ASN Kidney News | March 2016

March 2016 | Vol. 8, Number 3

Living Donor Protections Included in Act Introduced by Congress Inside

Services. The number of people affected by kid- Keeping Nephrology The proposed legislation would pro- ney disease is staggering. According to the Great hibit providers of life, disability, and National Institute of Diabetes, Digestive, Through a series of long-term care insurance from denying or and Kidney Diseases, 1 in 10 American “Distinguished Conversations” limiting coverage to living organ donors. adults—more than 20 million people— during ASN’s 50th year, KN It would also prevent insurers from are affected by some level of chronic kid- readers will hear from leaders charging higher premiums. In addi- ney disease (CKD), and the numbers are and colleagues about what tion, the bill clarifies that living organ increasing. A patient is added to the kid- makes nephrology great donors may use time allotted to ney waitlist every 14 minutes, and despite them through the Family the fact that this list is always growing, liv- and Medical Leave Act ing donation rates are decreasing. In all, Practice Pointers to recover from dona- 12 Americans die each day waiting for a The latest on kidney stone tion surgery and thus transplant. prevention, recurrence, and maintain their job se- The Living Donor Protection Act of treatment curity (Table 1). 2016 was introduced with bipartisan sup- “By creating job port by both houses of Congress, with security for living or- Reps. Jerrold Nadler (D-NY) and Michael Policy Update gan donors and ensur- Burgess (R-TX) and Sens. Mark Kirk (R- President’s 2017 budget new bill introduced ing them time to recover IL), and Kirsten Gillibrand (D-NY) pro- disappoints by Congress in February from their donation surger- posing the legislation. 2016 aims to encourage living ies, as well as ensuring education The American Society of Nephrology Findings organA donations and protect the rights of was one of 16 kidney health organizations concerning these new protections, this im- New genetic risk factors for living organ donors. The bill would also portant legislation will likely help count- that united to advance the legislation on kidney disease in type 2 set the stage for education efforts on liv- less Americans receive the gift of life,” said Kidney Community Advocacy Day in diabetes ing organ donation to be instituted by the ASN President Raymond C. Harris, MD, 2015. ASN will continue to work toward US Department of Health and Human FASN. Continued on page 2 Detective Nephron Will Nephron and medical student Glom crack a difficult History of Hemodialysis Could Help Guide Ethical case of hyponatremia? Use of Medical Resources By Tracy Hampton ngoing advances in technology healthcare dollars, many questions arise re- CJN.04780515 [published online Febru- and drug discovery continue to garding the most appropriate use of expen- ary 11, 2016]). Otransform numerous aspects of sive tests and therapies. “The medical research community is health, but making such breakthroughs A new paper in the Clinical Journal of feverishly developing new technologies and available to all who may benefit from them the American Society of Nephrology addresses drugs offering a plethora of treatment op- is often not possible, especially in the early such questions, using the history of the tions; however, the existence of these treat- days of their use. Furthermore, as society development and dissemination of main- ments does not direct how and for whom strives to address rising healthcare costs and tenance dialysis as a guide (Butler CA, et they should be used,” said lead author consider responsible distribution of limited al. Clin J Am Soc Nephrol. doi: 10.2215/ Catherine Butler, MD, of the University of Washington. “Increasingly, medical practitioners, lawmakers, and laypeople take part in debate about this complex distribution. This discourse is best coordinated by participants understanding a common structure of ethical evaluation.” Continued on page 5 2 | ASN Kidney News | March 2016

Living Donor Figure 1. Transplantation rates, 1988–2015 Continued from page 1 its passage into law. “Introduction of this bill is very timely since living kidney donation has been in a downward trend for a decade—6647 donors in 2004 compared with 5075 donors in 2015 (Figure 1). Quite paradoxically there has been a significant rise in ‘paired- exchange donations’ since 2008, account- ing for >1700 transplants so far in the US, and without this novel undertaking it is likely that the total number of living NOW AVAILABLE donor transplants would have been much worse,” said KN Editorial Board member Uday S. Nori, MD, a nephrologist with Ohio State University Wexner Medical Center in Columbus. “This observation underscores that there are serious systemic problems that need to be addressed urgently,” Nori said. “Although the specific causes for this trend remain unclear, it is widely believed that loss of wages during the donation time along with the fear of penalization by in- Courtesy: United Network for Organ Sharing, https://optn.transplant.hrsa.gov/ surance providers in the long-term are A NEW once-daily significant deterrents for living donor can- Table 1. Provisions of the Living Donor Protection Act didates. Successful passage of this new legislation would offer important incentives The bill promotes access to living kidney donations by: to heighten the interest in living donation.” Douglas Keith, MD, of the Univer- • Protecting Donors: prohibiting insurance companies from charging higher premiums and from denying or limiting sity of Virginia Medical Center, present- life, disability and long term care insurace to living donors • Securing Jobs: clarifying that living organ donors can use Family and Medical Leave Act time time to recover from treatment for ed findings at Kidney Week 2015 that showed a much lower living kidney dona- donation surgery and maintain their job security tion rate for African Americans compared • Educating Americans: directing HHS to improve efforts to educate Americans about living kidney donation with that for Caucasians, Hispanics, and Asians. His study looked at the impact have a large effect on African Americans. in the African American population of to recover from donation and keep their of organ transplant candidates’ socioeco- The gap in donation between Caucasians recipients and donors in the US. I sus- job—they have no benefits that allow for nomic environment on living kidney or and African Americans is driven in my pect few if any of the donors have life or this. The other issue is the loss of income hyperkalemia kidney-pancreas donation rates. opinion by two major issues. One is the disability insurance so that is not likely a while recovering from donation. Reim- Kidney News asked Keith whether pro- African American donor population has factor in their decision,” Keith said. bursing donors for lost wages while re- visions of the Living Donor Protection high rates of obesity, diabetes mellitus, “Family leave for donation could po- covering from donation may have a larger Act might help close the gap in living and hypertension, making them much tentially help this group since loss of em- effect on low socioeconomic groups. organ donation rates among those from higher risk for donation and more likely ployment due to donation in low socioec- Unfortunately, this legislation only pre- different socioeconomic environments. to be found unsuitable for donation and onomic populations is an issue,” he said. vents job loss but does not compensate “I think it may have a modest effect declined as donors. Second, socioeco- “Many people in low wage jobs cannot be employed donors for lost wages, a major on donation in general but I doubt it will nomic status is much lower on average off work for the 6 to 12 weeks required factor that may influence donation.” HYPERKALEMIAtreatment.com World Kidney Day Puts Spotlight on Kidney Disease in Children “Kidney Disease and Children” is the focus of World Kidney Day on March 10, 2016.

ach year, World Kidney Day seeks to raise that manifests in adulthood may occur more often awareness about the importance of the kid- in those with risk factors that could be detected in neys to overall health and to increase support childhood.” Efor reducing the incidence and impact of kidney dis- The American Society of Nephrology is working eases and associated health problems worldwide. with the American Society of Pediatric Nephrology Kidney diseases can affect children in various (ASPN) to recognize the importance of preventing and ways, ranging from treatable disorders without long- treating childhood kidney diseases on World Kidney term consequences to life-threatening conditions. Day in the US. Other events are being held around the Some children are born with kidney diseases and world from Japan to Buenos Aires, Argentina. others develop symptoms while very young. These The ASPN and Congressional Kidney Caucus symptoms in children are often nonspecific, and can will host a congressional briefing, “Kidney Disease be missed. Yet the missed symptoms can grow over in Children . . . Act Early to Prevent It,” on March are ASN, the Polycystic Kidney Disease Founda- time and result in adult chronic kidney disease. 10, 2016. The briefing aims to inform policymak- tion, National Renal Administrators Association, PP-US-PAT-00186 ©2016 Relypsa, Inc. “Early detection and a healthy lifestyle in chil- ers about the impact on families of having a child American Association of Kidney Patients, and Renal All rights reserved. All product names, trademarks, dren are crucial to mitigating the incidence of with kidney disease and the role Congress and regu- Physicians Association. The hearing is provided in and service marks are the property of Relypsa, Inc. 2/16 adult chronic kidney disease,” said ASN President latory agencies can play in the pediatric kidney dis- cooperation with the American Nephrology Nurses Raymond C. Harris, MD, FASN. “Kidney disease ease population. Among those supporting the event Association.

