms and Symptom Reporting: A Qualitative Study. The study included 55 semi-structured interviews with 42 patients on maintenance hemodialysis and with 13 dialysis clinic nurses and PCTs from nine US states. Thematic analysis was used to identify themes and subthemes within the data and to develop an overall schema. The interviews with patients revealed a range of symptoms related to hemodialysis that included cramping, thirst, dizziness, nausea, and post-dialysis fatigue. The patient interviews yielded seven major themes: (1) symptoms engendering symptoms; (2) acceptance that life is dependent on a machine; (3) the intrusiveness of dialysis on daily life; (4) need to develop adaptive coping strategies; (5) creating a narrative of personal symptoms; (6) negotiating loss of control; and (7) dealing with the limits of the dialysis delivery system. The staff interviews yielded three major themes: (1) searching for explanations of symptoms; (2) accepting the limits of their roles; and (3) dealing with the limits of the dialysis delivery system. Patients felt they reported only partial symptom burden, while healthcare providers believed patient symptoms were fully reported. Patients indicated that perception of symptoms as normal was the underlying factor in tendencies not to fully disclose their symptoms. Our findings provide insight into challenges and uncertainties faced by many patients as they endure and balance interconnected, perpetuating dialysis-related symptoms with competing life priorities. Overall, patients expressed reluctance in unprompted symptom reporting and desired more engagement with their providers around symptoms, the researchers said. Source: Dorough A, Narendra J, Flythe J. Perspective on hemodialysis-related symptoms and symptom reporting: a qualitative study. Abstract of a poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April , Austin, Texas. Uromodulin Associated with Reduced Risk for Graft Failure Austin, Texas Andrew Bostom, MD, of the Center for Primary Care and Prevention, Memorial Hospital of Rhode Island, Pawtucket, recently conducted an analysis of longitudinal follow-up data from a study of 91 recipients of kidney transplantation. The analysis was designed to examine the association between baseline serum uromodulin and the development of graft failure. Uromodulin is a kidney-derived glycoprotein and putative tubular function index. During longitudinal follow-up of a previous study, higher levels of uromodulin were associated with reduced risk for graft failure. That study included 91 recipients of kidney transplantation. There were 13 graft failure events among the 91 patients. Using a case-cohort design, Dr. Bostom performed an analysis of data from the FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) trial to examine the association between baseline serum uromodulin and the development of graft failure. Results of the analysis were reported during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Higher Serum Uromodulin Levels Are Independently Associated with Lower Risk for Graft Failure in Chronic, Stable Kidney Transplant Recipients. FAVORIT included 613 chronic, stable kidney transplant recipients; the analysis included data on a random subcohort with mean baseline serum uromodulin level of 67.8 ng/ml (standard deviation, ± 39.7 ng/ml). During a median of 4.1 years of follow-up, there were 226 graft failure events among the 613 transplant recipients. In unadjusted, weighted Cox proportional hazards models, there was an association between each standard deviation higher (+39.7 ng/ml) of uromodulin and a 41% lower risk for graft failure. Following adjustment for age, sex, smoking status, graft type, graft vintage, systolic blood pressure, serum phosphorus, estimated glomerular filtration rate (mean 45.5 ml/min/1.73m 2 ), and natural log urinary albumin creatinine (mean, mcg/ml), the association was attenuated, but persisted at 21% (hazard ratio, 0.79; 95% confidence interval, ). Higher serum uromodulin, a possible indicator of better preserved renal tubular function, was independently associated with reduced risk for graft failure in a large, multiethnic cohort of chronic, stable kidney transplant recipients, Dr. Bostom said. Source: Bostom A. Higher serum uromodulin levels are independently associated with lower risk for graft failure in chronic, stable kidney transplant recipients. Abstract of a poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April 10-14, 2018, Austin, Texas. Higher serum uromodulin, a possible indicator of better preserved renal tubular function, was independenty associated with reduced risk for graft failure in a large, multiethnic cohort of chronic stable kidney transplant recipients. Andrew Bostom, MD Tolvaptan Reduced Renal-Pain Associated Costs in ADPKD Patients Austin, Texas Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic kidney disease characterized by enlargement of bilateral renal cysts leading to loss of renal function. The TEMPO 3:4 trial demonstrated the efficacy of tolvaptan, a selective vasopressin V2-receptor antagonist. TEMPO 3:4 was a randomized, placebo-controlled trial involving 1445 patients over 3 years. An analysis of prespecified end points showed a significant reduction in the occurrence of renal pain and a slowing in progression of chronic kidney disease with tolvaptan. Researchers led by Callum Shephard recently conducted a study designed to assess the impact of tolvaptan compared with placebo on costs associated with renal pain events and CKD progression. Study results were reported during a poster session at the NKF Spring Clinical Meetings 2018 in a poster titled Impact of Tolvaptan on Costs Associated with Renal Pain and Chronic Kidney Disease among Patients with Autosomal Dominant Polycystic Kidney Disease. The cost-consequence analysis included 1000 patients with ADPKD and was conducted from a payer perspective. Publicaly available sources were utilized to obtain resource use costs, including labor, diagnostic, and pain relief medications and procedures. Costs by CKD stage were gathered from Golestaneh Rates of renal pain events and related costs were stratified by pain severity. Renal pain costs were assessed on-treatment: during the 3-year trial study period. Due to the hemodynamic effect of tolvaptan on estimated glomerular filtration rate, costs related to CKD were assessed off-treatment: at baseline prior to treatment and at 2 weeks after treatment withdrawal. There was an association between tolvaptan and 90 fewer renal pain events over the 3 years. Resulting pain-events related costs were lower with tolvaptan compared with placebo ($98,147 vs $161,299). Baseline total monthly costs related to CKD management were similar between tolvaptan and placebo ($1,419,784 vs $1,406,842). At 2 weeks after tolvaptan withdrawal, the slower rate of CKD progression with tolvaptan was reflected in lower monthly CKD costs compared with placebo ($1,872,196 vs $2,052,792). In conclusion, the researchers said, This analysis showed tolvaptan use affects renal pain and CKD costs. Future studies should include the cost of tolvaptan to assess the overall cost impact of tolvaptan. Source: Shephard C, Delavelle C, Riemer J, et al. Impact of tolvaptan on costs associated with renal pain and chronic kidney disease among patients with autosomal dominant polycystic kidney disease. Abstract of a poster presented at the National Kidney Foundation Spring Clinical Meetings 2018, April 10-14, 2018, Austin, Texas. Nephrology Times May/June

12 Conference Coverage Austin, Texas April 10-14, 2018 Icosapent Ethyl Reduces Triglycerides in Patients with Reduced Kidney Function and Diabetes Austin, Texas The risk of chronic kidney disease (CKD) increases with the presence of reduced kidney function and diabetes mellitus. Vascepa (icosapent ethyl), a high-purity ethyl ester of the omerga-3 fatty acid, eicosapentaenoic acid (EPA), is approved at 4 g per day as an adjunct to diet aimed at reducing triglycerides in adults with triglyceride level 500 mg/dl. Harold M. Szerlip, MD, and colleagues conducted a post hoc analysis of data from the ANCHOR trial. The 12-week ANCHOR study included 702 randomized patients treated with statins who were at increased risk for cardiovascular disease with triglycerides 200 to 499 mg/dl despite control of lowdensity protein cholesterol (LDL-C) (40-99 mg/dl). Results of the ad hoc data analysis were reported during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Icosapent Ethyl Reduces Potentially Atherogenic Lipid and Inflammatory Markers in High-Risk Statin-Treated Patients with Persistent High Triglycerides, egfr <90 ml/min/1.73 m 2, and Diabetes Mellitus. The analysis examined data on ANCHOR patients with estimated glomerular filtration rate (egfr) <90 ml/ min/1.73 m 2 for 3 months and diabetes mellitus at baseline. The cohort was 56% male, 97% white; mean age was 63 years. Participants were randomized to receive 4 g per day icosapent ethyl (n=98) or placebo (n=100). Compared with placebo, icosapent ethyl 4 g per day reduced triglycerides by 19.7% (P<.0001) with no increase in LCL-C; other potentially atherogenic and inflammatory parameters were also significantly improved with icosapent ethyl versus placebo. At baseline, serum creatinine was 0.9 mg/dl, egfr was 75.4 ml/min/1.73 m 2, and albumin was 4.5 g/dl for patients receiving icosapent ethyl; corresponding values at 12 weeks were 0.9 mg/dl, 79.1 ml/min/1.73 m 2, and 4.5 g/dl, respectively (all % change vs placebo, P.05). Compared with placebo, eicosapentaenoic acid levels increased by 676.2% in plasma and by 611.7% in red cells (P<.0001) for both. In statin-treated patients with reduced kidney function and diabetes mellitus with persistent high triglycerides, icosapent ethyl 4 g per day reduced triglyceride level and other atherogenic and inflammatory markers without raising LDL-C versus placebo, the researchers said. Source: Szerlip HM, Vijayaraghavan K, Ballantyne CM, et al. Icosapent ethyl reduced potentially atherogenic lipid and inflammatory markers in high-risk statin-treated patients with persistent high triglycerides, egfr <90 ml/ min/1.73 m2, and diabetes mellitus. Abstract of a poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April 10-14, 2018, Austin, Texas. The analysis was sponsored by Amarin Pharma, Inc. Patiromer Shown Safe and Effective in Three Clinical Trials in Patients with Hyperkalemia Austin, Texas Valtessa (patiromer), a sodium free, nonbasorbed potassium binder, is approved for treatment of patients in the United States and the European Union with hyperkalemia. Matthew Weir, MD, and colleagues recently conducted an analysis to examine the consistency of lowering serum potassium in trials of patiromer for hyperkalemia. Results of the analysis were reported during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Consistency of Serum Potassium Effects in Patiromer Clinical Trials. The researchers conducted a pooled analysis of data from three phase 3 clinical trials: (1) AMETHYST- DN, OPAL-HK, and TOURMALINE. AMETHYST-DN was a 52-week, open label study; OPAL-KH was a 12-week, two-part, single-blind study with a 4-week treatment phase and an 8-week placebo-controlled randomized withdrawal phase; and TOURMALINE was a 4-week, open label study. Eligible patients in all three studies had baseline serum potassium >5.0 meq/l (as measured by local laboratory results); inclusion criteria for patients in AMETHYST-DN and OPAL-HK were estimated glomerular filtration rate 15 to 59 ml/min/1.73 m 2 and be taking one or more renin-aldosterone system (RAAS) inhibitors. Patients in AMETHYST-DN also had to have type 2 diabetes mellitus. Overall, participants were 62% male, 96% white, and mean age was 66 years; 96% had hypertension, 65% had chronic kidney disease (CKD) stage 3b or higher, and 42% had serum potassium 5.5 meq/l at baseline. Patients were randomized to potassium starting doses by baseline serum potassium level (8.4 g/d to 33.6 g/day in AMETHYST-DN; 8.4 g/d to 16.8 g/d in OPAL-HK) or to potassium dosing (8.4 g/d ± food in TOURMALINE). The poster reported results over the first 4 weeks of each study by baseline serum potassium level strata (<5.5 meq/l to 5.5 meq/l). Efficacy results were available for a total of 653 patients: AMETHYST-DN, 304; OPAL-HK, 237; Tourmaline, 112. Patients with mild hyperkalemia at baseline had serum potassium reduced to <5.0 meq/l by day 3. Patients with moderate-to-severe hyperkalemia ( 5.5 meq/l) had serum potassium reduced to <5.5 meq/l by week 1 or 2. Overall, 629 participants (96%) had serum potassium levels 3.5 meq/l to 5.0 meq/l during weeks 1 to 4. Thirty-two percent of participants (n=209) reported adverse events; the most common adverse events were constipation (6%) and diarrhea (3%). There were no severe adverse events. The rate of hypokalemia, defined as serum potassium level <3.5 meq/l, was 1.5%. In conclusion, the consistency of clinical effect of patiromer has been shown in three trials of the treatment of hyperkalemia, predominantly in participants with CKD and diabetes on RAAS inhibitor therapy, the researchers said. Vascapa Reduces Triglycerides in Patients with Reduced Kidney Function and Elevated hscrp Austin, Texas Patients with kidney disease and elevated high-sensitivity C-reactive protein (hscrp) are at increased risk for cardiovascular disease. Vascepa (icosapent ethyl), a high-purity ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid, is approved at 4 g per day as an adjunct to diet to reduce triglycerides in adults with triglyceride level 500 mg/dl. Krishnaswami Vijsyaraghavan, MD, and colleagues conducted an ad hoc analysis of data from the ANCHOR trial to assess participants with reduced kidney function, defined as estimated glomerular filtration rate <90 ml/min/1.73 m 2 for 3 months, and elevated hscrp 2.0 mg/l at baseline. Results of the analysis were reported during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Icosapent Ethyl Reduces Potentially Atherogenic Lipid and Inflammatory Markers in High-Risk Statin-Treated Patients with Persistent High Triglycerides, egfr <90 ml/min/1.73m 2, and Elevated High-Sensitivity C-Reactive Protein 2.0 mg/l. The 12-week ANCHOR trial included 702 randomized patients treated with statins who were at increased risk for cardiovascular disease; triglyceride levels were 200 to 499 mg/dl despite low-density protein cholesterol (LDL-C) control. The ad hoc analysis included 152 ANCHOR participants; mean age was 64 years, 54% were male, and 99% were white. Patients were randomized to icosapent ethyl 4 g per day (n=72) or placebo (n=80). Triglyceride levels among patients in the icosapent ethyl group were reduced by 16.9% (P<.0001) with no increase in LDL-C, and improvements in other potentially atherogenic and inflammatory parameters compared with patients in the placebo group. At baseline, serum creatinine was 0.9 mg/dl, egfr was 72.4 ml/min/1.73 m 2, and albumin was 4.5 g/dl; corresponding values at 12 weeks were 0.9 mg/dl, 78.5 ml/min/1.73 m 2, and 4.4 g/dl (all % change vs placebo, P.05). Levels of eicosapentaenoic acid increased by 662.7% in plasma and 622.0% in red blood cells versus placebo (P<.0001 for both). In conclusion, the researchers said, In statin-treated patients with reduced kidney function and elevated hscrp with persistent high triglycerides, icosapent ethyl 4 g/day reduced triglycerides and other atherogenic and inflammatory markers without raising LDL-C vs placebo. Source: Vijayaraghavan K, Szelip HM, Ballantyne, CM, et al. Icosapent ethyl reduces potentially atherogenic lipid and inflammatory markers in high-risk statin-treated patients with persistent high triglycerides, egfr <90 ml/min/1.73 m 2, and elevated high-sensitivity C-reactive protein 2.0 mg/l. Abstract of a poster presented at the National Kidney Foundation Spring Clinical Meetings, April 10-14, 2018, Austin, Texas. The analysis was sponsored by Amarin Pharma, Inc. The 12-week ANCHOR trial included 702 randomized patients treated with statins who were at increased risk for cardiovascular disease. Source: Weir M, Mayo M, Yuan J, Conrad A. Consistency of serum potassium effects in patiromer clinical trials. Poster presented at the National Kidney Foundation Spring Clinical Meetings, April 10-14, 2018, Austin, Texas. The study was sponsored by Relypsa, Inc., a Vifor Pharma Group Company. 12 Nephrology Times May/June 2018