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Corporate Supporters ASN gratefully acknowledges the Society’s Diamond and Platinum Corporate Supporters for their contributions in 2015. Editorial Staff Editor-in-Chief: Richard Lafayette, MD, FACP Executive Editor: Dawn McCoy Content and Media Analyst: Kurtis Pivert Design: Lisa Cain Design Communications Assistant: Sara Leeds Diamond Level Editorial Board: Joseph Mattana, Winthrop University Hospital, New York, NY Linda McCann, RD, RCN, Satellite Dialysis, San Jose, CA Andrew King, MD, Scripps, San Diego, CA Pascale Lane, MD, FASN, University of Oklahoma Health Sciences Edgar V. Lerma, MD, FASN, University of Illinois – Chicago /Associates in Nephrology, SC Uday S. Nori, MD, Ohio State University Wexner Medical Center Glenda Payne, MS, RN, CNN, Nephrology Clinical Solutions Jeffrey Petersen, MD, Amgen Amy Williams, MD, Mayo Clinic, Rochester, MN

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March 2016 | ASN Kidney News | 5

number of maintenance hemodialysis sta- mation and work together with patients making dialysis centers: to do so would be History of tions guided by considerations of justice. to establish appropriate and individualized profoundly unethical.” Hemodialysis Later, as technology advanced, dialysis was treatment plans. Finally, the authors note Govind Persad, PhD, a junior faculty funded under an amendment to the Social that recent scrutiny of healthcare spend- fellow in ethics at Georgetown University, Continued from page 1 Security Act in 1972, and patients with end ing has put a focus on the just allocation added that it may be useful to bring nonclin- stage renal disease were entitled to receive of limited Medicare funds, and the utility ical components into the discussion. “The Butler noted that because the themes Medicare benefits. With this change, the fo- of dialysis is not simply being compared article makes the welcome and important explored in the history of dialysis are com- cus shifted to providing dialysis for all who among kidney failure patients but also in point that, at the level of health policy, dialy- mon and recurring among newly developed needed it, which lessened the ethical stress the context of payments for coronary stent sis must be compared to alternative medical medical technologies, they may serve as a of how to fairly distribute resources but cre- placement, supporting cancer research, or interventions. I would add that dialysis also template for future discussion in paral- ated new questions such as how to balance instituting preventive health programs. must be compared to non-medical inter- lel fields. As an example, the researchers longevity and quality of life and how to “Through the history of hemodialy- ventions,” he said. “One promising avenue highlight Medicare’s recently announced understand and respect patient preferences. sis, the 4 bioethical principles are weighed for further research is considering what ap- National Quality Strategy, which seeks to Also, with funding available through Medi- differently as forces of technologic innova- proach—whether the 4 principles or some- build a healthcare delivery system that’s care, a growing number of older patients tion, resource limitation, and social values thing else—is best for making these kinds of better, smarter, and healthier. It includes 3 with comorbidities began dialysis, and uti- change,” said Butler. Because of this vari- comparisons.” He noted that administrators aims—better care for the individual, better lization grew to the point that Dr. Scribner ability, creating sustainable ethical solutions and policymakers, such as those tasked with health for populations, and reduced health- suggested the need for a “deselection com- may require considering and addressing all implementing Medicare’s National Quality care costs—that can only be reached by ad- mittee” because the criteria for starting di- 4 ethical principles as fully as possible. Strategy, “frequently employ cost-effective- dressing multiple, and sometimes conflict- alysis had become so liberal. “I found the article very thorough and, ness analysis and cost-benefit analysis, but ing, values. Butler’s team found that the 4 principles to the best of my knowledge, very accurate. proposals for alternative approaches would In their Ethics Series paper that consid- forming the basis of clinical ethics—be- It is certainly one of the best expositions be welcome.” ers the history of hemodialysis, Butler and neficence, nonmaleficence, autonomy, and of one of the early bioethical dilemmas,” her colleagues trace the ethical conundrums justice—are emphasized to varying degrees said Albert Jonsen, PhD, emeritus profes- –––––––––––––––––––––– that arose at various times during the adop- over time. In the early days, the survival sor of Ethics in Medicine at the University tion and distribution of dialysis. “The first benefit offered by dialysis provided a strong of Washington’s School of Medicine. He Co-authors include Rajnish Mehrotra, formal method of medical ethics grew up argument for beneficence in initiating treat- noted that he and the late Dr. Scribner MD, MS, Mark Tonelli, MD, MA, and with the technology and set a precedent for ment, but it later became clear that the toll once talked about how commercial dialysis Daniel Lam, MD. many future medical resources,” Butler said. of treatment on quality of life sometimes had become, and Dr. Scribner noted that Disclosures: Daniel Lam receives some Hemodialysis was conceived in the outweighed the benefit, highlighting a he had often been asked why he didn’t pat- salary support from the Northwest Kidney 1940s, but it wasn’t until 1960, when the role for the concept of nonmaleficence. ent the shunt. “He said he had never given Centers as their Palliative Care Medical Ad- Quinton–Scribner shunt (designed by Also clear is that a well informed and au- it a thought, then went on to say that he visor. Wayne Quinton and Belding Scribner, tonomous person is in the best position to deplored the formation of so many dialysis The article, titled “The evolving ethics MD) allowed repeated vascular access, that consider whether initiating maintenance centers to exploit patients for whom dialy- of dialysis in the United States: A princi- maintenance dialysis became feasible. In dialysis will support his or her own values sis was of marginal value,” said Dr. Jonsen. plist bioethics approach,” is available at 1962, a committee of laypeople in Seat- and preferences. Therefore, clinicians must “He concluded that he had never made a http://cjasn.asnjournals.org/content/ear- tle attempted to fairly distribute a limited ensure that patients receive adequate infor- penny from the shunt or from such profit- ly/2016/02/10/CJN.04780515.abstract.

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Findings

Three new genetic risk factors for kidney disease in type 2 diabetes Three genetic variables are identified be associated with type 2 diabetes-related plasma glucose. Clinical, genetic, and genomic data, three were associated with as predictors of chronic kidney disease CKD. This process was carried out us- clinicogenomic models were compared, significant improvement in prediction (CKD) in Chinese patients with type 2 ing a large clinicogenomic dataset from a and the effect of the top selected genetic performance. These were the rs478333 diabetes, according to a study in Kidney prospective cohort of 2755 patients with variants on the clinicogenomic model variant of the gene G6PC2 and the International. type 2 diabetes from the Hong Kong Di- was assessed. The selected genetic vari- rs7754840 and rs7756992 variants of The study used a new three-stage pro- abetes Registry. ants were subsequently validated in two CDKAL1. Patients with the rs478333 cedure to test the hypothesis that genetic The model included 25 clinical vari- independent cohorts. variant had a faster decline in eGFR— B:15.5” variants associated with type 2 diabetes, ables and 36 genetic variants associated Of the top six single-nucleotide poly- greater than 4 percent per year. On me- T:15.25” obesity, and fasting plasma glucose might with type 2 diabetes, obesity, or fasting morphisms selected from the clinico- ta-analysis in replication cohorts, the as- S:14.75”

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• Proven control of serum phosphorus within B:10.25” S:9.5” KDOQI guidelines (4.88 mg/dL at Week 56)7,8 T:10” • Demonstrated safety and tolerability pro le over 52 weeks • Each AURYXIA tablet contains 210 mg ferric iron, equivalent to 1 g ferric citrate

References: 1. Fosrenol [package insert]. Wayne, PA: Shire US, Inc.; 2014. 2. Phoslyra [package insert]. Waltham, MA: Fresenius Medical Care North America; 2011. 3. PhosLo Gelcaps [package insert]. Waltham, MA: Fresenius Medical Care North America; 2012. 4. Renagel [package insert]. Cambridge, MA: Genzyme Corporation; 2015. 5. Renvela [package insert]. Cambridge, MA: Genzyme Corporation; 2015. 6. Velphoro [package insert]. Waltham, MA: Fresenius Medical Care North America; 2014. 7. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 Suppl 3):S1-S201. 8. Data on File 1, Keryx Biopharmaceuticals, Inc.

INDICATION AURYXIA is a phosphate binder indicated for the Overdose: AURYXIA contains iron. Iron absorption a risk for spontaneous abortion, gestational diabetes, Drug Interactions: Doxycycline should be taken at control of serum phosphorus levels in patients with from AURYXIA may lead to excessive elevations and fetal malformation. Rat studies have shown least 1 hour before AURYXIA. Cipro oxacin should chronic kidney disease on dialysis. in iron stores, especially when concomitant IV iron the transfer of iron into milk. There is possible infant be taken at least 2 hours before or after AURYXIA. is used. exposure when AURYXIA is taken by a nursing woman. Consider separation of the timing of the administration IMPORTANT SAFETY INFORMATION Accidental Overdose of Iron: Accidental overdose Pediatric: The safety and ef cacy of AURYXIA have of AURYXIA with drugs where a reduction in their of iron containing products is a leading cause of fatal not been established in pediatric patients. bioavailability would have a clinically signi cant effect Contraindication: AURYXIA is contraindicated in on safety or ef cacy. patients with iron overload syndromes. poisoning in children under 6 years of age. Keep this Adverse Events: The most common adverse events product out of the reach of children. Please see Brief Summary on following page. Iron Overload: Iron absorption from AURYXIA may with AURYXIA were diarrhea (21%), nausea (11%), lead to excessive elevations in iron stores. Assess Patients with Gastrointestinal Bleeding or constipation (8%), vomiting (7%), and cough (6%). You may report side effects to Keryx at iron parameters, serum ferritin and TSAT, prior to In ammation: Safety has not been established. Gastrointestinal adverse reactions were the most 1-844-44KERYX (844-445-3799). common reason for discontinuing AURYXIA (14%). and while on AURYXIA. Patients receiving IV iron may Pregnancy Category B and Nursing Mothers: ©2015 Keryx Biopharmaceuticals, Inc. require a reduction in dose or discontinuation of IV Overdosing of iron in pregnant women may carry PP-AUR-US-0173 08/15 iron therapy.

10412743_Jrnl_Ad_Label_Upd_Comp_King.indd 1 8/13/15 10:01 AM March 2016 | ASN Kidney News | 7

Adding insulin to metformin increases hypoglycemia risk sociations for rs478333 and rs7754840 remained significant after adjustment For diabetic patients on metformin who compared in propensity score-matched respectively—adjusted hazard ratio was for conventional risk factors. require treatment intensification, adding groups: 2436 patients taking metformin 1.30 with insulin compared with sulfo- The three implicated gene variants insulin rather than sulfonylurea is associ- plus insulin versus 12,180 patients tak- nylurea. seem to be novel predictors of CKD as- ated with an increased risk of hypogly- ing metformin plus sulfonylurea. Insulin intensification was also associated with type 2 diabetes in a Chi- cemia, reports a study in the Canadian At the time of treatment intensifica- sociated with a higher rate of recurrent nese population. Jian et al. believe that Medical Association Journal. tion, patients had been taking metformin hypoglycemia: 39.1 versus 30.0 per 1000 their three-step process may be useful Using the Veterans Health Admin- for a median of 14 months and had a person-years (hazard ratio of 1.39). Ac- for selecting predictors of clinical out- istration database, the researchers iden- median glycated hemoglobin level of 8.1 counting for competing risk of death, the comes in other large datasets including tified 178,341 patients who initiated percent. The follow-up data included 121 hazard ratio for initial hypoglycemia in clinical and genetic data [Jian G, et al. metformin treatment between 2001 and first hypoglycemic events among patients the insulin group was 1.28 [Roumie CL, Genetic and clinical variables identify 2008. Treatment was subsequently inten- who added insulin and 466 first hypogly- et al. Risk of hypoglycemia following B:15.5” predictors for chronic kidney disease sified using insulin in 2948 patients and cemic events among patients who added intensification of metformin treatment in type 2 diabetes. Kidney Int 2016; T:15.25” sulfonylurea in 39,990 patients. Risk of a sulfonylurea. Outcome rates were 30.9 with insulin versus sulfonylurea. CMAJ 89:411–420]. S:14.75” first or recurrent hypoglycemia event was versus 24.6 events per 1000 person-years, 2016; doi:10.1503/ cmaj.150904].

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For the control of serum phosphorus levels in patients with chronic kidney disease on dialysis

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10412743_Jrnl_Ad_Label_Upd_Comp_King.indd 1 8/13/15 10:01 AM 8 | ASN Kidney News | March 2016 Policy Update

Senate Finance Committee Eyes Kidney Care Components for New Bill By Rachel Shaffer atients with kidney disease may medical community regarding opportu- are specific to patients with kidney disease ongoing care of patients residing in rural Psee several positive changes to their nities to improve the care of people with and several that would have direct and areas, who could avoid the need to travel ESRD care options in 2016. A bipartisan chronic conditions and reduce related positive benefits: in dangerous weather or for prohibitively “Chronic Care Working Group” formed Medicare expenditures, the committee long distances. Permitting patients and Expanding telehealth access for by the Senate Finance Committee recent- received more than 1000 suggestions. their physicians the option to participate both home hemodialysis and home ly released a white paper outlining policy The white paper narrowed down the feed- in telehealth visits in some months—with changes they are interested in enacting back to approximately 20 policy options, peritoneal dialysis in-person visits at least quarterly (every this year—including several components which are on the short list for inclusion in Permitting home dialysis patients to in- three calendar months)—may incentivize related specifically to kidney care. a piece of legislation to be introduced later teract with their nephrologist for monthly patients to adopt home dialysis as a treat- visits via telehealth would create several ment option. After soliciting input in June 2015 this year. AmongB:7.25” the suggestions are two benefits. Telemedicine may be valuable for In its comments to the committee, from ASN and other stakeholders in the provisions for whichT:7” ASN advocated that

BRIEF SUMMARY

AURYXIA™ (ferric citrate) tablets contain 210 mg of ferric iron equivalent to 1 g ferric citrate for oral use.

INDICATIONS AND USAGE AURYXIA is a phosphate binder indicated for the control of serum phosphorus levels in patients with chronic kidney disease on dialysis.

CONTRAINDICATIONS AURYXIA is contraindicated in patients with iron overload syndromes (eg, 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 in which concomitant use of AURYXIA and IV iron was permitted, 55 (19%) patients treated with AURYXIA had a ferritin level >1500 ng/mL as compared with 13 (9%) patients treated with active control. Assess iron parameters (eg, serum ferritin and TSAT) prior to initiating AURYXIA and monitor iron parameters while on therapy. Patients receiving IV iron may require a reduction in dose or discontinuation of IV iron therapy. Accidental Overdose of Iron: Accidental overdose of iron-containing products is a leading cause of fatal poisoning in children under 6 years of age. Keep this product out of the reach of children. In case of accidental overdose, call a doctor or poison control center immediately. Patients with Gastrointestinal Bleeding or Inflammation: Patients with inflammatory bowel disease or active, symptomatic gastrointestinal bleeding were excluded from clinical trials. Safety has not been established in these populations.

ADVERSE REACTIONS Adverse reactions to a drug are most readily ascertained by comparison with placebo, but there is little placebo-controlled experience with AURYXIA, so this section describes adverse events with AURYXIA, some of which may be disease-related, rather than treatment-related. A total of 289 patients were treated with AURYXIA and 149 patients were treated with active control (sevelamer carbonate and/or calcium acetate) during the 52-week, randomized, open-label, active control phase of a trial in patients on dialysis. A total of 322 patients were treated with AURYXIA for up to 28 days in three short-term trials. Across these trials, 557 unique patients were treated with AURYXIA; 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. In these trials, adverse events reported for AURYXIA were similar to those reported for the active control group. Adverse events reported in more than 5% of patients treated with AURYXIA in these trials included diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). During the 52-week active control period, 60 patients (21%) on AURYXIA discontinued study drug because of an adverse event, as compared to 21 patients (14%) in the active control arm. Patients who were previously intolerant to any of the active control treatments (calcium acetate and sevelamer carbonate) were not eligible to enroll in the study. Gastrointestinal adverse events were the most common reason for discontinuing AURYXIA (14%). AURYXIA is associated with discolored feces (dark stools) related to the iron content, but this staining is not clinically relevant and does not affect laboratory tests for occult bleeding, which detect heme rather than non-heme iron in the stool.

DRUG INTERACTIONS

Doxycycline is an oral drug that has to be taken at least 1 hour before AURYXIA. Ciprofloxacin should be taken at least 2 hours before or after B:10.25” T:10” AURYXIA. Oral drugs that can be administered concomitantly with AURYXIA are: amlodipine, aspirin, atorvastatin, calcitriol, clopidogrel, digoxin, doxercalciferol, enalapril, fluvastatin, levofloxacin, metoprolol, pravastatin, propranolol, sitagliptin, and warfarin. 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 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: Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. It is not known whether AURYXIA can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted. 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. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes, and fetal malformation. Labor and Delivery: The effects of AURYXIA on labor and delivery are unknown. Nursing Mothers: 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. Pediatric Use: The safety and efficacy of AURYXIA have not been established in pediatric patients. Geriatric Use: Clinical studies of AURYXIA included 106 subjects aged 65 years and older (33 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 on dialysis, 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 IV iron is used. In clinical trials, one case of elevated iron in the liver as confirmed by biopsy was reported in a patient administered IV iron and AURYXIA.

PATIENT COUNSELING INFORMATION Dosing Recommendations: Inform 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. 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, and vomiting. Advise patients to report severe or persistent gastrointestinal symptoms to their physician.