13 Canagliflozin Safe and Effective in Patients with Reduced and Preserved Kidney Function Austin, Texas Glucose lowering in patients with type 2 diabetes can be achieved with sodium glucose co-transporter 2 inhibitors; the agents may confer renal benefits but because the glycemic efficacy is dependent on glomerular filtration rate (GFR), they are not approved for use in people with significantly reduced kidney function. Researchers recently performed a prespecified analysis of CANVAS (Canagliflozin Cardiovascular Assessment Study) data by baseline kidney function. The study randomized patients with type 2 diabetes with or at high risk of cardiovascular disease to either canagliflozin or placebo. Brendon L. Neuen, MBBS, reported results of the analysis during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Canagliflozin and Renal Outcomes in Patients with Chronic Kidney Disease. Prespecified renal outcomes were urinary albumin to creatinine ratio (UACR), and composites of end-stage renal disease (ESRD), renal death, and either 40% decline in estimated GFR (egfr) or doubling of serum creatinine. The analysis was conducted according to kidney function: egfr <60 ml/min/1.73 m 2 (reduced egfr) versus 60 ml/ min/1.73 m 2 (preserved egfr). Of 10,142 participants, 20.1% (n=2039) had baseline egfr <60 ml/min/1.73 m 2. Patients with reduced egfr had at least as large a placebo-adjusted reduction in UACR as did those with preserved egfr ( 23% vs 17%, P-heterogeneity=.01). For the composite outcome of 40% decline in egfr, ESRD, or renal death, the effect of canagliflozin was similar in patients with reduced and preserved egfr (hazard ratio [HR], 0.76; 95% confidence interval [CI], vs 0.53, 95% CI, , respectively; P-heterogeneity=.28). When doubling of serum creatinine was substituted for 40% decline in egfr in the renal composite outcome, findings were similar (HR, 0.81; 95% CI, vs 0.42; 95% CI, , respectively; P-heterogeneity=.21). The risk of serious adverse events with canagliflozin was similar in patients with reduced or preserved egfr (HR, 0.91; 95% CI, vs 0.70; 95% CI, , respectively; P-heterogeneity=.69). In summary, the researchers said, The effect of canagliflozin on the composite renal outcomes was large, particularly in people with preserved kidney function, with evidence of benefit for the egfr 60 ml/min/1.73 m 2 and <60 ml/min/.1.73 m 2 subgroups. Results for major safety outcomes were consistent across egfr 60 ml/min/1.73 m 2 and <60 ml/min/.1.73 m 2 subgroups. The effects in people with reduced kidney function will be more clearly defined in the ongoing Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE; clinicaltrials.gov identifier: NCT Source: Neuen BL, Ohkuma T, Neal B, et al. Canagliflozin and renal outcomes in patients with chronic kidney disease. Poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April 19014, 2018, Austin, Texas. Support for the study was provided by Janssen Research & Development, LLC. Volume Overload Kidney Transplant Recipients Require More Treatments vs Those with Hyperkalemia Austin, Texas In up to 60% of kidney transplantations with deceased donors and 8% with living donors, delayed graft function or dialysis occurs within 7 days following the procedure. Jacentha Buggs, MD, and colleagues conducted a retrospective cohort study to test the hypothesis that that is a difference in resource utilization based on the indication for dialysis in delayed graft function. The study used data on consecutive kidney transplant recipients with delayed graft function at a single transplant center from January 2012 through December Patients were grouped by hyperkalemia or volume overload. The analysis was performed with t test (continuous), chi-squared test (binary), and Cox regression for time to event. Results were reported during a poster session at the NKF 2018 Spring Clinical Meetings in a poster titled Resource Utilization in Delayed Graft Function Based on the Indication for Dialysis in Kidney Transplantation. During the study period, the transplant center performed 1131 kidney transplants; 902 involved a deceased donor and 229 involved a living donor. Of the 1132 procedures, 12.9% had delayed graft function (n=146; 72 with hyperkalemia and 74 with volume overload). There was no statistical difference between the two groups based on age, kidney donor profile index, or calculated panel reactive antibody value. Length of stay (days) was longer for patients with volume overload compared with hyperkalemia (15 days vs 10 days; P<.001). Patients with volume overload required three treatments, compared with two treatments for patients with hyperkalemia (P=.007). There were no statistical differences between the two groups in patient survival or graft survival. In conclusion, the researchers said, Patients with delayed graft function dialyzed for volume overload required more transplant admission dialysis treatments and had longer hospital stays than patients dialyzed for hyperkalemia. Further multicenter collaborations are essential to further investigate resource utilization for different indications of delayed graft function. Source: Buggs J, Boone J, Adesunkanmi M, et al. Resource utilization in delayed graft function based on the indication for dialysis in kidney transplantation. Abstract of a poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April 10-14, 2018, Austin, Texas Award Recipients Honored at NKF Spring Clinical Meetings Leading kidney disease researchers, clinicians, patient advocates, government officials, and corporate partners were honored at the National Kidney Foundation 2018 Spring Clinical Meetings Glenn M. Chertow, MD, professor of medicine at Stanford University and chief of Stanford School of Medicine s Division of Nephrology, received the foundation s highest honor, the 2018 David M. Hume Award. The award honors a distinguished scientist-clinician in the field of kidney and urologic disease who exemplifies high ideals of scholarship and humanism in an outstanding manner. Dr. Chertow s research has focused on clinical epidemiology, health-services research, decision sciences, and clinical trials in acute and chronic kidney disease. Krista L. Lentine, MD, PhD, is the 2018 recipient of the Dr. Shaul Massry Distinguished Lecture award. Dr. Lentine is professor of medicine and the medical director of living kidney donation at SSM Health at St. Louis University Hospital. Her work is concentrated in novel integration and application of national registries, administrative claims data, and other electronic health information as they relate to topics in transplant epidemiology, outcomes, economics, and policy. Dr. Lentine presented the 2018 Massry Lecture, Balancing Risk and Autonomy in Living Kidney Donation A New Framework for Shared DecisionMaking, on April 11 at the Spring Clinical Meetings. The 2018 Donald W. Seldin Distinguished Award was presented to Jeffrey S. Berns, MD, professor of medicine and pediatrics at the Perelman School of Medicine at the University of Pennsylvania. The award honors excellence in clinical nephrology in the tradition of more of the foremost teachers and researchers in the field. Dr. Berns is also the associate chief of the Renal, Electrolyte, and Hypertension Division, director of the Nephrology Fellowship Training Program, and associate dean for graduate medical education. Lesley A. (Stevens) Inker, MD, MS, was honored with the 2018 Garabed Eknoyan Award, recognizing individuals who have worked to make life better for people living with kidney disease through contributions to NKF initiatives such as the Kidney Disease Outcomes Quality Initiative or clinical research in kidney disease. Dr. Inker is an attending physician and director of the Kidney and Blood Pressure Center in the William B. Schwartz MD Division of Nephrology at Tufts Medical Center and associate professor at Tufts University School of Medicine. The 2018 Corporate Innovator Award was given to Keryx Biopharmaceuticals. In November 2017, the US FDA expanded approval of Auryxia (ferric citrate) tablets to include treatment of iron deficiency anemia in adults with non-dialysisdependent chronic kidney disease. Alan S. Kliger, MD, is the recipient of the 2018 J. Michael Lazarus Distinguished Lecture. Dr. Kliger is a clinical professor of medicine at Yale University School of Medicine and vice president and medical director of clinical integration at Yale New Haven Health System. He presented the 2018 Lazarus lecture titled Quality and Safety in Dialysis: Emphasis on Achieving Zero Preventable Infections on April 13 at the Spring Clinical Meetings. The 2018 Public Service Award was presented to Andrew S. Narva, MD, director of the National Kidney Disease Education Program at the National Institutes of Health. He is also the chief clinical consultant for nephrology for Indian Health Services and provides care for patients at Zuni Pueblo via a telemedicine clinic and at Walter Reed National Military Center. Harry Senekjian, MD, was given the 2018 Medical Advisory Board Distinguished Service Award, recognizing individuals for their educational activities and community service in promoting the mission of the NKF on a local level. Dr. Senekjian is a member of the clinical faculty at the University of Utah and the current chairman of the Medical Advisory Board of the NKF of Utah and Idaho. The 2018 Celeste Castillo Lee Patient Engagement Award was presented to Risa Simon. The award is given to a kidney patient who exemplifies the foundation s mission and Lee s legacy of putting patients at the center of all aspects of Healthcare through their involvement with NKF and community partners. Ms. Risa is a preemptive kidney transplant recipient whose personal experience with kidney disease led her to proactively seek a living donor. She now advocates for others to do the same. Angela Yee Moon Wang, MD, PhD, received the 2018 Joel D. Kopple Award honoring an individual who had made significant contributions to the field of renal nutrition. Dr. Wang is a clinician-scientist at the University of Hong Kong, Queen Mary Hospital. Her research has demonstrated the integral connections between nutrition and kidney and heart health, and have clarified the causes of protein energy wasting syndrome, a frequent and dangerous complication for patients with kidney failure. Nephrology Times May/June

14 News Pharmacist Intervention Reduces Cardiovascular Risk in Patients with CKD TAKEAWAY POINTS A subgroup analysis of results for the REACH trial was conducted to evaluate the effect of a community pharmacy-based intervention on estimated cardiovascular risk in a subset of patients with chronic kidney disease. The primary outcome of interest was change in the estimated cardiovascular risk from baseline to 3 months. The estimated cardiovascular risk in the intervention group was reduced from 25.7 to 20.9, compared with 28.7 to 28.6 in the control group over a 3-month period; after adjustment, the relative reduction was 20%. Chronic kidney disease (CKD) is a major risk factor for cardiovascular events. According to Yazid N. Al Hamarneh, BSc(Pharm), PhD, and colleagues, patients with CKD are underserved when it comes to cardiovascular risk reduction efforts. Approximately one in 10 adults in Canada are living with CKD and suboptimal treatment to reduce the risk of cardiovascular events is associated with an increased risk for progression to end-stage renal disease (ESRD). It is important to identify and manage patients with early stage CKD to slow the progression of kidney dysfunction, prevent or delay the development of ESRD, and reduce cardiovascular events among that patient population. Cardiovascular disease accounts for approximately 40% of overall deaths in CKD patients; clinical guidelines now recommend including CKD as part of cardiovascular risk assessments, yet many patients report never having had a cardiovascular risk assessment from their primary care provider. Pharmacists are well positioned to identify patients with CKD, determine cardiovascular risk, and assist in disease management. Pharmacists in Alberta, Canada, can order and interpret laboratory tests, conduct medication management assessment, and prescribe medications. Dr. Al Hamarneh and colleagues conducted a prespecified subgroup analysis based on results of the REACH trial, a multicenter randomized trial demonstrating that a community pharmacybased case finding and intervention program led to a 21% reduction in cardiovascular risk over a 3-month period when compared with usual care. Results of the subgroup analysis were reported in the American Journal of Kidney Diseases [2018;71(1):42-51]. The pharmacist intervention included patient, laboratory, and individualized cardiovascular risk assessments; treatment recommendations; adaptation of prescriptions and/ or initiation of prescriptions; and regular monthly follow-up for 3 months. The primary outcome of interest was change in estimated risk of cardiovascular events from baseline to 3 months following randomization. Secondary outcomes were change between baseline and 3 months following randomization in individual cardiovascular risk factors, the risk for developing ESRD, medication use and dosage, and the impact of rural versus urban residence on the difference in change in estimated cardiovascular risk. The REACH trial enrolled 723 patients from January 2014 to June 2015; follow-up was completed in September Of the 723 patients in the total cohort, 290 had CKD and were randomly assigned to receive the intervention (n=147) or to receive usual pharmacist and physician care (n=143). At baseline, the two groups were well balanced in demographic and clinical parameters. Mean age of the cohort was 65.5 years, 55.2% were men, 80.3% were white, 85.9% had at least a high school education, and 36.2% were employed. Mean body mass index was 33.2 kg/m 2 and 24.5% of the participants were currently using tobacco. Hypertension was the most common comorbidity (90%), followed by dyslipidemia (86.6%), diabetes (82.1%), and vascular disease (35.5%). Study inclusion criteria called for patients to have at least one poorly controlled risk factor: 76.5% of patients with diabetes had poor glycemic control as measured by hemoglobin A1c (HbA1c) concentration; 70.5% had poorly controlled blood pressure; 51% had poorly controlled dyslipidemia measured by low-density lipoprotein cholesterol concentration; and 24.5% were current tobacco users (categories not mutually exclusive). Fifty-nine percent of the patients had known CKD; 41% had previously unrecognized CKD, 83% had elevated albumincreatinine ratios, 9% had reduced estimated glomerular filtration rates (egfrs), and 8% had abnormal results for both tests. Those with previously unrecognized CKD were referred to their treating clinician and received pharmacist care according to the study allocation. Over the 3-month follow-up, in the intervention group the estimated cardiovascular risk was reduced from 25.7 to 20.9; in the control group the risk was reduced from 28.7 to Following adjustment for baseline characteristics and center effect, the results corresponded to a relative reduction of 20% (absolute reduction, 5.03; 95% confidence interval [CI], ; P<.001) in estimated cardiovascular risk over a 3-month period. The largest contributor to the reduction in cardiovascular risk in patients with diabetes was reduction in HbA1c concentration, followed by reduction in systolic blood pressure, total cholesterol to high-density lipoprotein cholesterol, then self-reported tobacco cessation. In patients without diabetes, the largest contributor to the risk reduction was reduction in systolic blood pressure, followed by reduction in total cholesterol to high-density lipoprotein cholesterol ratio, and tobacco cessation. In patients in the intervention group with egfrs <60 ml/min/1.73 m 2, the 5-year predicted risk of ESRD was reduced from 8.9% at baseline to 3.4% at 3 months; there was no change in risk of ESRD in the control group. This corresponded to a 27% relative reduction in predicted risk for ESRD (absolute difference, 2.38; 95% CI, 7.48 to 2.73). The reduction was not statistically significant. Overall, the reduction in cardiovascular risk was larger in patients who lived in rural areas compared with patients who lived in urban areas. Limitations to the analysis cited by the authors included the short follow-up period and the lack of a well-accepted risk assessment equation to calculate cardiovascular risk in patients with CKD; this analysis used the Framingham risk assessment equation, although that equation may underestimate cardiovascular risk in patients with CKD. The UK Prospective Diabetes Study risk assessment equation was used for patients with diabetes, and the International Model to Predict Recurrent Cardiovascular Disease risk assessment equation was used for patients with previous vascular disease. In summary, the authors said, This subgroup analysis demonstrated that a community pharmacy-based intervention program reduced cardiovascular risk and improved control of individual cardiovascular risk factors. This represents a promising approach to identifying and managing patients with CKD that could have important public health implications. 14 Nephrology Times May/June 2018