Printed in USA PP-AUR-US-0173 08/15

10412743_Jrnl_Ad_Label_Upd_Comp_King.indd 2 8/13/15 10:01 AM enroll in Medicare Advantage plans enroll inMedicareAdvantageplans Permitting patientswithESRDto in Medicare Advantage plans—ESRDis kidney failure are notpermittedtoenroll Under current law, peoplewhodevelop visits from theirown home. with theirnephrologist forsomemonthly allowing ues tosupport patientstointeract place atdialysisfacilities,butASNcontin- mitting telehealth interactions that take tee’s proposal is currently limited to per- needs inanygiven month.Thecommit- if thatmore appropriately meetsclinical monthly clinicalassessmentvisitin-person the optiontochooseconducttheir Both patientsandphysiciansmustretain requires ongoing,intensive treatment. are essentialforapatientpopulationthat ASN emphasized thatpatientsafeguards

Statement onPresidentObama’s 2017 BudgetProposal President’s Kidney Research 2017BudgetShortchanges By ASNPresidentRaymond C.Harris, MD, FASN By GrantOlan L O Renal Disease Program alonecosts $80 billion.The Medicare End-Stage million AmericansandcostsMedicare Kidney diseaseaffectsmore than20 change NIDDKandkidneyresearch. 2017 budgetproposal wouldshort- NIDDK in2016.Regrettably, his curing abudgetincrease forNIHand Obama forhisboldleadershipinse- DK’s budgetfor2017wouldremain Instead,similarly shortchanged. NID- other 26institutesandcentersare Diseases (NIDDK),andmostofthe Diabetes andDigestive andKidney would gototheNational Institute of tiative. None of the additional funds Innovative Neurotechnologies) Ini- (Brain Research through Advancing sion Medicine Initiative, andBRAIN include theCancerMoonshot, Preci- ful ofadministrationprioritiesthat entire increase wouldgotoahand- for atotalof$33billion.However, the NIH fundingoverall by $825million President’s proposal wouldincrease calling nonstarters. some congressional appropriators are ties, itrelies onbudgetgimmicksthat Health (NIH)andotherASNpriori- increases fortheNational Institutes of cess. Althoughtheproposal includes ofthecongressionalstart budgetpro- budget proposal for2017,theofficial With thosebudgetgimmicks,the ASN wascommendingPresident ooking backtothistimelastyear, Barack Obama released his n February 9,2016,President management (CCM)payment codes new andexistingchroniccare kidney diseasestobenefitfrom Allowing patientswithadvanced a recently created codethatreimburses conditions. This conceptbuilds upon people withmultiple high-severity chronic who dedicatetimetocoordinating care for codethatwouldreimbursenew physicians The committeeproposeda developing est inincludingitthefinallegislation. thecommittee’scontinue tosupport inter- Medicare-enrolled individualsandwill proved care asother coordination services same freedom ofchoiceandaccesstoim- mittee tograntESRDbeneficiariesthe this program. ASNencouragedthecom- in ders patientsineligibletoparticipate the onlypre-existing conditionthatren- NIDDK funding,ASNisspearhead- advocates collaboratively forincreased in Friends ofNIDDK,acoalitionthat a 7%increase over 2016.Asaleader quest forNIHof$34.5billion,about izations, isadvocating fora2017re- ties, andacademicresearch organ- groups, medicalandscientificsocie- health than 200patientandvoluntary said. nificant savingsto Medicare,” Harris with kidneydiseaseandresult insig- that couldimprove thecare ofpatients ate theseandothernovel therapies ditional fundingisneededtoacceler- NIDDK-funded kidneyresearch. Ad- because ofadvances madethrough kidney research. Changeisontheway NIDDKand al wouldshortchange “Regrettably, his2017budgetpropos- mond C.Harris, MD,FASN, recalled. and NIDDK,” ASNPresident Ray- securing abudgetincrease forNIH ma in2016forhisboldleadership flat at$1.966million. syndrome andchronic kidney disease. ing ofthepathogenesisnephrotic kidney have shapedourunderstand- For example,geneticistsfocused onthe thanks toNIDDK-fundedresearch. breakthroughs inthepastseveral years kidney care costs. ney research are lessthan 1%oftotal budget. Yet federalinvestments inkid- $35 billion,more thanNIH’s entire ASN, in partnership with moreASN, in partnership “ASN commendedPresident Oba - There have beenseveral major alysis care. Thisexclusion wasnotlegisla- they receive standard—and lifesaving—di- ing thesame90-dayperiodduringwhich eligibility fortheexistingCCMcodesdur- with end-stagerenal disease(ESRD)from pitalizations, andbetterlong-termhealth. ing themsuperiorqualityoflife,fewerhos- high-severity codeswouldoffer—provid- coordination proposed thatthenewly from the proactive, comprehensive care gram. CKDpatientscouldbenefitgreatly combination triadsintheMedicare pro- 4 ofthe5mostcostlychronic condition conditions, andCKDisincludedamong ic kidneydiseasehave 5ormore co-morbid high-severity). conditions (butwhichare notnecessarily for care ofpeoplewithmultiplechronic go where thedollarsare andfunding and HIV/AIDsisclear. Researchers tute andcenter(Figure 1). NIH 2016fundingincreases by insti- ranked nearthebottomoflist a 10%increase over 2017.NIDDK for NIDDKof$2.165billion,about advocate for a2017budgetrequest ing thekidneycommunity’s to efforts sustained funding isneededtoaccel- funded kidneyresearch. Additional, advances made through NIDDK- ducting humanclinicaltrials. spare the expenseandtimeofcon- cations usingkidneycellsthatwould for screening prescription new medi- aswell asarapidmethod laboratory method for growing kidneys in a new Just last year, scientists announced a Figure 1.NIHfundingincreaseby instituteandcenter Figure Current CMSpolicyexcludes patients More than50%ofpatientswithchron- “The story ofcancer,“The story disease, heart Change isonthewaybecause of for kidneyresearch.” NIDDK sustainablefundingincreases enoughtoprovideif we are visionary progress ispossiblewithkidneydisease a chronic diseasetoday. Thatkindof sentence inthe1980stoessentially ed. “HIV/AIDswent from adeath Frank “Chip” Brosius, MD,comment- search Advocacy CommitteeChair increases drive innovation,” ASNRe- tomorrow. awaiting thepossibilityofahealthier ing hopetothemillionsof patients carries apalpablehumantoll, deny- work ofresearchers across thecountry thegroundbreakingability tosupport to maintainandstrengthen NIDDK’s nificant savingsto Medicare. Afailure with kidneydisease and result insig- that couldimprove thecare ofpatients erate theseandothernovel therapies March 2016| etyofNephrologyASN.pdf. online.org/policy/webdocsAmericanSoci- mendations, pleasevisit:http://www.asn- For more detailsconcerningASN’s recom- todraftingandintroducingforward abill. for theseandotherpoliciesastheymove tee membersandstafftobuildsupport will continue to interact with commit- on medicationsynchronization. ASN conditions andcommissioningofastudy in itsbillare qualitymeasures forchronic mendations the committee mayinclude severity codes. most likelytobenefitfromhigh- thenew andwouldbeamongthe CCM services, equitableaccessto kidney diseasedeserve ASN strongly believes thatpatientswith process. during theCMS rulemaking tively mandated, but rather, implemented Among otherbeneficialpolicy recom- ASNKidneyNews |

9 10 | ASN Kidney News | March 2016 Practice Pointers Kidney Stones: New and Not So New Issues This month, Alex Constantinescu, MD, of the American Society of Nephrology Practicing Nephrologists Advisory Group speaks about the latest on kidney stones. Dr. Constantinescu is associated with the Joe DiMaggio Children’s Hospital, pediatric nephrology, in Hollywood, FL.

KN: Are we facing a higher incidence of phate stones), protease inhibitors (leading to various cant risk factors for its formation again. Stone composi- nephrolithiasis? stone compositions, including drug-containing crys- tion is helpful, although it may not be available in all Recent evidence suggests that over the past 4 decades, tals), with excess calcium supplementation (some is cases. Supersaturation values in 24-hour urine collec- the incidence of kidney stones has increased in adults good; too much is bad), loop diuretics, steroids, and tion are helpful in adults, whereas in children, either from 3.8 percent to 8.8 percent (1). In children, over ketogenic diet being among the most common causa- ratios with urine creatinine as the common denomina- the past 25 years, it has increased at a rate of 6 percent tive agents (7). tor, or values based on body weight and surface area are to 10 percent annually, reaching 50 cases per 100,000 more frequently used. The American Urological Asso- KN: Are there new studies to identify the adolescents (2). ciation published evidence-based guidelines for medical presence of, and complications from, kidney management of kidney stones in 2014. Increasing fluid KN: What may be the reason(s) for this increase, stones? intake, limiting sodium intake, and maintaining a nor- and is it reflected in stone composition? Most patients with renal colic undergo radiologic stud- mal calcium diet are recommended, independently of Over the past 50 years, a few notable changes have ies in the emergency department. Although a radiologic the stone composition. Specific dietary restrictions are taken place: a rise in body mass index, a higher rate study of the kidneys, ureters, and bladder can identify based on stone composition or the biochemical abnor- of obesity, and a higher purine intake. Several stud- calcium-containing radiopaque stones but not radiolu- mality noted. Lifestyle changes should be monitored ies have found significant correlations between these cent ones, such as those composed of uric acid, ultra- closely, and drug therapy (i.e., thiazide diuretics, allopu- factors and the higher incidence of kidney stones but sonography and non–contrast medium computed to- rinol, alkali) may be needed in carefully selected cases could not conclude that they were the only respon- mography cannot differentiate between the various types (12). Rule et al. (13) and colleagues identified younger sible culprits. An analysis of 11,099 kidney and ure- of calculi, even though they can detect smaller stones. white men with a family history of kidney stones, and teral stones between 1990 and 2010 revealed gender The Image Gently campaign was the origin of the quest uric acid composition of either symptomatic or asymp- differences in the biochemical composition of calculi for safer and more accurate imaging studies that can tomatic calculi, to have the highest risk for recurrence, (3). Although calcium-containing stones remained the identify, and even attempt to differentiate, the composi- and they suggested a nomogram that can be the start of most common, females had an increase in total kidney tion of the stones. The use of a reduced dose of radiation prevention trials. stones from ~30 percent to ~40 percent and a signifi- appears not to diminish the ability to diagnose a ureteral cant increase in the incidence of uric acid stones. By stone larger than 5 mm (8). In addition, dual-energy References contrast, males had a stable rate of uric acid stones computed tomography (9) appears to be able to differen- 1. De SK, Liu X, Monga M. Changing trends in the (~11 percent) and showed an increase in the incidence tiate between calcium oxalate and hydroxyapatite stones American diet and the rising prevalence of kidney of cystine and struvite stones, along with a higher per- as well as the supersaturation values do. If the imaging stones. Urology 2014; 84:1030–1033. centage of apatite per stone. study cannot only identify the stone but also give infor- 2. Tasian GE, Copelovitch L. Evaluation and medical mation about the stone composition with acceptable cer- management of kidney stones in children. J Urol KN: Who is at high risk for the development of tainty, a specific therapy plan can be established much 2014; 192:1329–1336. renal calculi (i.e., ethnicity, race, disease states, sooner, preventing complications from the long-standing 3. Moses R, et al. Changes in stone composition over diet, medications)? calculus. In children, the stones are smaller, and such im- two decades: evaluation of over 10,000 stone analy- Although known genetic factors contribute to ~50 per- aging studies may expose them to higher radiation doses. ses. Urolithiasis 2015; 43:135–139. cent of all kidney stones (i.e., in hyperoxaluria, cystinu- Therefore, the quest for the ideal diagnostic imaging test 4. Halbritter J, et al. Fourteen monogenic genes ac- ria, Dent’s disease, medullary sponge kidney, polycystic continues. In women, a history of urolithiasis has been count for 15% of nephrolithiasis/nephrocalcinosis. kidney disease, in total, 30 known kidney stone genes), associated with a higher risk of chronic kidney disease, J Am Soc Nephrol 2015; 26:543–551. not all genes have been identified, which suggests that even the need for dialysis (10). 5. Turney BW, et al. Diet and risk of kidney stones in epigenetic factors play a significant role. Surprisingly, the Oxford cohort of the European Prospective In- KN: What are the benefits and limitations, if 14 monogenic genes account for only 15 percent of vestigation into Cancer and Nutrition (EPIC). Eur any, of minimally invasive techniques for the cases of nephrolithiasis and nephrocalcinosis (4). J Epidemiol 2014; 29:363–369. treatment of urolithiasis? In the United States, an analysis of data from the Na- 6. Mirheydar HS, et al. What is the incidence of kid- tional Health and Nutrition Examination Survey from Some calculi smaller than 5 to 10 mm in both children ney stones after chemotherapy in patients with lym- 1974 to 2010 found a correlation between stone preva- and adults can pass spontaneously, or with help of hy- phoproliferative or myeloproliferative disorders? Int lence and increased caloric intake, as well as with diets dration, diuretics, b-blockers, or a combination thereof. Braz J Urol 2014; 40:772–780. rich in dark green vegetables, flour or cereal products, Unfortunately, some other calculi require surgical in- 7. Izzedine H, Lescure FX, Bonnet F. HIV medica- fish or shellfish, corn products, and added sugars, and tervention. The discomfort caused by renal stones and tion-based urolithiasis. Clin Kidney J 2014; 7:121– an inverse correlation with a high intake of citrus fruits, their possible complications (e.g., infections, decrease 126. as expected (1). in kidney function) have made early therapy a neces- 8. Moore CL, et al. Accuracy of reduced-dose com- In Europe, the Oxford cohort of the European Pro- sity. In addition, the need for faster recovery with the puted tomography for ureteral stones in emer- spective Investigation into Cancer and Nutrition con- least tissue damage created an impetus for using en- gency department patients. Ann Emerg Med 2015; sisted of 51,336 participants and identified vegetarians doscopic procedures, with less frequent extracorporeal 65:189–198. as the subgroup with a lower risk for kidney stones, in shock wave lithotripsy and open surgical procedures for 9. Liu Y, et al. Differentiating calcium oxalate and hy- particular those with high intakes of fresh fruits, whole- nephrolithiasis being very rarely needed. An analysis of droxyapatite stones in vivo using dual-energy CT grain cereals, and magnesium-rich foods. The higher- this shift in surgical management confirmed this obser- and urine supersaturation and pH values. Acad Ra- risk group was characterized by a diet high in meat, vation, with more than double the use of ureteroscopy diol 2013; 20:1521–1525. meat products, and zinc-rich foods, such as seafood, and a decline in the use of extracorporeal shock wave 10. Shoag J, et al. Risk of chronic and end stage kid- dairy products, nuts, and beans, consistent with the role lithotripsy over the past 20 years (11). Because this ap- ney disease in patients with nephrolithiasis. J Urol of zinc in mineralization and calcification processes (5). proach contributed to a decline in readmission rates, 2014; 192:1440–1445. A kidney stone risk of 5.5 percent was found after this trend may continue. 11. Ordon M, et al. The surgical management of kidney chemotherapy in patients with lymphoproliferative stone disease: a population based time series analy- disorders, and the stone formers had higher serum uric KN: What can be done to prevent the recurrence sis. J Urol 2014; 192:1450–1456. acid, calcium, and potassium concentrations. Also, dia- of renal calculi? 12. Pearle MS, et al. Medical management of kidney betes mellitus, hypertension, and hyperlipidemia were There is no doubt that patients who have experienced stones: AUA guideline. J Urol 2014; 192:316–324. common in patients with de novo kidney stones (6). one kidney stone want to avoid a recurrence. This re- 13. Rule AD, et al. The ROKS nomogram for predict- The known risk factors for urolithiasis also include quires an accurate identification of the factors that led ing a second symptomatic stone episode. J Am Soc medications such as topiramate (causing calcium phos- to the formation of the calculus and represent signifi- Nephrol 2014; 25:2878–2886.

Available symposia include:

From Thursday, November 5, 2015 Educational • Biosimilars on the Horizon: Biologics and Biosimilars in Anemia Management Support provided by an educational grant from Hospira, a Pfizer Company.

Symposia • Grading the Evidence for Hepatitis C Therapies: Can We Do Better than a “C”? Now Support provided by an educational grant from Merck. • Iron-Based Phosphate Binders: Pharmacology Available for Patients with CKD and ESKD Support provided by an educational grant from Keryx Biopharmaceuticals, Inc.

• Management of Secondary Hyperparathyroidism: Online The Role of Vitamin D Support provided by an educational grant from OPKO Renal.

The online versions of From Friday, November 6, 2015 11 Educational Symposia • Calcium or No Calcium: That Is the Question presented during ASN Kidney Support provided by an educational grant from sanofi US. Week 2015 are now available • Cystinosis: What the Adult Nephrologist Needs to Know for free at www.asn-online.org/ Support provided by an educational grant from Raptor Pharmaceuticals. learningcenter. • Maintenance Therapy in ANCA Vasculitis: Give Enough but Not Too Much Support provided by an educational grant from Genentech.

• New Agents in the Management of Hyperkalemia Support provided by an educational grant from ZS Pharma.

• The Role of Intravenous Iron in Chronic Dialysis Support provided by an educational grant from Fresenius Medical Care Renal Therapies Group. Please note that CME, CNE, and CPE credits are not available for From Saturday, November 7, 2015 this activity. • Anemia, Erythropoiesis, and the Nephrologist Support provided by an educational grant from AstraZeneca and FibroGen.

• Management of Chronic Hyperkalemia Support provided by an educational grant from Relypsa.