15 News Managing Warfarin Therapy in Hemodialysis Patients with Atrial Fibrillation The mainstay therapy to reduce the risk of stroke in patients with atrial fibrillation is warfarin. Thromboembolic risks are reduced with the use of target international normalized ratio (INR) between two and three without a significant increase in the risk of major bleeding. Compared with the general population, the risk of thromboembolic events is higher in patients with advanced chronic kidney disease. There is no clear consensus on the benefit versus harm for use of anticoagulation in patients on hemodialysis. Some studies have shown a decrease in mortality and risk of stroke with warfarin; others have reported an increased risk of bleeding with no significant impact on risk of ischemic stroke or mortality. Further, guidelines from various national and international societies offer conflicting recommendations: some call for the use of warfarin in hemodialysis patients with atrial fibrillation, while others advise against using warfarin for primary thromboembolic prophylaxis in patients with atrial fibrillation on hemodialysis. In guidelines from the Kidney Disease Improving Global Outcomes, routine anticoagulation of patients with stage 5 CKD with atrial fibrillation for primary prevention of stroke is not indicated. There is a correlation between time in therapeutic range (TTR), measured by the Rosendaal method, and bleeding and thromboembolic complications; there is also an association between a TTR of <60% and major bleeding, increased mortality, and systemic embolism. Limited data have shown that hemodialysis patients on warfarin have lower TTR than the general population. Researchers in Canada, led by Hamad Bahbahani, MD, recently conducted a retrospective cohort study designed to compare nephrologist-led management of warfarin in terms of achieved TTR and frequency of INR testing with specialized thrombosis clinic-led management in a population of patients on hemodialysis. Study results were reported online in BMC Nephrology [doi: / s x]. The study included patients from the McGill University Health Centre, where anticoagulation with warfarin is managed by nephrologists (institution A), and the Jewish General Hospital, where warfarin-based anticoagulation is managed through an anticoagulation clinic led by hematologists (institution B). Both institutions are in Montreal, Quebéc, Canada. Primary end points were: (1) mean TTR, based on the Rosendaal method; (2) proportion of patients achieving TTR 60%; and (3) mean frequency of INR testing. At institution A, 65% of hemodialysis patients on warfarin achieved TTR 60% compared with 43.3% of patients at institution B who achieved that target level of TTR. Between January 1, 2015, and November 26, 2016, the researchers identified 341 patients in institution A and 300 in institution B who were undergoing hemodialysis for at least 3 months. At institution A, 16.7% (n=57/341) had documented history of atrial fibrillation; 36.8% (n=21/300) of them were on warfarin at the end of the study period. At institution B, 54 patients (18%) had history of atrial fibrillation and 55.5% of those (n=30) were on warfarin. Following application of inclusion and exclusion criteria, the final TTR analysis included 20 patients in institution A and 30 patients in institution B. Mean age was 75.6 years in the institution A group and 79.3 years in the institution B group; the cohorts were 60% male in both institutions. Distribution of comorbidities associated with increased risk of stroke such as previous cerebrovascular accident, type 2 diabetes mellitus, hypertension, congestive heart failure, and valvular atrial fibrillation were similar in the two groups, as was hemodialysis vintage. Duration of hospitalization of patients at institution A was shorter than that of patients at institution B (mean 10.9 days vs mean 20 days); the difference was not statistically significant. At institution A, mean TTR based on the Rosendaal method was 61.8% compared with 60.5% at institution B. Mean frequency of INR testing was every 6 days at institution A compared with every 13.9 days at institution B. At institution A, 65% of hemodialysis patients on warfarin achieved TTR 60% compared with 43.3% of patients at institution B who achieved that target level of TTR. Following adjustment for hemodialysis vintage, total duration of hospitalization, and total duration of outpatient antibiotic use, the odds ratio of patients achieving TTR 60% was 2.22 (95% confidence interval, ). At institution A, the average annual number of INR tests was 60, compared with 26 at institution B. At a total cost of 0.50$ (Canadian), the average annual cost of INR testing per patient at institution A was approximately $30.00 (Canadian), compared with a total per test cost of $12.50 (Canadian) for an average annual cost of INR testing at institution B, for an average annual cost of INR testing per patient of $ (Canadian). Nephrologist-led warfarin management resulted in significant overall cost savings despite more frequent INR testing. (The cost analysis was based on laboratory and professional fees specific to the Province of Quebéc, Canada.) The study had some limitations, including the relatively small sample size and the inclusion of only two dialysis centers, limiting the statistical power of the outcome measures and the generalizability to all hemodialysis patients; and the observational design of the study that may have allowed for the possibility of unmeasured bias. In conclusion, the researchers said, There was no statistical difference in mean TTR between nephrologist-led management of warfarin to that of anticoagulation clinicled management. However, the former achieved a trend of higher proportion of patients with optimal TTR which was associated with more frequent monitoring and greater cost-effectiveness. TAKEAWAY POINTS There is no clear consensus on benefit versus harm for use of warfarin in patients on hemodialysis with atrial fibrillation. Researchers in Canada conducted a retrospective cohort study to compare nephrologist-led management of warfarin therapy with that led by a specialized anticoagulation clinic. The study was conducted at two institutions in Montreal, Quebéc, Canada. The final analysis included 20 patients with nephrologist-led management and 30 with anticoagulation clinic-led management. There was no statistical difference between the two groups in time in therapeutic range (TTR); however, patients in the nephrologist-led group achieved a trend toward a higher proportion of patients with optimal TTR. There was also a significant overall cost savings associated with nephrologist-led warfarin management. Nephrology Times May/June

16 News Kidney Disease Quality of Life Subscales and Risk of Death or Hospitalization in Older Patients TAKEAWAY POINTS Prediction tools regarding risk of death and hospitalizations among older adults receiving maintenance dialysis often do not consider health-related quality of life in that patient population. Researchers conducted a longitudinal study of 3500 adults 75 years of age to examine the extent of association of subscales of the Kidney Disease Quality of Life (KDQOL-36) subscales with adverse outcomes in older patients on dialysis. The strongest association with mortality and future hospitalizations was seen with the 12-item Short Form Health Survey physical component summary. For older patients with kidney disease, many of whom have limited life expectancy and a significant burden of symptoms and comorbidities, health-related quality of life is increasingly being recognized as an important patientcentered outcome. Instruments designed to measure health-related quality of life include items related to physical health, mental health, symptoms, and limitations. In older patients with kidney disease, prognostication of adverse outcomes in that patient population may be possible utilizing health-related quality of life assessment instruments. There are few data available on the association of health-related quality of life and mortality or hospitalizations in cohorts limited to older adults receiving maintenance dialysis. Rasheeda K. Hall, MD, and colleagues conducted a longitudinal cohort study designed to determine the extent of the association of Kidney Disease Quality of Life-36 (KDQOL-36) subscales with adverse outcomes in older adults on maintenance dialysis. The researchers sought to test the hypothesis that healthrelated quality of life from the KDQOL-36 may be useful for prognostication. Results of the study were reported online in BMC Nephrology [doi: /s ]. The cohort included 3500 adults 75 years of age receiving dialysis in the United States in 2012 and Cox and Fine and Gray models were used to evaluate the association of KDQOL-36 subscales with the risk of hospitalization and death. The models were adjusted for sociodemographic variables, hemodialysis access type, laboratory values, and Charlson index scores. The analytic cohort included 3132 patients. At baseline, average age was 80.5 years, 50.1% (n=1570) were male, and 22.9% (n=675) were dual eligible Medicare and Medicaid beneficiaries. Mean time since initiation of dialysis was 5.98 years and average Charlson comorbidity index was 7.4. The majority of the cohort (64.5%, n=2018) had an arteriovenous fistula. Mean KDQOL-36 subscale scores were 345 for the 12-item Short Form Health Survey (SF-12) physical component score; 50.9 for the SF-12 mental component score; 78.5 for symptoms/problems; 74.3 for effects of kidney disease; and 52.6 for burden of kidney disease. No one in the cohort achieved the maximum score for SF-12 physical component or mental component score. The cohort was stratified into quintiles based on scores for five subscales of the KDQOL-36: (1) SF-12 physical component summary; (2) SF-12 mental component summary; (3) burden of kidney disease; (4) symptoms of kidney disease; and (5) effects of kidney disease. Scores of patients in the first quintile were the lowest, those in the fifth quintile were the highest. During the study period, 880 individuals died following completion of the KDQOL-36 (median follow-up was 512 days). The risk of death was higher among individuals in the first quintile (relative to the fifth quintile) for all five subscales in unadjusted analyses. The associations were attenuated following adjustment for sociodemographic characteristics, time since initiation of dialysis, Charlson index, access type, and laboratory values. When all five KDQOL-36 subscales were combined in a model with covariates, only the participants in the first quintile maintained a significantly higher hazard of death (hazard ratio [HR], 1.55; 95% confidence interval [CI], ). Race, gender, time since initiation of dialysis, hemoglobin, and Charlson index also maintained significant associations with time to death. Of the 3132 study participants, 64.6% (n=2023) were hospitalized at least once after the date of completion of the KDQOL-36 over the study period (median follow-up of 203 days). Among those, 36.1% (n=730) later died during the observation period. However, 92.2% (n=673) died at least 7 days after the hospitalization. The average length of stay was 5.6 days. In unadjusted analyses, risk of hospitalization was higher in participants in the first quintile for all five KDQOL-36 subscales. The associations were attenuated following adjustment for sociodemographic characteristics, time since initiation of dialysis, Charlson index, access type, and laboratory values. When all five subscales were combined in a model with covariates, the higher hazard of hospitalization was maintained in participants in the first quintile for the SF-12 mental component summary (HR, 1.39; 95% CI, ) and the SF-12 physical component summary (HR, 1.29; 95% CI, ). The researchers cited some limitations to the study, including deriving the cohort from a single large dialysis organization, perhaps limiting the generalizability of the findings to all patients 75 years of age worldwide, particularly those with shorter time since initiation of dialysis and those in the United States receiving dialysis in non-profit dialysis organizations or federal programs. The cohort included only those patients who completed the KDQOL-36, potentially limiting the generalizability of the findings to those who are able to complete the KDQOL-36. The available data did not include all measured confounders identified in previous studies, such as new medical diagnoses, medications, blood pressure, weight gain, lean body mass, depression, social support, level of care, and prior hospitalizations. In addition, there were insufficient data on the most common reasons for hospitalizations. Finally, the analyses did not capture serial KDQOL-36 data, preventing the researchers from assessing the association of worsening quality of life or functional status with mortality and hospitalizations. In conclusion, the researchers said, We report that among KDQOL-36 subscales, SF-12 physical component summary has the potential to enhance prognostication of survival and future hospitalizations in older adults receiving dialysis. If validated in other studies, this finding may support routine quality of life assessments and integration of health-related quality of life and clinical data into prediction tools that ultimately enhance risk stratification and shared decision-making for older adults receiving maintenance dialysis. 16 Nephrology Times May/June 2018

17 News Models of Phosphate Kinetics in the Setting of Hemodialysis High plasma phosphate concentration, hyperphosphatemia, is an electrolyte disturbance in patients with chronic kidney disease (CKD); 40% of 45% of patients with end-stage CKD experience it. The usual treatment to maintain phosphate concentrations in the normal range is dialysis. In general, maintaining a normal phosphate balance in patients on dialysis is desirable because it may help prevent severe complications such as vascular calcifications, renal osteodystrophy, and hyperparathyroidism. Preventing hyperphosphatemia relies on an understanding of phosphate kinetics in dialysis patients. Physiologic modeling has been used to gain new insights into phosphate behavior, and various models to describe and quantify intra- and/or interdialytic phosphate kinetics have been suggested; however, there are few studies comparing the available models. Sisse H. Laursen, MSc, and colleagues in Demark conducted a systematic review and analysis of existing published models of phosphate metabolism in the setting of maintenance hemodialysis therapy. They reported results of the review in the American Journal of Kidney Diseases [2018; 71(1):75-90]. Eligibility criteria were studies of phosphate modeling within hemodialysis therapy published prior to August 31, The search was restricted to full-text peer-reviewed journal articles in English that focused on intradialytic or intra- and interdialytic phosphate kinetic modeling. Excluded studies focused only on dialytic phosphate removal, peritoneal dialysis, hemodiafiltration treatment, hemofiltration treatment, and/or urgent dialysis. The researchers evaluated 1964 nonduplicate studies; of those, 11 were included in the analysis. The 11 studies comprised nine different phosphate models. The model approaches included 1-, 2-, 3-, and 4-compartment structures; the number of model parameters ranged from two to 11. All 11 studies agreed that the observed mobilization of phosphate requires some kind of generation term. In addition, the intra- and extracellular compartments were set to be equal to the included compartments in the majority of the studies. Using the Newcastle-Ottawa Scale with 14 quality indicators, the scores of the included studies ranged from two to 11. Two of the studies were ranked low quality, six were medium quality, and three were considered high quality. The studies ranked high quality were more likely to have been published recently; the exception was a study from 2012 with a score of four that was assessed as poor quality (the score is preliminary because the model has not yet been validated). The three indicators that were most frequently met were: (1) transparency of the model approach; (2) presentation of the model parameters; and (3) conclusions. The indicators that were considered to be of a lower quality were: (1) treatment setup and (2) study design. All of the studies were in agreement that a model should consist of a minimum of two compartments to ensure stabilization of phosphate. Four of the models suggest that it can be difficult to predict and describe phosphate rebound even using a 2-compartment structure. The studies also indicate that for kinetic phosphate models to succeed, they should have high accountability and accuracy. Limitations to the analysis cited by the authors included reviewing studies that used varying treatment setups and sampling methods; focusing solely on phosphate modeling in the setting hemodialysis therapy without considering hemodiafiltration models; and reviewing only studies published in English. Many parameters known to influence phosphate balance are not included in existing phosphate models that do not fully reflect the physiology of phosphate metabolism in the setting of hemodialysis. Moreover, models have not been sufficiently validated for their use as a tool to simulate phosphate kinetics in hemodialysis therapy, the authors said. TAKEAWAY POINTS Researchers in Denmark conducted a systematic review and analysis of studies describing models of phosphate metabolism in the setting of maintenance hemodialysis. Of 1964 nonduplicate studies evaluated, the review and analysis included 11, comprising nine different phosphate models with 1-, or 4-compartment assumptions. The analysis found that parameters known to influence phosphate balance are not included in existing phosphate models that do not fully reflect the physiology of phosphate metabolism in the setting of hemodialysis. NKF Spring Clinical Meetings Patients with ADPKD on Peritoneal Dialysis: Long-Term Clinical Outcomes Austin In patients with autosomal dominant polycystic kidney disease (ADPKD) on peritoneal dialysis, there have been reports of complications, including hernia, membrane failure, and peritonitis. However, there are few data on the long-term clinical outcomes of patients with ADPKD on peritoneal dialysis. Boonphiphop Boonpheng, MD, and colleagues conducted a meta-analysis designed to examine the risks of death, technique failure, and peritonitis in this patient population. The researchers reported results of the analysis during a poster session at the NKF 2018 Spring Clinical Meetings. The poster was titled Outcomes of Patients with Autosomal Dominant Polycystic Kidney Disease on Peritoneal Dialysis: A Meta-Analysis. Studies that evaluated outcomes of patients with ADPKD on peritoneal dialysis including the risks of death, technique failure, and peritonitis were identified via a systematic review was conducted in Medline, EMBASE, and Cochrane databases from inception through October The random-effect, generic inverse variance method of DerSimonian and Laird were used to extract and combine effect estimates from individual studies. The meta-analysis included 12 observational studies representing a total of 14,673 patients on peritoneal dialysis; of the 14,673 patients, 931 had ADPKD. Compared with ADPKD status, there was an association with significantly decreased mortality risk with pooled odds ratio (OTR) of 0.68 (95% confidence interval [CI], ). There were no associations of ADPKD with the risk of technique failure (pooled OR, 0.80; 95% CI, ) or peritonitis (pooled OR, 0.88; 95% CI, ). There was no publication bias as assessed by the funnel plots and Egger s regression asymmetry test. P values for the risks of mortality, technique failure, and peritonitis in patients with ADPKD were 0.90, 0.28, and 0.60, respectively. In conclusion, the researchers said, Compared with non-adpkd patients on peritoneal dialysis, our study demonstrated that ADPKD patients on peritoneal dialysis have a 0.68-fold decreased mortality risk. There are no associations of ADPKD with the risks of technique failure or peritonitis. Source: Boonpheng B, Thongprayoon C, Wijarnpreecha K, et al. Outcomes of patients with autosomal dominant polycystic kidney disease on peritoneal dialysis: a meta-analysis. Abstract of a poster presented at the National Kidney Foundation 2018 Spring Clinical Meetings, April 10-14, 2018, Austin, Texas. Nephrology Times May/June

18 News Uric Acid Concentrations and Outcomes in Chronic Kidney Disease TAKEAWAY POINTS Researchers conducted a prospective observational cohort study to examine whether there is an association between uric acid concentrations and outcomes in patients with chronic kidney disease (CKD). Data from the Chronic Renal Insufficiency Cohort study were utilized to examine associations between uric acid concentration and the outcomes of kidney failure and allcause mortality. In earlier stages of CKD, uric acid concentration is an independent risk factor for kidney failure; there is a J-shaped relationship between uric acid concentration and allcause mortality. In patients with chronic kidney disease (CKD), concentrations of plasma uric acid increase due to reductions in glomerular filtration rate (GFR). Hyperuricemia is associated with gout and is also a suspected risk factor for other conditions associated with metabolic syndrome, including hypertension, diabetes mellitus, and cardiovascular diseases. Acute kidney injury may also occur in the presence of high uric acid, and hyperuricemia may also lead to CKD and disease progression due to endothelial dysfunction, activation of the renin-angiotensin-aldosterone system, inflammation, and oxidative stress. Results of previous studies have shown associations between higher concentrations of uric acid and the development of CKD. There are fewer data on the association of uric acid concentrations and outcomes in patients with CKD. It is also unclear whether uric acid is a matter of lower estimated GFR (egfr) or is casually associated with adverse outcomes in CKD. Anand Srivastava, MD, MPH, and colleagues recently conducted a prospective observational cohort study designed to examine the possible association between adverse events and uric acid concentrations. The researchers utilized data from the CRIC (Chronic Renal Insufficiency Cohort), a prospective cohort study of patients with established CKD. Study results were reported in the American Journal of Kidney Diseases [2018;71(3): ]. The study predictor was baseline uric acid concentrations. The outcomes of interest were kidney failure, defined as initiation of dialysis or kidney transplantation, and all-cause mortality. Study participants were 3885 individuals with CKD stages 2 to 4 who were enrolled in the CRIC study between June 2003 and September Follow-up continued through March At baseline, mean uric acid concentrations were higher in men (7.7 vs 7.0 mg/ dl), black participants (7.8 vs 7.1 mg/dl in white participants), those with a history of diabetes (7.6 vs 7.2 mg/dl), those with a history of cardiovascular disease (7.7 vs 7.3 mg/dl), participants who used diuretics (7.9 vs 6.7 mg/dl), and participants who used angiotensin converting enzyme inhibitors or angiotensin receptor blockers (7.6 vs 6.9 mg/dl). Concentrations of uric acid were lower in participants who used urate-lowering medications (6.9 vs 7.5 mg/ dl) (P<.001 for all comparisons). During follow-up (median, 7.9 years), 885 participants reached the end point of kidney failure. Following adjustment for demographics, comorbid conditions, medications, and laboratory data, the association between baseline uric acid concentration and subsequent kidney failure was mildly attenuated. Associations between uric acid concentrations (both as a continuous variable and quartiles) and kidney failure were significantly confounded by egfr. In participants with egfrs 45 ml/min/1.73 m 2, there was an independent association between higher concentrations of uric acid and risk for kidney failure (adjusted hazard ratio [HR] per 1-standard deviation greater baseline uric acid, 1.40; 95% confidence interval [CI], ). There was no association between higher uric acid concentrations and risk for kidney failure among participants with egfrs of <30 ml/min/1.73 m 2. The HR in participants with egfrs of 30 to 44 ml/min/1.73 m 2 was nominally higher (adjusted HR, 1.13; 95% CI, ), but the finding did not reach statistical significance. During the median 7.9 years of followup, 789 study participants died. Following adjustment for demographic characteristics, comorbid conditions, medications, and pertinent laboratory data, there was a nonlinear J-shaped relationship between uric acid concentrations and all-cause mortality (P=.007). There was no evidence of statistical interaction between uric acid concentration by sex (P for interaction=.1), urate-lowering medications (P=.2), body mass index (P=.45) or egfr (P=.7) for the outcome of all-cause mortality. In sensitivity analysis, results of the primary analysis did not qualitatively change after substituting egfr with measured GFR. In addition, repeating the analysis censoring at the onset of kidney failure did not qualitatively change the nonlinear relationship between uric acid concentration and all-cause mortality. The researchers cited some limitations to the study, including the observational design, making it difficult to infer causality between the observed associations between concentrations of uric acid and progression of CKD and mortality. In addition, there was the possibility of residual confounding following multivariable adjustment. Finally, the researchers only analyzed uric acid concentrations at baseline; they did not have access to follow-up measurements to adjust for changes in uric acid concentrations over time. In conclusion, the researchers said, Hyperuricemia in CKD is associated with mortality in a J-shaped relationship and, among those with egfrs 45 ml/min/1.73 m 2, with higher risk for subsequent kidney failure. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD. 18 Nephrology Times May/June 2018

19 When patients phosphate binder therapy was not successful... SWITCHING TO VELPHORO MADE A WORLD OF DIFFERENCE Double the percentage of patients achieved phosphorus goal with half the pill burden* 1 Visit RealWorldVelphoro.com TO SEE THE DIFFERENCE A SWITCH CAN MAKE INDICATION Velphoro (sucroferric oxyhydroxide) is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. IMPORTANT SAFETY INFORMATION Velphoro must be administered with meals. Velphoro tablets must be chewed and not swallowed whole. To aid with chewing and swallowing, the tablets may be crushed. Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, following major gastrointestinal (GI) surgery, or with a history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies with Velphoro. Monitor effect and iron homeostasis in such patients. In a parallel design, fixed-dose study of 6 weeks duration, the most common adverse drug reactions to Velphoro chewable tablets in hemodialysis patients included discolored feces (12%) and diarrhea (6%). Velphoro can be administered concomitantly with oral calcitriol, ciprofloxacin, digoxin, enalapril, furosemide, HMG-CoA reductase inhibitors, hydrochlorothiazide, losartan, metoprolol, nifedipine, omeprazole, quinidine and warfarin. Take doxycycline at least 1 hour before Velphoro. Velphoro should not be prescribed with oral levothyroxine. Please see Brief Summary on adjacent page or visit for full Prescribing Information. * A retrospective analysis of pharmacy data assessed the real-world effectiveness of Velphoro in 1,029 adult in-center hemodialysis patients who were switched to Velphoro during routine care. The study compared the proportion of patients with phosphorus levels 5.5 mg/dl and the mean prescribed phosphate binder pills/day at baseline (3 months prior to Velphoro; binders included sevelamer carbonate, calcium acetate, and lanthanum carbonate) and during Velphoro follow-up (6 months after switch to Velphoro, n=424). This was a noninterventional analysis and did not impact prescriptions or prescribing patterns. 1 Reference: 1. Coyne DW, Ficociello LH, Parameswaran V, et al. Real-world effectiveness of sucroferric oxyhydroxide in patients on chronic hemodialysis: A retrospective analysis of pharmacy data. Clin Nephrol. 2017;88(2): Velphoro is a registered trademark of Vifor Fresenius Medical Care Renal Pharma Ltd. Distributed by: Fresenius Medical Care North America Waltham, MA Fresenius Medical Care, all rights reserved. PN Rev. A 12/2017

20 Brief Summary: Please see Full Prescribing Information for additional information INDICATIONS AND USAGE Velphoro (sucroferric oxyhydroxide) is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis. DOSAGE AND ADMINISTRATION Velphoro tablets must be chewed and not swallowed whole. To aid with chewing and swallowing, tablets may be crushed. The recommended starting dose of Velphoro is 3 tablets (1,500 mg) per day, administered as 1 tablet (500 mg) 3 times daily with meals. Adjust by 1 tablet per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly. DOSAGE FORMS AND STRENGTHS Velphoro (sucroferric oxyhydroxide) chewable tablet 500 mg. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, following major gastrointestinal surgery, or with a history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies with Velphoro. Monitor effect and iron homeostasis in such patients. ADVERSE REACTIONS In a parallel design, fixed-dose study of 6 weeks duration, the most common adverse drug reactions to Velphoro chewable tablets in hemodialysis patients included discolored feces (12%) and diarrhea (6%). The following adverse reactions were identified during post approval use of Velphoro, and were reported voluntarily from a population of uncertain size. Gastrointestinal Disorders: tooth discoloration Skin and Subcutaneous Tissue Disorder: rash To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Medical Care North America at or FDA at FDA-1088 or DRUG INTERACTIONS Velphoro can be administered concomitantly with oral calcitriol, ciprofloxacin, digoxin, enalapril, furosemide, HMG-CoA reductase inhibitors, hydrochlorothiazide, losartan, metoprolol, nifedipine, omeprazole, quinidine and warfarin. Take doxycycline at least 1 hour before Velphoro. Velphoro should not be prescribed with oral levothyroxine. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B: Reproduction studies have been performed in rats and rabbits at doses up to 16 and 4 times, respectively, the human maximum recommended clinical dose on a body weight basis, and have not revealed evidence of impaired fertility or harm to the fetus due to Velphoro. However, Velphoro at a dose up to 16 times the maximum clinical dose was associated with an increase in post-implantation loss in pregnant rats. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Labor and Delivery No Velphoro treatment-related effects on labor and delivery were seen in animal studies with doses up to 16 times the maximum recommended clinical dose on a body weight basis. The effects of Velphoro on labor and delivery in humans are not known. Nursing Mothers Since the absorption of iron from Velphoro is minimal, excretion of Velphoro in breast milk is unlikely. Pediatric Use The safety and efficacy of Velphoro have not been established in pediatric patients. Geriatric Use Of the total number of subjects in two active-controlled clinical studies of Velphoro (N=835), 29.7% (n=248) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. OVERDOSAGE There are no reports of overdosage with Velphoro in patients. Since the absorption of iron from Velphoro is low, the risk of systemic iron toxicity is low. Hypophosphatemia should be treated by standard clinical practice. Velphoro has been studied in doses up to 3,000 mg per day. HOW SUPPLIED/STORAGE AND HANDLING Velphoro are chewable tablets supplied as brown, circular, bi-planar tablets, embossed with PA 500 on 1 side. Each tablet of Velphoro contains 500 mg iron as sucroferric oxyhydroxide. Velphoro tablets are packaged as follows: NDC Bottle of 90 chewable tablets Storage Store in the original package and keep the bottle tightly closed in order to protect from moisture. Store at 25 C (77 F) with excursions permitted to 15 to 30 C (59 to 86 F). PATIENT COUNSELING INFORMATION Inform patients that Velphoro tablets must be chewed and not swallowed whole. To aid with chewing and swallowing, the tablets may be crushed [see Dosage and Administration]. Velphoro should be taken with meals. Instruct patients on concomitant medications that should be dosed apart from Velphoro [see Drug Interactions]. Inform patients that Velphoro can cause discolored (black) stool. Inform patients that Velphoro can stain teeth. Inform patients to report any rash to their healthcare professional. Distributed by: Fresenius Medical Care North America 920 Winter Street Waltham, MA Patents apply, visit Fresenius Medical Care North America. All rights reserved.