KW Educational Symposia Ad.indd 1 3/1/16 12:13 PM

! 14 DistinguishedConversations:

| ASNKidneyNews | I Richard Lafayette, MD, editor-in-chief, ASNKidney News viewed for this series. individual inter - delighted he agreed to be the first 300 visitinglecturesand/orprofessorships. We are edited 49books,inwell morethan andparticipated ments, publishedmorethan 700scientificarticles, He hasheldatleast25editorialboardappoint - Royal CollegeofPhysicians, amongmany others. of Nephrology, Association, AmericanHeart andthe National Kidney Foundation, Society International Healsohasbeenhonoredbyand teaching. the ence, G.NarinsAward for andtheRobert education science, theJohnP. Peters Award for clinicalsci- has wontheASNHomerW. SmithAward for basic . Report and World America’s programby leadingnephrology U.S. News he was director, Brigham’s renal division was named division. During the period from 1979 to 2001, when in1976to joinitsdistinguished nephrology Harvard California, SanFrancisco, in1969, before at arriving Institute) andthenmoved of totheUniversity tothe NationalHeart, Lung,(precursor andBlood Institute research training at the National Heart College of Medicine, in 1966. He did his kidney the BronxMunicipalHospitalCenter, Einstein Albert medicineresidencyat and completedhisinternal ofPittsburgh SchoolofMedicine in 1962 University nephology. MedicalSchool,Harvard andaninimitableleaderin A. Levine Distinguished Professor of Medicine at division atBrighamandWomen’s Hospital, Samuel M. Brenner,Barry MD, Director Emeritus of the renal MedicalSchool, mentoratHarvard hisearly interview at Vanderbilt SchoolofMedicine, University chose to President Raymond C.Harris, MD, Chief ofNephrology us [email protected]. versary. We hopeyouwillenjoy itgreatly. Pleaselet coincides withthecelebrationofASN’s 50thanni- future. Itiswonderfulandfittingthatthisseries past andhowwe cancontinuetoimprove inthe nephrology, especiallyhowithasbeengreatinthe their opinionsandrecollectionsaboutthefield of or mostesteemedcolleaguesfor a discussionof toinvite innephrology theirmentors,leaders heroes, Nephrology Great.”Nephrology We have asked established News t is a pleasure to introduce a new series at A former president of ASN, triple threat this true Dr. hisMDdegree from the Brenner earned For installmentoftheseries, thefirst ASN , “Distinguished Conversations: Keeping March 2016 Kidney Keeping Nephrology Great nephrologist? Dr. Dr. Harris: Brenner, howdidyouendupbecominga Raymond C.Harris, MD “I was enamoredbytheresearchprocess” at thetime. which wasmytarget,andIthinkthissaidsomethingaboutdrive andambition many ofmycoursecredits atthegraduatelevel. So Ibeathimbymonths, afew was driven todobetter. By thatImeangraduatedwithhonorsin32months, under his photo, “undergraduate school—3 years,” and when I went to college I physics andhiscontributionstothisevolving field. andspurredintrigued megreatly metoread withhisstory extensively aboutatomic He wasabrilliantatomicphysicist,who,althoughnotknown tomepersonally, who washeadoftheManhattan Project, responsible formakingtheatomicbomb. ground andlittleexternalguidanceregarding career development. in growing upisthatIwasdisadvantaged intermsofourmodestfamilyback- came from apoorfamilywhere noonehadbeeneducated.My greatest advantage myself andmadesomeexplosionsthatstainedtheceilings. as giftspure compoundsandglassware; thelatterIbroke repeatedly. Ialsoburned experiments at home, and my parentsgreat gave delight. I did lots of chemistry me all thedifferent unicellularorganismsmoving through thefield.Thisfilledme with teenager, Ialready hadamicroscope andwaslookingatpondwateridentifying gave meencouragement andboostsalongtheway. my life. Still, any successthatflowed to mewasbecauseof themany peoplewho undistracted, andundisturbedstudy, issomethingIhave engagedinthroughout studying 15hoursperday, 6or7daysaweek. This “deep work,” aformofintense, My earlylifeisastudyofbrightboy, self-motivated anddriven toadvance by half theclasswasinvolved—something Ithink is unheard oftoday. bench research. Theschoolprovided fundsfor2monthsofsummer research and 50% ofthefreshman class attheendofyear stayed over thesummertodo Holy Grail. results intheJournal a year ofBiological later. Chemistry Menten enzyme,whichIdid. kineticsforthisnew We publishedthepaperon the had beenonthefaculty, Segal assignedmethetaskof working outtheMichaelis– was renowned forenzymologybecauseMaud Menten, ofMichaelis–Menten fame, laboratory. He enzyme—a5'-nucleotidase—andsince hadidentifieda new Pitt week, andifyou comehere, Iwantyou towork inmylaboratory.” fundamental atomic physics, he said,“You willgeta letter of acceptance later this professor ofbiochemistry. At theendofalengthy discussionaboutanti-matterand that mostinterested by me.ThereHarold Iwasinterviewed Segal, a young assistant atseveral medicalschools,butitwastheUniversityI interviewed ofPittsburgh When Oppenheimer graduatedfrom Princeton, hewrote intheclassyearbook The personwhohelpedmethemostwasamannamedJ. Oppenheimer,Robert I attendedLongIsland University inBrooklyn, whichgave meascholarship. I In intriguedby myyouth, thenaturalsciences. Iwasvery When Iwasayoung Icontinuedtowork inresearch whilegoing tomedicalschool.At that time, I wasenamored by theresearch process. The scientific method tome was the medicalschool atPittWhen Istarted inSeptember inSegal’s 1958,Ialsostarted Barry M.Brenner,Barry MD DistinguishedConversations:

Keeping Nephrology Great “Three to four uninterrupted years of laboratory experience” oflaboratory years “Three tofour uninterrupted who arecreativeanddriven. forthose withinoroutsidethecurriculum open toopportunities Dr. Yes, Harris: Ithinkthatyou’re exactlyright.We needtobe sampling thefluid,there wasretrograde flow from more ofthe distalportions did, wasIrealized longoil blockbelow thatunlessIhadavery where Iwas ing theureter wouldraiseintratubularpressure. What they didn’t do,andI by withanoilblock, similartohow producing intratubularobstruction block- across thetubule. The experiments were doneby dilatingtheproximal tubule of theradiusproximal totheisotonic fluidflux tubulewasproportional the more thetubulewasdilated,greater theabsorptionrate.So thesquare Southwestern Medical School,Dallas) pickeditup. The hypothesisstatedthat in Germany and then Floydtory Rector and Donald Seldin (University of Texas disproved hypothesis. thegeometry That hypothesiscameoutofGertz’s labora- thank you forhelpingmewiththatprotocol?” Ihadentered hisinnersanctum. conference. For timehesawmeasked,“Did thenext6months,every Iever well whenthere are cysts inthemedulla,” whichiswhathedidattheStanford need to do is talk about the concentrating mechanism and how it’s not working cysticdisease.Ishowed toBerliner andsaid,“Allmedullary thearticle you saved. There, aboutayear earlier, wastheprotocol ofthesamepatientwith unbound issuesoftheNew England Journal ofMedicine thatIhadmeticulously before.” Ididn’t remember where butIwent homethatnightandscoured my had senthim,andafterIdoneso,told“IthinkI’ve seenthiscase clinicopathological conference. He askedmetolookover thecaseprotocol they came tomeand said hehadbeeninvitedtoStanford tobethe discussant at a micropuncture technical team. Within amonth ofmy joining thelab, Berliner be applied—liketheintrigueofawatchmakerforhiscraft. of themicropuncture technique,withthemicro-analytical skillsthatneededto experience.”laboratory Ijoinedhislabbecausewasintriguedwiththedelicacy sibilities. CometoNIHandwe willgive years you of 3or4uninterrupted are programs thatwilldiluteyour energybecauseyou willhave clinicalrespon- Frank Epstein, ArnoldRelman, and William Berliner said,“Those Schwartz, Although Ihadalready beenacceptedforfellowship trainingwithAlexLeaf, turned outtobeRobert Berliner, director ofkidneyresearch atNIH. and my interns.At lunch,Davis came backwith this person I didn’t know…it the session was over the care of patients I felt good about it and left to supervise sion andthepersonhebrought withhimalsoaskedmesomequestions. When didn’t know. IinvitedRobert Davis.or slides.Asanexpert, He showed upwithsomebodyI blackboard becauseinthosedaysthere were no fundsforustomakephotocopies could blockitwithaninhibitorofRNAsynthesis.Idrew allthefigures onthe that took90minutestounfoldbefore thesodiumcurrent increased, andthey bladder.urinary Theyshowed thatitwasaDNA-dependentRNAsynthesisstep man onthemechanismofinductionsodiumcurrent by aldosterone intoad Chair IrvingLondonpresided over thesession. campus mostknowledgeable aboutthetopicyou were presenting. Department entifically orientedand you were expectedtobringthesessionpersonon sponsible forgivingatalkonscholarlytopicoftheirchoice.It hadtobesci- called “morning prayers,” where eachofthe30residents inrotation wasre- residency todiscussthecasesthatcameinnightbefore, we hadwhatwere blessed withauniqueopportunity. Instead ofhavingmorningreport foryour When Ididmymedicalresidency Einstein inNew atAlbert York, Ialso was that Idon’t thinkare offered to young peopletoday, andIthinkthat’s atragedy. in as just another student. It me extremely well.served These were opportunities well ontheexams.him for6monthsandalsodidvery the slidesetsandtakeexamsalongwithyour class,” hesaid.Iworked with “Work withmeduringthedayinmylab, butyou stillhave toberesponsible for complex–mediated diseases,andlikeSegal, heurgedmetowork inhislab. Frankcontacted thechairmanofthatdepartment, Dixon, thefatherofimmune Then I had the good fortune ofdoingthemicropunctureThen Ihadthegoodfortune experimentthat At NIH,Iworked withayoung woman,Julia Troy, whowasleadingthe I presented thematerialover thecourseof45minutes.Davis ledthediscus- One day I gave atalkonPNASpaperby George Porter andIsidore Edel- Thus Segal and Dixon redesigned the curriculum to fit me rather than slot me The second year ofmedicalschoolinvolved thestudyofpathology. Segal advantage of those opportunities. advantage ofthoseopportunities. having whobothhelpedyouandallowed mentors youtotake Dr. Right,and Harris: andtakingadvantageoftheopportunities while doingresearch” slowly“I tookanofferbecauseIcouldgrow aclinicalservice opment, theseinterchanges proved beneficial. very common practicesintoday’s scientificcommunity, butinmyearlycareer devel- the result intheshrinkingdroplet techniquethattheyemployed. ofanartifact and, more halfwrong! important, Their studiessuggestingathird factorwere that we volume expanded, some that we didn’t, and they got only half right— something else.) We brought themunknown plasmasamplesfrom somedogs so-called third factor. (Third factormeaningnotGFR,aldosterone, but had already publishedseveral papersandhadahalf-dozen inpress aboutthis saline led to the release of a natriuretic third factor, whereas the Dallas group Wright and I failed to obtain evidence showing that volume expansion with we’re wrong.” them. Rector lookedatthedataandimmediatelysaidtome,“You’re rightand essential. So Ipaidmyairfare toDallas andshowed thedraftmanuscriptto Seldin before we published.HebutIthoughtitwas thoughtthatunnecessary said Iwashappytodosobutalsowantedshare theresults withRector and Berliner told metowriteuptheresults forJournal ofClinicalInvestigation I . highestimatesreported byblocks, Iobtainedtheartificially Dallas group. square oil oftheradiustubule.On theotherhand,whenIusedshort was dilated,thereabsorption ratedidnotincrease, soitwasinsensitive tothe mal physiologicvalue fortherat.Under thesecircumstances where thetubule and theestimatedsinglenephron GFRwasapproximately 30nL/min,thenor- much more than10mLofbloodvolume! be nearly10mL/minGFRinarat—animpossibleresult. The ratdoesn’t have about 300nL/min,whichifmultipliedby 30,000nephrons perkidneywould multiplied the two, which gives you the single nephron GFR, it would come to concentration ratio and the volume per minute collected because if they did and nephron into thepipette. They didnotestimatethetubulefluid-to-plasma ducer systembecausewe were now working atanother government institution. crocirculation. trans- TheNIHbasicallymadealong-term loanofthisservo-null built adevicethatallowed forreal-time measurement ofpressures intherenal mi- research. In thiswayIcouldgrowclinical service. itslowly atmyown pacewhiledoing so muchtoprotect mypersonalresearch timeasIdidnotwanttoinheritabig Sleisenger, chief of medicine at the VA. I took the latter offer because I wanted I received Earley, invitationsfrom Larry head ofrenal atUCSF, andfrom Marvin job offerunlessthe return address is San Francisco.” Andofcourseitwas. finish here, butit’ I said to Jane when I got home, “I don’t know where we’re going to live after we could actually touch it.Ilookedtoward thecityanditwasmost beautiful thing. about. So Itookawalkacross theGolden Gate Bridge. Thefogcamein,and I inthe1960s.Iwantedtoseewhatitwasallat theheightofHaight-Ashbury “Barry, you’re goingto do this,” andpaidforthetrip. paidme $2000 a year.of the military) Yet my wife Jane, a schoolteacher, said, son anditwasamore seniorperson.My asafellow atNIH(Iwasnotpart salary a fellow, in nephrology my name. knew everybody Talk about pure good fortune. lecture, sothatattheendoffirstASNmeetingandmy year as third, “Transplantation.” Physiology” andwasgiven by Berliner. Anotherwascalled“Dialysis,” andthe lecturethe-art titlesat the firstmeetinginLos Angeles? One wascalled“Renal 1967, theyear ofthefirstASNmeeting.Anddo you know thethree state-of- Actually, hypothesiswas donein ourwork onthesquare oftheradiusgeometry These two examples of sharing data prior to publication are, I believe, un- A year later, IwasbackinDallas meetingagainwithRector andSeldin. Fred becausethensomethingthatnever happensdidhappen.I tellyou thisstory So longoilblocks,there by wasnoretrograde puttinginthesevery backleak, Julie Troy and I both moved to San Francisco in 1969. While at NIH, we had I listenedtoBerliner give histalk,then onmyown upto Iflew San Francisco I hadtopaygothemeetingbecauseBerliner wouldonlysendoneper- Berliner presented Brenner mydataandtalkedaboutBarry 5or6timesinhis s goingtobeSan Francisco. Iwon’t openanyenvelope witha March 2016| ASNKidneyNews | Continued onpage 16