21 Focus on Transplantation News Immediate-Release versus Extended-Release Tacrolimus in African Americans One-third of deceased donor kidney transplant recipients in the United States are of African ancestry, despite African Americans constituting 13% of the US population. Results of immunosuppression trials are often not generalizable to African American kidney transplant recipients because that patient population is often under-represented in those studies. Compared with kidney transplant recipients of European ancestry, rates of rejection and transplant loss are greater among patients of African ancestry; those differences are due to both immunologic and nonimmunologic factors. Genetics may play a role in the disparity of outcomes as well. The commonly used immunosuppressive drug tacrolimus is an agent for which patient genotype affects dosing. Tacrolimus pharmacokinetics are affected by sex, ethnicity, concomitant medications, and genetic polymorphisms. Tacrolimus is metabolized via CYP3A4 and CYP3A5 enzymes primarily in the gut and liver; the intrinsic tacrolimus clearance capacity of CYP3A5 predominates over CYP3A4. Loss-of-function alleles CYP3A5*6, CYP3A5*7 are found only in individuals of African ancestry; CYP3A5*3 is present in most Americans of European ancestry and in Asians. The presence of those alleles results in marked diminution of CYP3A5 enzyme activity (CYP3A5 nonexpressers). The CYP3A5*1 allele, present predominately but not exclusively in individuals of black African descent, encodes CYP3A5 enzymes associated with rapid tacrolimus disposition (CYP3A5 expressers), leading to subtherapeutic concentrations and increased dose requirements. Using steady-state 24-hour pharmacokinetic profiling, Jennifer Trofe-Clark, PharmD, and colleagues recently conducted a study designed to further understanding of the differences in tacrolimus exposure between African American CYP3A5 expressers and CYP3A5 nonexpressers. Results of the study were reported in the American Journal of Kidney Diseases [2018;71(3): ]. ASERTAA (A Study of Extended Release Tacrolimus in African Americans) was an open-label, prospective, randomized, 2-sequence, 3-period crossover, pharmacogenetics study conducted at the University of Pennsylvania, the University of Illinois, and Washington University School of Medicine (St. Louis) between November 25, 2013, and July 30, The primary outcome of interest was a comparison of steady-state pharmacokinetics of once-daily LCPT (originally LifeCycle Pharma Tacrolimus [Envarsus XR in the United States]) tablets dosed 15% lower than total daily twice-daily tacrolimus (i.e., immediate-release tacrolimus [IRT-Tac]) dose with evenly divided twice-daily IR-Tac capsules in stable African American kidney transplant recipients. Secondary outcomes included confirmation of the total daily dose reduction in the LCPT group after conversion from IR-Tac, and a comparison of the safety and short-term efficacy of the two formulations. Using a fixed-block randomization scheme, generated by an independent statistician prior to study initiation, patients were assigned in a 1:1 ratio to one of two sequences: sequence I: patients continued their current IR-Tac dose until study day 7, then switched to LCPT; sequence II: patients started on LCPT at 15% total lower daily dose than IR-Tac until study day 7, then switched to IR-Tac at its previous twice-daily dose. Participants all received the second assigned treatment from day 8 to day 21. At days 7, 14, and 21, 24-hour pharmacokinetic profiles were obtained. Following randomization, 27 patients were assigned to sequence I and 23 to sequence II; of those 50 patients, 46 completed the entire pharmacokinetics study of three 24-hour assessments. Of the 46 with complete data, 76% (n=35) were CYP3A5 expressers. The two treatment sequence groups were similar in demographic and transplant characteristics; 25 had preexisting diabetes. A total of 42 participants entered the extension phase (21 in each treatment group); the extension phase was completed by 18 participants in the LCPT group and 20 in the IR-Tac group. Among CYP3A5 expressers, LCPT peak concentration (C max ) was 31.4% lower (P<.001) than that of IR-Tac; LCPT area under the curve from time 0 to 24 hours (AUC 0-24 ) was 12.2% higher (P=.04) than that of IR-Tac. Among nonexpressers, C max and AUC 0-24 were similar between IR-Tac and LCPT groups. With IR-Tac, compared with nonexpressers, tacrolimus C max was 33% higher in CYP3A5 expressers (P=.04). The difference was 11% with LCPT (P=.4). In an ad hoc analysis according to genotype, there were no statistically significant differences in adverse events. There were no reports of infectious episodes during the pharmacokinetics portion of the study. Limitations to the study cited by the researchers included the small sample size, the pharmacokinetic design of the study (rather than a clinical efficacy study), and the short follow-up period. In conclusion, our study demonstrates that with the use of IR-Tac, achievement of therapeutic tacrolimus concentrations in most African Americans resulted in much higher peak concentrations, with potential for enhanced toxicity and adverse outcomes. With LCPT, the shape of the pharmacokinetics profile was not affected by CYP3A5 genotype, and tacrolimus exposure was maintained at ~80%of the IR-Tac total daily dose. Results from this study additionally indicate that the pharmacokinetics of LCPT is less influenced by CYP3A5 genotype in African Americans, and LCPT had distinctive pharmacogenetics differences compared to IR-Tac in this population. Studies are ongoing to determine whether these pharmacogenetics differences represent an opportunity for LCPT to optimize immunosuppressive management in African American patients and thereby narrow health outcome disparities in kidney transplantation. TAKEAWAY POINTS Researchers conducted a randomized prospective crossover study to further understanding of the differences in tacrolimus exposure between African American CYP3A5 expressers and CYP3A5 nonexpressers. Approximately 80% of participants were CYP35 expressers; there were no significant differences in area under the curve from time 0 to 24 hours or in peak concentration of tacrolimus between expressers and nonexpressers during administration of either immediaterelease tacrolimus (IR-Tac) or extendedrelease tacrolimus (LCPT). Peak concentration of tacrolimus with administration of IR-Tac was 33% higher in CYP3A5 expressers compared with nonexpressers; the difference was 11% with LCPT. Nephrology Times May/June

22 News Focus on Transplantation Case Study of Patients with Predominant Mesangial C1q Deposits TAKEAWAY POINTS Researchers studied renal graft biopsy specimens with negative to mild proteinuria and/or hematuria to confirm the existence of cases of predominant mesangial C1q deposits in that patient population. Five pediatric patients (male to female ratio, 1:1.15) met inclusion criteria. The samples from the included cases represented 0.01% of all samples investigated. The study results confirmed the existence of cases with predominant but silent C1q deposits in the mesangium who have negative to mild proteinuria. In 1985, researchers described C1q nephropathy (C1qN). The condition is characterized by (1) the presence of predominant or co-dominant mesangial C1q deposits detected by immunofluorescence microscopy; (2) corresponding mesangial or paramesangial electron-dense deposit (EDD); and (3) absence of clinical and serological evidence of systemic lupus erythematosus (SLE). Patients present with proteinuria in the nephrotic range and are resistant to steroid treatment. Previous studies have revealed the clinical heterogeneity of C1qN, with some cases having normal urinalysis results. Takahiro Kanai, MD, PhD, and colleagues recently conducted a long-term observational study designed to confirm the existence of cases with predominant mesangial C1q deposits and negative or mild proteinuria and/or hematuria. The researchers examined renal graft biopsy specimens demonstrating negative to mild proteinuria, defined as 1+ by dip stick test, and/or hematuria, defined as 1+ by dip stick test. Results of the study were reported online in BMC Nephrology [doi. org/ /s ]. The study included 414 serial cases with negative to mild proteinuria and/or hematuria who underwent renal transplantation. Specimens of renal graft biopsy were obtained from the Kidney Center in Tokyo Women s Medical University between 2002 and Cases included 334 adults >19 years of age and 80 pediatric patients two to 18 years of age. Of the total cohort, 242 were male and 172 were female. Eligibility criteria included predominant mesangial C1q deposits 2+ or greater on a ±4 scale by the definition of C1q deposits, and a follow-up period of >10 years after detection of the predominant C1q deposits in the mesangium. Exclusion criteria included morphologic features of membranoproliferative glomerulonephritis type 1 or fulfillment of the diagnostic criteria for SLE due to mesangial C1q deposits. Patient medical records were reviewed, including notation of the age at detection of predominant mesangial C1q deposits, sex, original renal disease, reason for the renal graft biopsy, and blood pressure levels. The review also included results from laboratory tests, including degree of proteinuria and hematuria, anti-c1q antibody titers, and serum creatinine levels. Medication data were also collected, including use of steroids, immunosuppressants, angiotensin receptor blockers (ARBs), and angiotensin converting enzyme (ACE) inhibitors. Light microscopy revealed averages of 28 glomeruli, all of which showed minor glomerular abnormalities. At study selection, five pediatric patients (male to female ratio, 1:1.5) met the criteria for C1qN. The samples from those five patients represented 0.01% of all samples studied. Original renal diseases of the five patients were renal hypoplasia, focal segmental glomerulosclerosis, autosomal recessive polycystic kidney disease, Alport syndrome, and chronic tubulointerstitial nephritis. Mean age at time of renal transplantation was 8.8 years. Reasons for renal graft biopsy when predominant C1q deposits were detected were due to protocol in four cases and mild proteinuria in one case. Protocol renal graft biopsies were conducted an average of 2.2 times (range, 1-3 times) prior to detection of predominant mesangial C1q deposits. None of the five cases presented with hypertension or signs or symptoms of infection at the time of detection of predominant mesangial C1q deposits. Following detection of predominant mesangial C1q deposits, follow-up ranged from 10 to 11 years. At the time of detection of predominant mesangial C1q deposits, two cases presented with mild proteinuria (1+ by dip stick tests) without hematuria. The remaining three cases had normal results to urinalysis. Anti-C1q antibody titers were in the normal range for all five cases. Four of the cases had normal serum creatinine levels and stable renal function. One patient had a moderate increase in serum creatinine levels, from 0.5 to 1.2 mg/dl, due to acute rejection. The patient maintained stable renal function after that. None of the patients presented with persistent proteinuria and/ or hematuria 2+ by dip stick test, and no cases presented with hypertension or developed SLE. The immunosuppressive agents the five patients were given included tacrolimus hydrate (adjusted to target level of 3-5 ng/ml, (mycophenolate mofetil (700 mg/m2/day), and methylprednisolone (1-4 mg/day). Two of the patients had received an ARB (losartan potassium at 100 mg/day or 25 mg/day) at the time of diagnosis. All patients had received ARBs 10 years after the predominant C1q deposits were detected. None of the patients had received ACE inhibitors at time of detection of predominant C1q deposits or 10 years later. Light microscopy revealed averages of 28 glomeruli, all of which showed minor glomerular abnormalities. Immunofluorescence microscopy revealed predominant mesangial C1q deposits and co-deposits. With the exception of one case whose specimen also exhibited staining in some capillary loops, Cq1 deposits were limited to the mesangium or para-mesangium areas. Only one case showed IgA deposits. All selected specimens showed EDDs in the mesangium on electron microscopy. One case had subendothelial deposits and two cases had subepithelial deposits. None of the cases showed tubuloreticular inclusions or foot process effacements. This long-term observational study on transplanted kidneys confirms that there are cases with predominant but silent C1q deposits in the mesangium who have negative or only mild proteinuria with minor glomerular abnormality. This provides a first step towards a better understanding of the role of predominant mesangial C1q deposits, the researchers said. 22 Nephrology Times May/June 2018

23 The Only Iron Replacement Therapy That Maintains Hemoglobin Triferic is an innovative iron therapy that effectively treats the iron loss and anemia that hemodialysis patients suffer from. Gives Iron When and Where Patients Need it Triferic enters the blood via dialysate and donates its iron immediately to transferrin, making red blood cells and maintaining hemoglobin. Increases Healthy Red Blood Cells Hemoglobin enables red blood cells to carry oxygen to all parts of the body, providing energy. Proven Safety Profile No iron trapped in the liver and no increase in ferritin, inflammation, toxicity or infections. No anaphylaxis. Decrease in blood transfusions. 1 The Only FDA Approved Drug Indicated to Replace Iron and Maintain Hemoglobin in Adult CKD-HD Patients To schedule a web-enabled presentation on the benefits that Triferic can provide to your patients us at trifericpres@rockwellmed.com or call Triferic Rockwell Medical IMPORTANT SAFETY INFORMATION Warnings and Precautions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving parenteral iron products. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after hemodialysis until clinically stable. Personnel and therapies should be immediately available for the treatment of serious hypersensitivity reactions. Hypersensitivity reactions have been reported in 1 (0.3%) of 292 patients receiving Triferic in two randomized clinical trials. Iron status should be determined on pre-dialysis blood samples. Post dialysis serum iron parameters may overestimate serum iron and transferrin saturation. Adverse Reactions The most common adverse reactions (>3% and at least 1% greater than placebo) in controlled clinical studies include: headache, peripheral edema, asthenia, AV fistula thrombosis, urinary tract infection, AV fistula site hemorrhage, pyrexia, fatigue, procedural hypotension, muscle spasms, pain in extremity, back pain, and dyspnea. For full Safety and Prescribing Information please visit 1 In Clinical Trials vs. Placebo. Triferic [Package Insert]. Rockwell Medical, Wixom, MI, September The Triferic logo and blood drop character are Registered Trademarks of Rockwell Medical, Inc.

24 Conference Coverage ANNA National Symposium Highlights Las Vegas, Nevada April 15-18, 2018 The American Nephrology Nurses Association (ANNA) held its 2018 National Symposium in Las Vegas, Nevada, April 15-18, The meeting included posters and presentations on topics such as hemodialysis, chronic kidney disease, acute kidney disease, use of telemedicine in pediatric nephrology care, and treatment with direct-acting antiviral therapy for patients with hepatitis C on dialysis. 24 Nephrology Times May/June 2018

25 Jami S. Brown, DHEA, RN, CNN, presented a poster titled Strategies to Prevent Acute Kidney Injury (AKI) and Dialysis-Requiring Acute Kidney Injury (AKI-D) in Patients with HIV. The poster described a 43-year-old patient with a history of HIV, hypertension, myocardial infarction, and type 2 diabetes mellitus. The patient reported a decrease in urination one week after a heart catherization. It is important for nurses to translate the knowledge of nephrology into practice and think critically when providing care to patients with HIV in order to minimize the risk of AKI and prevent complications associated with AKI-D, the poster noted. In a poster titled Telemedicine Use in the Pediatric Renal Transplant Population, Cindy Richards, BSN, RN, CNN, Children s Hospital of Alabama, described a telemedicine program designed to provide care to pediatric kidney transplant recipients in rural areas. A nephrology and transplant center is working in cooperation with the state health department and a hospital with an existing telemedicine program. The center has a dedicated office to be utilized for telemedicine visits and local health department nursing staff have been trained to use equipment that will allow the physician to auscultate lung and heart sounds. The hope for the program is to decrease the number of no-show clinic visits, and improve our patients outcomes and lengthen the life of the allograft for these patients, Ms. Richards said. Suzanne Joynt, nurse unit manager, Renal and Gastroenterology Services, Auckland District Health Board, New Zealand, presented a poster titled Dialysis Fatigue How Can We Best Assess Our Patients and Help Them to Manage This? Ms. Joynt conducted a literature search to identify assessment tools to aid in objective measurement of fatigue in patients on maintenance dialysis. Of the 24 tools studied, the Fatigue Severity Scale (FSS) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) will be tested at the author s center due to ease of use and the information gathered that will enable healthcare providers to formulate plans of care. While managing fatigue in hemodialysis patients can be a challenge, nurses have the ability to influence their patients on how to best manage their fatigue, Ms. Joynt said. Peritoneal dialysis in older patients with end-stage renal disease (ESRD) was the topic of a presentation from Nida Quirong-Jones of the Einstein Medical Center in Philadelphia, Pennsylvania. In her presentation, Peritoneal Dialysis in Octogenarians, she notes that peritoneal dialysis is underutilized in the very old population, especially those over the age of 80 years. The author describes the experience with elderly peritoneal patients with an average age of 83 years and finds that octogenarian ESRD patients can successfully do peritoneal dialysis at home with the help of their care partners and comprehensive training The peritoneal dialysis training nurse must be patient, resourceful, and supportive in the elderly patient s desire to successfully perform peritoneal dialysis at home, she said. In a poster titled Depression and Medication Adherence in Patients on Hemodialysis, Zorica Kauric-Klein, APRN-BC, PhD, reported that approximately 80% of a cohort of 118 patients on chronic hemodialysis were found to have moderate depression. The analysis also demonstrated that depression was a significant predictor of nonadherence to blood pressure medication therapy in that patient population. Depression is a modifiable risk factor, and interventions that address depression in conjunction with adherence to blood pressure regimens need to be tested in the hemodialysis population, the author said. Rebecca J. Bartlett, PhD, RN, and colleagues reported on the Feasibility of an Intervention to Slow Progression of Chronic Kidney Disease [CKD]. The presentation included a description of a pilot study to assess the feasibility and acceptability of delivering ISTOP-CKD (Intervention Strategies to Overcome Progression of CKD), an intervention designed for patients with CKD stage 3 and comorbid diabetes and hypertension. The study included 15 patients randomized to ISTOP- CKD and 15 to attention control groups. Knowledge significantly increased in the ISTOP-CKD group compared with the control group (P<.05). Recruiting stage 3 CKD patients is challenging; this study highlights the importance of increasing patients awareness of CKD in stage 3 to increase patient activation, self-management, and slow CKD progression, the authors said. Improving patients experience with hemodialysis was the subject of a presentation by Erica Kang, BsN, RN. She described an innovation developed at a communitybased hospital in Toronto, Canada, that included the utilization of home design hemodialysis machines for in-hospital patients. In a poster titled Utilizing a New Model of Care to Improve Patients Experience on Hemodialysis, Ms. Kang reviewed a pilot project that evaluated the efficacy of a care model for patients who were unable to tolerate conventional three times weekly hemodialysis. Upon completion of the trial run, patients in the new model group had fewer visits to the emergency department and fewer hospital admissions compared with a control group. The pilot project was successful and led to an expansion of the unit in January 2017, accommodating 14 patients including those with congestive heart failure, Ms. Kang said. The peritoneal dialysis training nurse must be patient, resourceful, and supportive in the elderly patient s desire to successfully perform peritoneal dialysis at home. Nida Quirong-Jones Joni-Jill Tobrocke, RN, CNN, and Wanda Flynn, BS, CNN, CEN, presented a poster titled Honor Thy Nurse: Establishing a Nursing Honor Guard, that described a program designed to recognize men and women who have dedicated their professional lives to nursing, and to pay respect to fellow nurses (retired or active NP, RN, or LPN), at the end of life s journey, for the devotion and commitment they demonstrated in caring for the vulnerable. Since its founding 4 years ago, the Honor Guard has been called upon for 18 services. The presence of the Honor Guard provides recognition of the nurse who has died, and the nurses who are members of the Honor Guard consider it both an honor and a privilege to participate in final services for their fellow nurses, the authors said. Patients with chronic kidney disease have altered taste function, and are at higher risk of hyperkalemia that may require chronic use of patiromer. In a study sponsored by Relypsa, a Vifor Pharma Group Company, Jeanene Fogli and colleagues conducted a study to examine the compatibility of patiromer with apple and cranberry juices, as alternatives to water. Results were reported in a poster titled In Vitro Total Potassium-Binding Capacity of Patiromer When Mixed with Apple or Cranberry Juice. The mean total potassium-binding capacity of patiromer suspended in apple juice was 8.8 meq/l at both high and low dilutions. For cranberry juice cocktail, the values were 8.6 meq/l for high dilutions and 8.6 meq/l for low dilutions. The mean result for water was 9.1 meq/l. The differences were not considered clinically relevant. There was no adverse impact on the in vitro total potassium-binding capacity when patiromer was mixed with apple juice or cranberry juice cocktail, the authors said. Fresenius Medical Care North American Provides Funding for Scholarships At the ANNA National Symposium, Fresenius Medical Care North America announced the names of five recipients of educational scholarships. The five scholarship recipients were selected from 32 applicants; each will receive $4000 ahead of the fall 2018 academic term. The scholarships are made possible through a $20,000 grant from Fresenius Medical Care North America. The five scholarship recipients are Genna Hirsch, RN, CDN, who is pursuing her bachelor s degree in nursing at Fort Hays State University, Hays, Kansas; Sonya Jeevanandam, BSN, CND. RN, who is a candidate for a master s degree in nursing; Stacey Meier, BS, RN, pursuing a master s in education; Amber Paulus, BSN, RN, CPHQ, a second-year PhD candidate at Virginia Commonwealth University, Richmond; and James Thomas, RN, CDN, who is a candidate for a master s degree in nursing with a focus on leadership and management. As a leader in renal care, we are committed to recognizing the passion and dedication of nephrology nurses across the country, said Ron Rodgers, executive vice president, Fresenius Medical Care North America and president, Fresenius Kidney Care. Congratulations to the scholarship recipients and thank you for the incredible work you do for people living with kidney disease. Nephrology Times May/June

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27 Polycystic kidney disease (PKD) is characterized by the progressive enlargement of numerous fluid filled cysts in the kidney. The 2 main types of PKD are ARPKD,* and the most commonly seen ADPKD. 1,2 In your patients with ADPKD COULD KIDNEY DAMAGE BE GOING UNNOTICED? egfr levels can remain steady over many years, but enlarging cysts continue to increase kidney volume, damaging renal tissue. 2,3 Learn about the early signs of disease progression at UncoverPKD.com and screen your patients if you suspect they may be at risk. *Autosomal recessive polycystic kidney disease. Autosomal dominant polycystic kidney disease. Estimated glomerular filtration rate. References: 1. Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60: Braun WE. Autosomal dominant polycystic kidney disease: emerging concepts of pathogenesis and new treatments. Cleve Clin J Med. 2009;76(2): Grantham JJ. Autosomal dominant polycystic kidney disease. N Engl J Med. 2008;359(14): Otsuka America Pharmaceutical, Inc. August US17EUP0019

28 News Briefs Study Results Reported at Annual Dialysis Conference At the Annual Dialysis Conference in Orlando, Florida, March 3-6, results of a study conducted in Canada were reported. Manish M. Sood, MD, led the study that found that patients with end-stage renal disease due to autosomal polycystic kidney disease (ADPKD) are significantly more likely to receive a kidney transplant and to use home hemodialysis, compared with patients without ADPKD. Survival rates of patients with ADPKD are also higher, according to an article in Renal and Urology News. Compared with non-adpkd patients, those with ADPKD had 7-fold greater odds of undergoing pre-emptive kidney transplantation, 2.4-fold greater odds of undergoing any kidney transplantation, and 2.7-fold increased odds of using home dialysis. In addition, the mortality rate during the 12 years of the study period in the ADPKD group was 21% compared with 34.1% among patients without ADPKD. The lower mortality rates were seen regardless of whether the initial ESRD treatment modality was intermittent hemodialysis (26.8% vs 39%) or peritoneal dialysis (17.4% vs 24.7%). Jynarque Is First FDA-Approved Treatment for ADPKD Jynarque (tolvaptan) has received approval from the US FDA as the first treatment to slow decline in kidney function in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Otsuka Pharmaceutical Co., Ltd., manufacturers of tolvaptan, made the announcement of FDA approval in a press release in April. AKPKD is a progressively debilitating and painful disorder in which fluid-filled cysts develop in the kidneys over time. The cysts enlarge and impair the kidney s ability to function normally, leading to kidney failure in most patients. ADPKD is diagnosed in approximately 140,000 patients in the United States, and parents have a 50% chance of passing the disease on to each of their children. Tolvaptan s efficacy was demonstrated in two trials: the 1-year REPRISE study and the 3-year TEMPO study. In both trials, decline in kidney function was slowed in adults at risk for rapidly progression ADPKD receiving tolvaptan. In the Otsuka press release, Michal Mrug, MD, investigator on the REPRISE trial said, The progressive nature of ADPKD means that kidney function gets worse over time, eventually leading to end-stage renal disease Todays approval is great news for adults at risk for rapidly progressing ADPKD because by slowing the decline in kidney function, this therapy may give them more time before kidney transplant or dialysis. LATE-BREAKER Valtessa Supplemental NDA Approved by FDA In early May 2018, Veltassa (patiromer) received FDA approval of a supplemental New Drug Application (snda) for use with or without food. According to a May 8 press release from Relypsa, a Vifor Pharma Group company, the label approval was effective immediately for the treatment of patients with hyperkalemia. Since the US approval of Veltassa two years ago, we have seen how the availability of this medicine has been able to significantly transform the way physicians treat hyperkalemia. We are pleased with the FDA s approval of this supplement and believe the updated label will provide patients with greater flexibility in incorporating Veltassa in their daily treatment regimen, said Scott Garland, president of Relypsa. An estimated 3 million individuals in the United States with stage 3 or 4 chronic kidney disease and/or heart failure have hyperkalemia, defined as elevated levels of blood potassium. Hyperkalemia increases the risk of abnormal heart rhythms and sudden death. Some patients with CKD taking medications to delay progression of their underlying disease may experience hyperkalemia as a side effect. Such medications include renin angiotensin aldosterone system inhibitors (i.e., angiotensin receptor blockers, aldosterone antagonists, and angiotensin-converting-enzyme inhibitors). The label update was based on results from the phase 4 TOURMALINE study. Results demonstrated that there was no statistically significant difference in achieving the study end point between a group taking Veltassa with food and a group taking it without food. TOURMALINE randomly assigned 114 patients with blood potassium >5.0 meq/l to receive once-daily Veltassa at a starting does of 8.4 g either with or without food. Overall, 87.3% of the with food group and 82.5% of the without food group achieved potassium levels in the target level range ( meq/l) at either week 3 or week 4. In general, patients with higher levels of potassium had greater reductions in potassium. In multivariable analysis adjusting for baseline potassium, race, estimated glomerular filtration rate, and type 2 diabetes, results were consistent. Relypsa Research Grants Awarded to Three Institutions In a press release in April, Relypsa, a Vifor Pharma Group company, announced the presentation of three research grants to supplement institutional funding for nephrology and/or cardiology fellows who are researching hyperkalemia and other disorders. Alain Romero, PhD, PharmD, Relypsa vice president of medical and scientific affairs, said, Our research grants aim to improve patient care, encourage disease awareness, and educate healthcare organizations and professionals. We are excited for the recipients of the Relypsa Nephrology and Cardiology Research Grant Program and look forward to seeing the results of their research. The grants will fund research in areas key to improving care for patients with kidney and heart disease: (1) defining the frequency of hyperkalemia in solid organ transplant recipients and correlating episodes of hyperkalemia to clinical episodes; (2) exploring the influence of levels of potassium and urea on fibrosis in animal models of renal dysfunction; and (3) following patients prospectively at a single site who require either a renin angiotensin system blocker and/or a mineralocorticoid receptor antagonist to improve blood pressure and/or cardiac function. The grants were awarded to the University of Cincinnati, Emory University, and the University of Chicago. Corporate Charitable Foundation Launched by Fresenius Medical Care North America In April, Fresenius Medical Care North America announced the launch of the Fresenius Medical Care Foundation. According to a press release, the foundation is a nonprofit created to address the environmental, social, and economic conditions that increase the risk for chronic kidney disease (CKD). The foundation will be funded by match donations from Fresenius employees, medical staff, and other individuals up to $1 million in its inaugural year. In the press release, Bill Vale, chief executive officer of Fresenius Medical Care North America, said, We strive to treat the whole patient not just for their condition and recognize the unique role we can play in furthering the national dialogue around chronic kidney disease and transplant awareness. When we look outside the walls of our dialysis clinics, we know we must help people at risk for developing kidney disease and our new foundation is a significant step toward that important, long-term goal. As part of the foundation s first year, Fresenius employees assembled 4000 Healthy Eating, Active Lifestyle kits that were distributed to school students in 28 Nephrology Times May/June 2018

29 News Briefs Chicago; in addition, the foundation will donate $50,000 to the YMCA of Chicago to support Camp Duncan, a medical summer camp program for children with diabetes and kidney disease. Kim Sonnen, senior vice president and payer relations and communications at Fresenius Medical Care North America and chairperson of the foundations board of directors, said, Our goal is to get ahead of the curve to create a healthier generation of adults., If we begin promoting a healthy, active lifestyle early in life, we may be able to reduce the prevalence of kidney disease starting education at a young age is central to the mission of our foundation. Fresenius Kidney Care Announces Five-Star Ratings Success Fresenius Kidney Care, a division of Fresenius Medical Care North America, and one of the leading networks of dialysis facilities in the United States, issued a press release announcing that it achieved the highest results in the industry as a result of the government s Five-Star Quality Rating System. The scores are based on the Five-Star Quality Rating System by the Centers for Medicare & Medicaid Services based on a series of measurements of clinical performance and patient outcomes. Ron Rodgers, executive vice president of Fresenius Medical Care North America and president of Fresenius Kidney Care, said, Our Five-Star success demonstrates our commitment to the highest quality of patient care. These results are a testament to our family of caregivers and physicians across the US who are the foundation of our five-star quality. The ratings represent the fourth consecutive year that Fresenius Kidney Care had a significant increase in the percentage of clinics achieving a rating of five out of five stars; 659 of Fresenius clinics achieved the highest rating. Jeffrey Hynes, MD, chief medical officer for Fresenius Kidney Care, said, This recognition is a direct result of our dedicated staff who work every day to improve the lives of our patients. The Five-Star rankings reflect our success in reducing hospitalizations, infections, and other key quality measurement reflected in the ratings. Our disciplined approach to quality is key to our ongoing success. Major Meetings American Society of Nephrology Kidney Week 2018 October 23-28, 2018 San Diego, California Annual Dialysis Conference March 13-16, 2019 Dallas, Texas Renal Physicians Association Annual Meeting 2019 March 28-31, 2019 Chicago, Illinois American Nephrology Nurses Association 2019 National Symposium April 14-17, 2019 Dallas, Texas National Kidney Foundation Spring Clinical Meetings 2019 May 7-11, 2019 Boston, Massachusetts American Transplant Congress 2019 June 1-5, 2019 Boston, Massachusetts Nephrology Times May/June

30 Abstract Roundup ACUTE KIDNEY INJURY Rates of AKI Lower with TAVR versus SAVR Nephrology Dialysis Transplantation. doi.org/ /ndt/gfy097 In randomized trials, rates of acute kidney injury are lower with transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR). There are limited nationally representative real-world data on the comparative rates of AKI for TAVR versus SAVR and predictors and prognostic implications of AKI after aortic valve replacement (AVR). Nilay Kumar, MD, and Neetika Garg, MD, conducted an analysis to compare rates of AKI and dialysis requiring AKI (AKI-D) in TAVR versus SAVR; the researchers also sought to identify predictors of AKI and prognostic implications of AKI in patients undergoing TAVR or SAVR. The analysis included 8004 unweighted TAVR procedures and 29,355 unweighted SAVR procedures representing the entirety of procedures nationwide. Mean age of all patients undergoing AVR was 70.9 years and 42.3% were female. In a propensity-matched cohort of 4889 pairs of TAVR and SAVR procedures, there was an association between TAVR and significantly lower rates of AKI (odds ratio [OR], 0.73; 95% confidence interval [CI], ; P<.001) and AKI-D (OR, 0.69; 95% CI, ; P=.03) compared with SAVR. There was an association between AKI and significantly higher rates of in-hospital mortality with both TAVR (OR, 7.16; 95% CI, ; P<.001) and SAVR (OR, 9.43; 95% CI, ; P<.001). In a large propensity-matched cohort of TAVR and SAVR procedures, TAVR was associated with significantly lower rates of AKI and AKI-D compared with SAVR. AKI and AKI- D are predictors of poor in-hospital outcomes in TAVR as well as SAVR, the researchers concluded. CHRONIC KIDNEY DISEASE CKD Associated with Complications after Pancreatectomy Regardless of Stage Journal of Gastrointestinal Surgery. doi: /s Patients with severe chronic kidney disease (CKD) undergoing pancreatectomy are at increased risk for adverse outcomes; however, the impact of milder CKD on this patient population is unclear. Further, there are some data suggesting that, due to physiologic changes associated with aging, CKD may be over diagnosed in patients >65 years of age. Derrick Antoniak, MD, and colleagues conducted a study designed to examine outcomes in older patients with mild CKD undergoing pancreatectomy for malignancy. The study cohort included 16,173 patients who underwent pancreatectomy from 2005 to Mean IMPORTANT SAFETY INFORMATION CONTRAINDICATION: AURYXIA (ferric citrate) is contraindicated in patients with iron overload syndromes WARNINGS AND PRECAUTIONS: Iron Overload: Monitor ferritin and transferrin saturation (TSAT). Patients may require a reduction in dose or discontinuation of concomitant intravenous (IV) iron Risk of Overdosage in Children Due to Accidental Ingestion: Accidental ingestion and resulting overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Advise patients to keep AURYXIA out of the reach of children PREGNANCY AND LACTATION: Overdosing of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes and fetal malformation. Rat studies have shown the transfer of iron into milk. There is possible infant exposure when AURYXIA is taken by a nursing woman ADVERSE REACTIONS: In clinical trials, likely adverse reactions occurring in >5% of patients treated with AURYXIA were discolored feces, diarrhea, constipation, nausea, vomiting, cough, abdominal pain and hyperkalemia To report suspected adverse reactions, contact Keryx Biopharmaceuticals at FOR MORE INFORMATION, VISIT AURYXIA.COM 2018 Keryx Biopharmaceuticals, Inc. PP-AUR-US /18 30 Nephrology Times May/June 2018

31 Abstract Roundup T:21 S:14 age was 66 years (range, 18-90), median preoperative creatinine was 0.80 mg/dl, and median preoperative estimated glomerular filtration rate was ml/min/1.73 m2. Three percent of the patients died and 23% experienced a major complication. In results of adjusted analyses, there was an association between increased risk for major complications and CKD stage 2 (adjusted odds ratio [aor], 1.24; 95% confidence interval [CI], ); CKD stage 3a (aor, 1.50; 95% CI, ); CKD stage 3b (aor, 1.56; 95% CI, ); and CKD stage 4 (aor, 2.17; 95% CI, ). CKD stage 4 was also associated with increased mortality (aor, continued on next page For the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD) not on dialysis Designed to be dif ferent AURYXIA is the only oral iron tablet approved by the FDA for the treatment of iron deficiency anemia specifically in adult patients with CKD not on dialysis Proven effective in patients who were previously intolerant of or had an inadequate therapeutic response to traditional oral iron supplements - Patients in the Phase III pivotal trial achieved results without the use of ESAs or IV iron - 52% of patients achieved the primary endpoint of a hemoglobin increase of 1.0 g/dl by Week percentage-point increase in mean TSAT at Week 16 from baseline Discontinuation rates due to adverse reactions were similar between AURYXIA and placebo (10% vs 9%) Convenient mealtime dosing Each tablet contains 210 mg of elemental iron ESAs=erythropoiesis stimulating agents Please see Brief Summary including patient counseling information on following page

32 Abstract Roundup continued from previous page 2.68; 95% CI, ). There was no association with age and the relationship between CKD and either outcome. CKD of any stage was associated AURYXIA (ferric citrate) tablets for oral use containing 210 mg of ferric iron equivalent to 1 g AURYXIA for oral use. INDICATION AND USAGE AURYXIA is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease not on dialysis. CONTRAINDICATIONS AURYXIA is contraindicated in patients with iron overload syndromes (e.g., hemochromatosis). WARNINGS AND PRECAUTIONS Iron Overload: Iron absorption from AURYXIA may lead to excessive elevations in iron stores. Increases in serum ferritin and transferrin saturation (TSAT) levels were observed in clinical trials. In a 56-week safety and efficacy trial evaluating the control of serum phosphate levels in patients with chronic kidney disease on dialysis in which concomitant use of intravenous iron was permitted, 55 (19%) of patients treated with AURYXIA had a ferritin level >1500 ng/ml as compared with 13 (9%) of patients treated with active control. Assess iron parameters (e.g., serum ferritin and TSAT) prior to initiating AURYXIA and monitor iron parameters while on therapy. Patients receiving intravenous iron may require a reduction in dose or discontinuation of intravenous iron therapy. Risk of Overdosage in Children Due to Accidental Ingestion: Accidental ingestion and resulting overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Advise patients of the risks to children and to keep AURYXIA out of the reach of children. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to adverse reaction rates in the clinical trials of another drug and may not reflect the rates observed in practice. Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis Across two trials, 190 unique patients with CKD-NDD were treated with AURYXIA. This included a study of 117 patients treated with AURYXIA and 116 patients treated with placebo in a 16-week, randomized, double-blind period and a study of 75 patients treated with AURYXIA and 73 treated with placebo in a 12-week randomized double-blind period. Dosage regimens in these trials ranged from 210 mg to 2,520 mg of ferric iron per day, equivalent to 1 to 12 tablets of AURYXIA. Adverse reactions reported in at least 5% of patients treated with AURYXIA in these trials are listed in Table 1. Table 1: Adverse Reactions Reported in Two Clinical Trials in at least 5% of patients receiving AURYXIA Body System Adverse Reaction AURYXIA % (N=190) with an increased risk of postoperative major complication, and severe CKD was associated with increased mortality among patients undergoing pancreatectomy for malignancy. Placebo % (N=188) Any Adverse Reaction Metabolism and Nutrition Disorders Hyperkalemia 5 3 Gastrointestinal Disorders Discolored feces 22 0 Diarrhea Constipation Nausea 10 4 Abdominal Pain 5 2 During the 16-week, placebo-control trial, 12 patients (10%) on AURYXIA discontinued study drug because of an adverse reaction, as compared to 10 patients (9%) in the placebo control arm. Diarrhea was the most common adverse reaction leading to discontinuation of AURYXIA (2.6%). DRUG INTERACTIONS Orally administered doxycycline has to be taken at least 1 hour before AURYXIA. Orally administered ciprofloxacin should be taken at least 2 hours before or after AURYXIA. Oral drugs that can be administered concomitantly with AURYXIA are: amlodipine, aspirin, atorvastatin, calcitriol, clopidogrel, digoxin, diltiazem, doxercalciferol, enalapril, fluvastatin, glimepiride, levofloxacin, losartan, metoprolol, pravastatin, propranolol, sitagliptin, and warfarin. Oral medications not listed above There are no empirical data on avoiding drug interactions between AURYXIA and most concomitant oral drugs. For oral medications where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of the administration These associations were not diminished in elderly patients. Our findings could inform preoperative counseling and decision-making, the researchers said. of the two drugs. The duration of separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Consider monitoring clinical responses or blood levels of concomitant medications that have a narrow therapeutic range. USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary There are no available data on AURYXIA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted using AURYXIA. Skeletal and encephalic malformation was observed in neonatal mice when ferric gluconate was administered intraperitoneally to gravid dams on gestation days 7-9. However, oral administration of other ferric or ferrous compounds to gravid CD1-mice and Wistar-rats caused no fetal malformation. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes and fetal malformation. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20% respectively. Clinical Considerations The effect of AURYXIA on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. Lactation: Risk Summary There are no human data regarding the effect of AURYXIA in human milk, the effects on the breastfed child, or the effects on milk production. Data from rat studies have shown the transfer of iron into milk by divalent metal transporter-1 (DMT-1) and ferroportin-1 (FPN-1). Hence, there is a possibility of infant exposure when AURYXIA is administered to a nursing woman. The development and health benefits of breastfeeding should be considered along with the mother s clinical need for AURYXIA and any potential adverse effects on the breastfed child from AURYXIA or from the underlying maternal condition. Pediatric Use: The safety and efficacy of AURYXIA have not been established in pediatric patients. Geriatric Use: Clinical studies of AURYXIA included 292 subjects aged 65 years and older (104 subjects aged 75 years and older). Overall, the clinical study experience has not identified any obvious differences in responses between the elderly and younger patients in the tolerability or efficacy of AURYXIA. OVERDOSAGE No data are available regarding overdose of AURYXIA in patients. In patients with chronic kidney disease, the maximum dose studied was 2,520 mg ferric iron (12 tablets of AURYXIA) per day. Iron absorption from AURYXIA may lead to excessive elevations in iron stores, especially when concomitant intravenous iron is used. In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient on dialysis administered IV iron and AURYXIA. PATIENT COUNSELING INFORMATION Dosing Recommendations: Instruct patients to take AURYXIA as directed with meals and adhere to their prescribed diets. Instruct patients on concomitant medications that should be dosed apart from AURYXIA. Advise patients not to chew or crush AURYXIA because tablets may cause discoloration of mouth and teeth. Adverse Reactions: Advise patients that AURYXIA may cause discolored (dark) stools, but this staining of the stool is considered normal with oral medications containing iron. AURYXIA may cause diarrhea, nausea, constipation, vomiting, hyperkalemia, abdominal pain, and cough. Advise patients to report severe or persistent gastrointestinal symptoms to their physician. Accidental Ingestion: Advise patients to keep this product out of the reach of children and to seek immediate medical attention in case of accidental ingestion by a child. Issued 11/2017 Rev Keryx Biopharmaceuticals, Inc. Printed in USA PP-AUR-US /18 DIABETIC NEPHROPATHY Diabetic Nephropathy and Altered Expression of WFS1 and NOTCH2 Genes Diabetes Research and Clinical Practice. doi.org/ /j.diabres In light of the increase in the incidence of type 2 diabetes mellitus (T2DM) and the importance of early diagnosis and management of complications associated with T2DM, particularly diabetic nephropathy, there has been increased interest in the genetic factors that affect the risk of T2DM and related nephropathy. Sahar A. Sharaf, MD, and colleagues conducted a study designed to examine the expression of the genes KCNJ11, ABCC8, JAZF1, WFS1, PPARG, NOTCH2, and EXOSC4 in peripheral blood in patients with T2DM. The study cohort included 30 patients with T2DM without complications, 30 patients with diabetic nephropathy, and 40 healthy controls. Gene expression was studied using quantitative real time polymerase chain reaction array. Compared with patients with no T2DM-related complications, those with diabetic nephropathy had higher expression of NOTCH2 and lower expression of KCNJ11, JAZF1, WFS1, and PPARG genes. KCNJ11, JAZF1, WFS1, PPARG, and EXOSC4 expression showed significant negative correlation with microalbumin; NOTCH2 expression had significantly positive correlation with microalbumin. There was significant negative correlation between expression of WFS1 and hemoglobin A1c (HbA1c); there was no significant correlation between expression of NOTCH2, KCNJ11, JAZF1, PPARG, and EXOSC4 and HbA1c. Risk ratio of the expression of the studied genes demonstrated that WFS1 and NOTCH2 had the highest risk ratio (30) and the highest sensitivity and specificity in relation to diabetic nephropathy; they were the best predictors among the included genes at a cut off value of for WFS1 and for NOTCH2. In conclusion, the researchers said, Altered expression of WFS1 and NOTCH2 genes may play a role in pathogenesis and development of diabetic nephropathy in patients with T2DM. These results may contribute in early identification and management of diabetic nephropathy.

33 Abstract Roundup NEPHROLOGY NURSING National Survey Results Revealed Nephrology Nursing Journal. 2018; 45(2): Beth T. Ulrich, EdD, RN, FACHE, FAAN, and Tamara M. Kear, PhD, RN, CNS, CNN, reported results of a research survey they conducted for the American Nephrology Nurses Association in collaboration with Nephrology News & Issues. The survey was conducted in January 2018 and was designed to provide a comprehensive national assessment of the overall health and safety of nephrology nurses as well as an overview of nephrology nurses work environments. Survey respondents included more than 1000 nephrology nurses working in nephrology settings nationwide. Most of the respondents (94%) said they were satisfied with their nursing career; 91% said they would recommend nursing to others, while the majority also indicated they would recommend nephrology nursing as a career. When asked about areas of concern, respondents included staffing, exposure to hazards, long hours of work, and discrimination. Approximately 40% of respondents said they planned to leave their current position within 12 to 36 months, but added that higher salary and benefits would cause them to reconsider. The survey also revealed areas of opportunities for improvements in nephrology nurse work environments, including staffing, optimizing the knowledge and skills of registered nurses, and mental and physical health. RENAL NUTRITION Effects of Oral Nutritional Supplements in Patients on Hemodialysis Journal of Renal Nutrition. doi.org/ /j. jrn In dialysis-dependent end-stage renal disease (ESRD) patients, protein-energy wasting is common and strongly associated with mortality and adverse outcomes. Intradialytic oral nutritional supplements (ONS) reduced the risk of mortality in that patient population. There are few data available on the associations between ONS and other outcomes. Debbie Benner, MA, RD, CSR, and colleagues conducted a retrospective evaluation of a pilot program that provided ONS to patients at a large dialysis organization in the United States. The evaluation aimed to examine the associations between the administration of ONS and clinical and nutritional outcomes. The evaluation compared patients receiving ONS (n=3374) with matched controls (n=3374) with serum albumin 3.5 g/dl. The controls were identified from facilities not participating in the ONS program. Electronic medical records were used to extract data on death, missed dialysis treatments, hospitalizations, serum albumin, normalized protein catabolic rate, and postdialysis body weight. Among patients in the ONS program, compared with controls, there was a 69% reduction in deaths (hazard ratio [HR], 0.31; 95% confidence interval [CI], ; P<.001) and 33% fewer missed dialysis treatments (incidence rate ratio, 0.77; 95% CI, ; P<.001). Results regarding nutritional markers were mixed: serum albumin was lower and normalized protein catabolic rate values and postdialysis body weights were higher among patients in the ONS program compared with the control group during follow-up. In conclusion, the researchers said, Our evaluation confirmed the beneficial effects of ONS in reducing mortality and improving some indices of nutritional status for hypoalbuminemic hemodialysis patients. We also report the novel finding that ONS can reduce the number of missed dialysis treatments. These results support the use of intradialytic ONS as an effective intervention to improve the outcomes in hemodialysis patients with low serum albumin. Sarcopenia and Nutritional Status in Hemodialysis Patients Journal of Renal Nutrition. doi.0rg/ /j. jrn A study led by Juliana Giglio, MS, sought to determine whether there is an association with diminished muscle mass, diminished muscle, or both (sarcopenia) and worse nutritional status, poor quality of life, and hard outcomes including hospitalization and mortality among elderly patients on maintenance hemodialysis. The multicenter observational longitudinal study included 170 patients on maintenance hemodialysis from six dialysis centers. Mean age of participants was 70 years and 65% were male. Sarcopenia is defined by the European Working Group on Sarcopenia in Older People as the presence of both low muscle mass by appendicular skeletal + low muscle function by handgrip strength. The current study assessed participants clinical and nutritional status and quality of life at baseline. Hospitalization and mortality were recorded during 36 months of follow-up. Reduced muscle mass was seen in 64% of the patients, 52% had reduced muscle strength, and 37% had sarcopenia. Compared with patients without sarcopenia, those with sarcopenia were older, were more likely to be male, and had worse clinical and nutritional conditions. There was a strong association between reduced muscle mass and poor nutritional status, and low muscle strength was associated with worse quality of life domains. In multivariate Cox analyses adjusted by age, sex, dialysis vintage, and diabetes mellitus, there was an association between low muscle strength alone and sarcopenia and higher rates of hospitalization. Sarcopenia was also a predictor of mortality. The researchers said, In conclusion, in this sample, comprised of elderly patients on maintenance hemodialysis, sarcopenia was associated with worse nutritional and clinical conditions and was a predictor of hospitalization and mortality. TRANSPLANTATION Prophylaxis with Direct-Acting Antivirals Safe and Effective in Transplantation Recipients Annals of Internal Medicine. doi: /m The mortality rate among patients with end-stage kidney disease on dialysis is high. With the efficacy and safety of treatments for hepatitis C virus (HCV), discarded kidneys from donors infected with HCV may be a neglected public health resource. Christine M. Durand, MD, and colleagues recently conducted an open-label nonrandomized trial designed to assess the tolerability and feasibility of using directacting antivirals (DAAs) as prophylaxis prior to and following kidney transplantation from HVC-infected donors to non HVCinfected recipients (HCV D+/R transplantation). Merck Sharp & Dohme Corp. was the primary funding source for the trial. The study cohort included 10 HCV D+/R kidney transplant candidates >50 years of age with no available living donors. The intervention consisted of transplantation of kidneys from deceased donors 13 to 50 years of age with positive HCV RNA and HCV antibody test results. All recipients received 100 mg grazoprevir (GZR) and 50 mg elbasvir (EBR) immediately prior to transplantation. Patients receiving kidneys from donors with genotype 1 infection continued receiving GZR and EBR for 12 weeks following transplantation; patients receiving kidneys from donors with genotype 2 or 3 infection had 400 mg sofosbuvir added to GZR and EBR for 12 weeks of triple therapy. The primary safety outcome was the incidence of adverse events related to the GZR-EBR regimen. The primary efficacy outcome was the proportion of recipients with an HCV RNA level below the lower limit of quantification 12 weeks following prophylaxis. There were no treatment-related adverse events among the 10 HCV D+/R transplant recipients. There was no HCV RNA detected in any recipient 12 weeks after treatment. Pre- and post-transplantation HCV treatment was safe and prevented chronic HCV infection in HCV D+/R transplant recipients. If confirmed in larger studies, this strategy should markedly expand organ options and reduce mortality for kidney transplant candidates without HCV infection, the researchers said. Nephrology Times May/June

34 From the Field Rick Collins Tips for Contract Negotiations The emergence of Parsabiv (etelcalcetide) has spotlighted holes in provider contracts that resulted in lost reimbursement for renal providers. The loss of reimbursement could have been prevented in many cases had payer contracts been negotiated more wisely. In this month s article we will look at contract terms that providers should avoid. While the examples that follow focus on outpatient dialysis contracts, the same principles apply to contracts for professional services. ALL-INCLUSIVE, GLOBAL, BUNDLED, AND PER DIEM A side effect of the implementation of the Centers for Medicare & Medicaid End-Stage Renal Disease Prospective Payment System (CMS ESRD PPS), the Bundle, in 2011 is that commercial payers decided they should also bundle dialysis services into one all-inclusive rate. Prior to 2011, most commercial contracts reimbursed dialysis treatments and drugs separately. Once the CMS Bundle was implemented, commercial payers began bundling dialysis services in a manner similar to Medicare, but with important differences. For example, the CMS Bundle anticipates that providers will receive the base rate plus additional reimbursement for comorbid conditions, home training, outliers, drugs given during dialysis that are unrelated to a patient s ESRD, and vaccines, among others. Commercial payers either missed or ignored these critical payments made in addition to the CMS Bundle base rate. Instead, many payers pushed providers to accept a single payment for all services, labor, medications, labs, and supplies provided to ESRD patients regardless of whether the services were related to the patient s ESRD. Further, some providers even agreed to contracts that failed to offer additional reimbursement for home training. When Parsabiv was introduced, many providers found that commercial payers would not pay separately for this new drug because the provider had agreed that ALL services, medications, etc., related to a patient s ESRD were included in the contracted rate. There were no clauses that allowed for the creation of new drugs that could add significant costs to providers without adding any additional reimbursement. Without additional reimbursement, providers were effectively discouraged from providing this new drug that could have benefitted some of their patients. In addition to Parsabiv, providers have found that antibiotics given for non-esrd reasons are not reimbursed nor are vaccines given to patients. The non-esrd drugs and vaccines can be reimbursed in other provider settings, including the physician s office, if the contracts for those providers cover them. CONTRACTS THAT INCLUDE SPECIFIC CODES Another type of contract causing problems for providers are those that specify only certain procedure codes as covered. For example, if an outpatient dialysis program agrees to a contract only for revenue code 0821 (in-facility hemodialysis) with procedure code 90999, any other revenue or procedure code billed on the claim will not be paid. Similar to all-inclusive contracts, no allowance is made for vaccines, drugs given for non-esrd reasons, or new ESRD drugs, A big mistake made by programs offering home dialysis is not including the codes for home training in their commercial contracts. In this case, no additional amounts will be paid for training services because the corresponding codes are not listed in the contract. MANAGED CARE COVERAGE NOT ALWAYS THE SAME AS MEDICARE COVERAGE A common misunderstanding regarding contracts with Medicare Advantage payers is that Medicare Advantage Plans pay exactly the same as Medicare. In reality, procedures and services covered by traditional Medicare are only the minimum standards for Medicare Advantage payers as they can cover more services and pay more than traditional Medicare. However, the introduction of Parsabiv and the move of Sensipar (cinacalcet) from Part D to Part B coverage has befuddled some payers. Several had not updated their systems to reimburse for Parsabiv when it was first introduced into the market and thus denied this medication in error. Others failed to update their systems to reimburse Sensipar when included on an outpatient dialysis claim. As of this writing, some payers are still struggling to modify their claims processing systems so they will pay correctly for these drugs. Interestingly enough, if Parsabiv and Sensipar were denied in error, the payer normally does not go back and locate these claims and pay what they should have. Instead, the payers leave it up to the provider to go back and refile, adjust, or appeal the denials. Unfortunately, if the payer has not updated their system when the provider refiles or adjusts their claims, the payer denies the services incorrectly again. However, if providers fail to refile, adjust or appeal claims that were incorrectly denied, they may miss the payer s timely filing deadlines for appeals and adjustments. It is a game in which the odds are stacked against the provider even though the provider is correct in expecting reimbursement. While difficult, it is usually not impossible to have payers go back and reprocess claims correctly, but it may require a lot of time and persistence on the part of the provider. REVIEW YOUR CURRENT CONTRACTS AND UPDATE/RENEGOTIATE NOW So, what can you do to protect yourself going forward? First, find out if you are being paid for all of the services you are billing. Second, if you are being paid, are you being paid at the correct rate? If you are not being paid correctly, review your payer contracts to see what is covered and the rate at which it is covered. If you find the item is being paid, but at the wrong rate, providers should contact the payer immediately to notify them of the error and ask them to reprocess claims paid incorrectly. If you find that certain procedures are not being paid, review your payer contracts to see if they are included. If not, contact the department of the payer that handles provider contracting and insist on the addition of drugs and procedures not currently covered. Rick Collins is the director of business development for Sceptre Management Solutions, LLC., a company that specializes in billing for dialysis, nephrology, and interventional nephrology programs. Please direct your comments or questions to him at rcollins@sceptremanagement.com or Nephrology Times May/June 2018

35 Nephrology Times Gives You Analysis of Key Journal Studies Focus on Transplantation Abstract Roundup From the Field You get even more at nephtimes.com Check out the online-exclusive content and round out your nephrology news experience. Nephrology Times Practical News, Trends, and Analysis

36 CRRT BUILT FOR my ICU. The PRISMAFLEX System is one of the best tools we ve used in our ICU. And with Baxter s support, we can do so much for our patients now that we ve implemented our Super User Program and CRRT Task Force. Juan Carlos Aycinena, MD Dr. Aycinena dedicated himself to becoming a nephrologist because he wanted to be able to offer hope to the sickest patients. In the past 4 years that he has been using the PRISMAFLEX System, he feels like his team has been able to do so much more for those patients, especially since implementing a CRRT Task Force. Including Baxter on that Task Force was an important decision and just one example of how we are always striving to partner with our customers. Baxter is committed to supporting Dr. Aycinena and his team as they continue to optimize their CRRT program. Watch Dr. Aycinena s story at renalacute.com/stories COMPLETE SUPPORT PATIENT SAFETY FLEXIBILITY The PRISMAFLEX Control Unit is intended for: Continuous Renal Replacement Therapy (CRRT) for patients weighing 20 kilograms or more with acute renal failure and/or fluid overload. Therapeutic Plasma Exchange (TPE) therapy for patients weighing 20 kilograms or more with diseases where fluid removal of plasma components is indicated. Rx Only. For safe and proper use of this device, refer to the Operator s Manual. Baxter and Prismaflex are registered trademarks of Baxter International Inc. or its subsidiaries. USMP/MG120/ /18