15 Distinguished Conversations: Keeping Nephrology Great

Continued from page 15

We were using the device to measure pressures in peritubular capillaries outer medullary potassium channel (ROMK1). He then cloned the thiazide- and for experiments looking at peritubular capillary control of proximal sensitive NaCl cotransporter, and then NKCC2, the thick ascending limb reabsorption when at a meeting in Munich, I was talking to Klaus Thurau, transporter, and then the calcium-sensing receptor, all in a period of 3 years. who said, “We don’t have any interest in this but you might, Barry. We have Hebert went on to Yale, was elected to the National Academy of Sciences some rats that are showing cherry red spots on the surface of the kidney. We and, sadly, died suddenly at the age of 61. Hediger went off to Zurich, and assume they are arteriovenous malformations.” I knew instantly that these then to Bern, where he directs an institute of molecular research. Jonathan were surface glomeruli. Lytton went home to Calgary, Canada, where he is now chairman of the I asked him to send me a dozen rats so I could take a closer look. A week department of biochemistry. It was a very special time—a Camelot for us at or so later, I got a call from Lufthansa cargo at San Francisco airport telling Brigham, with these people adding an enormous dimension to the research. me a box of rats had arrived. I went down to the airport to fetch the rats So you now have a sense of how I got into nephrology and how my 1966 2016 and sign whatever documents were needed, and counted not 12 but 11 rats, early career was bolstered by very good fortune, being given very important whereas the manifest said 12. So one rat escaped through a small hole. After problems to work on (e.g., the existing hypothesis for explaining proximal that, I would never let my family fly Lufthansa, for fear the sole escapee absorption), exploiting those unique rats with surface glomeruli, doing the might be eating through the cables that connect the wings to the body of pure basic science drill on glomerular ultrafiltration, but then leap-frogging the plane. it into a clinical context and showing how the glomerular hypertension plays We quickly confirmed that the red spots on the surface were indeed glo- a role in the progression of kidney disease. meruli, and the pulse contours were highly refined. In the latter sense, what we did was take the various renal diseases, all of We sent half the rats for breeding to the people who took care of animals which progress, and say there is a final common pathway that underlies the at the VA hospital. We labeled them “Munich Wistar Rats” in honor of progression of all of them. It doesn’t mean that this is the sole mechanism. the city in which they were discovered, the way people would at that time It doesn’t mean that everything is explained by this hypothesis, but it went name hemoglobins—for the city where a particular mutation in a hemo- a long way toward unifying disparate entities into something that made a globin molecule was identified. The name stuck—they are still called Mu- more coherent story. For me, it was one of the major milestones of my career. nich Wistar Rats. So we recorded the glomerular capillary pressures, and from there we Dr. Harris: I think your career is a paradigm of someone who were able to do the biophysics of the glomerular circuit. In collaboration has been interested in basic science and has always been with Bill Deen and Channing Robertson from the Chemical Engineering willing and able to translate it into clinically relevant issues. Department at Stanford, we were able to do the quantitative assessment of the ultrafiltration coefficient and a lot of the regulatory steps. Well, for me, it was following a single thread. The nephron GFR is driven more by plasma flow than by hydraulic pressure. It’s a low pressure system, To our membership and leaders, “A finding that led us in the direction of understanding whereas when we made the first measurements and I looked in Robert Pitts’ progression of renal disease” book, Physiology of the Kidney and Body Fluids, the estimate of glomerular pressure was assumed to be 90% of the systemic pressure, not 40% as we to our community and supporters, We prepared several papers on the dynamics of glomerular ultrafiltration, had demonstrated. When you think about it, how could a capillary endure and in the eighth paper, which was intended to examine the effect on the such pressure? But the single thread took those pressure measurements from dynamics of the reduction in renal mass surgically created, we were struck by low to higher values when nephron reduction occurred, whether by disease and to the generations of nephrologists the increase in single nephron GFR and the rise in glomerular capillary pres- or by surgical reduction of renal mass. Now I am preoccupied with more of sure that drove that rise in GFR. It dawned on me, “Well, maybe this rise the same thread. What if you are born with fewer nephrons? Isn’t that like in GFR as an adaptation to reduced renal mass is not a good thing because renal reduction by surgery and doesn’t that constitute a potential risk for who have advanced kidney care for 50 years, over time, the remnant kidney deteriorates and capillaries, like blood vessels progression of renal disease? in general, don’t tolerate high pressure.” We have no trouble comprehend- As you know, it does. But I have been unsuccessful in 30 years at getting ing how arterioles are damaged by hypertension, so why would there not be physicians to use the simple surrogate for low nephron number, namely low damage in capillaries if hypertension is imposed at that level? That led us birth weight. Question number one: What was the endowment of nephrons in the direction of understanding progression of renal disease and the inter- a patient started with? Instead, everyone starts at the same place—it is ruption of disease progression by lowering of those glomerular pressures. wrongfully assumed that everyone starts out with 1 million nephrons in First we lowered glomerular pressures by dietary protein restriction and this each kidney. It’s the number every student remembers. Not a million plus proved to be beneficial long-term. Then we needed a pill—because who is or minus 30%, which is the reality. going to give up their beefsteak? Thank You. The pill had to be something other than a pill that only lowered systemic Dr. Harris: You’re right. What I think we should be doing is blood pressure because up to that time, every antihypertensive drug was a getting a better birth history, but also finding better ways to vasodilator, and although they lowered systemic pressure, they opened up image and actually count glomeruli. I think that’s the next the afferent arteriole and the glomerular pressure did not decline. Therefore frontier. there was no renal benefit to be expected. But we had been working on the effect of angiotensin II, which we showed constricted the efferent arteriole, Yes, and to make that a clinically feasible assessment in toddlers and young not the afferent, and believed that if there was something that could relax people as a baseline. Anyway, I’ve been frustrated with my inability to con- the efferent arteriole, that would be a way to lower intraglomerular pressure vince our renal colleagues that these steps must be taken. But I have reason selectively. And then came the ACE inhibitors captopril and enalopril, both to be encouraged. At Giuseppe Remuzzi’s invitation, I gave a plenary lecture of which indeed lowered intraglomerular pressure dramatically and thereby on nephron endowment at the last ISN meeting in Cape Town in March minimized progressive glomerular injury. 2015. The audience seemed impressed. I am pleased that a symposium on the theme of this lecture will be held under Remuzzi’s leadership in Ber- “Bringing molecular biology to the renal division at gamo, Italy, in April 2016. Brigham” Dr. Harris: So I think that your work is not done. In 1976, I along with a number of our San Francisco VA team accepted positions at Brigham and Women’s Hospital in Boston. An early recruit to Well, it’s what keeps me on the younger side of my 78 years. It keeps me go- our new program, Steve Hebert, was at that time perfusing isolated tubules. ing. I remain deeply immersed in the issues that fascinate me, and I continue I also recruited Matthias Hediger, who, with Ernie Wright, had used expres- to devote myself to my favorite indoor hobby, deep work. sion cloning to identify the sodium-glucose cotransporter-1 and show that One final thing. I would like to express my unbounded gratitude and mutation of the transporter resulted in glucose-galactose malabsorption. His love to my wife, Jane, our children, Rob and Jen, and our grandchildren, work was beautiful—I admired it and I got him to come to Brigham. I also Sam, Max, Elliott, and Abigail. I also thank all the fellows who taught me recruited another molecular biologist, Jonathan Lytton, so I had these two so much. I especially thank Julia Troy, the most able technical assistant the young scientists doing pure molecular biology in our renal division. micropuncture field has ever known. When I bound all the articles she and I Hebert was so taken with their work that he took an intramural sab- wrote together over the years into a book, I inscribed in the front cover, “To batical. He stopped perfusing tubules and learned how to do the molecular Julia Troy. With you, the voyage has been wonderful. Without you, I would biology. His first success, with a fellow named Kevin Ho, was to clone renal never have left the shore.” www.asn50.org 1966 2016

To our membership and leaders, to our community and supporters, and to the generations of nephrologists who have advanced kidney care for 50 years, Thank You.

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Look for an announcement about this exciting member benefit on March 16, 2016. March 2016 | ASN Kidney News | 19 Detective Nephron

Detective Nephron, world-renowned for expert analytical skills, trains budding physician-detectives on the diagnosis and treatment of kidney diseases. L.O. Henle, a budding nephrologist, presents a new case to the master consultant.

Nice Glom (the new medical student) enters the room along with L.O. Henle to present a case.

Nephron What do you have for me today Henle? cell damage. This damage may be manifested as subtle neurological Henle looks at Glom symptoms such as gait disturbances that can only be detected by special neuropsychometric testing. Glom I have a 65-year-old man with a serum sodium concentration of Glom 112 mEq/L. Amazing! Nephron Nephron Hyponatremia! My favorite electrolyte disorder. What is the first Well, getting back to our case, since our patient is apparently question you need to ask? asymptomatic, there is no need to use hypertonic saline. Mildly symptomatic and the so-called “asymptomatic” (looking at Henle) Henle Whether the patient has symptoms? hyponatremia reflect almost complete adaptation to hypotonicity with mild degrees of cerebral edema. Full adaptation takes 48–72 Nephron Exactly. Given the severity of this hyponatremia, we need to h and that is where the difference lies between acute and chronic know if we need to treat immediately with hypertonic saline to hyponatremia. Hypertonic saline is not needed in this case and avoid life-threatening cerebral edema. Severe symptoms such as we have more time to focus on the underlying pathophysiology seizures and coma indicate significant cerebral edema and require causing hyponatremia. the use of NaCl 3% 100 mL IV bolus, which you could repeat twice if symptoms persist. Moderate symptoms such as confusion Nephron Glom, why don’t you tell me more about this patient? indicate a lesser degree of cerebral edema but still significant Glom enough to be dangerous and also require the use of NaCl 3% but He is a 65-year-old homeless man with a significant history of in slow infusion. Remember, severely symptomatic or moderately alcohol abuse. He was found down in the street by the police who symptomatic hyponatremia are medical emergencies and need to be brought him to our emergency department. It seemed the patient treated with hypertonic saline. was inebriated initially but was alert and oriented for me. On exam, his BP = 100/60 mm Hg, heart rate = 79 bpm, RR = 20. He Henle I interviewed the patient and did a full neurological exam. The looked disheveled and malnourished. Cardiopulmonary exam was patient is asymptomatic. unremarkable. Abdominal exam was benign. Neurological exam was normal, as Henle said. Overall, he seemed euvolemic. His Nephron (upset) That is not entirely true, is it? Evidence has emerged over the initial laboratory examination revealed a Na = 112 mEq/L, K = 2.5 last several years suggesting that all hyponatremias are symptomatic mEq/L, Cl = 95 mEq/L, TCO2 = 25 mEq/L, Glucose = 75 mg/dL, to a degree. Even mild chronic hyponatremia in the range of 125 to BUN = 3 mg/dL, Cr = 0.3 mg/dL, Alb = 3.2 g/dL. POsm = 280 135 mEq/L is not only associated with increased mortality but also mOsm/kg. So, it seems he has pseudohyponatremia, but I thought increased morbidity in the form of subtle attention deficits, gait we don’t see this anymore since the way the laboratory measures disturbances, falls, fractures, and osteoporosis. sodium concentration has changed?

Glom I did not know that. Nephron (shocked) That is a common misconception. Two-thirds of all clinical laboratories in the US still use indirect ion selective Nephron (smiling) Are you familiar with the concept of regulatory volume electrode technology to measure sodium concentration on a routine decrease or RVD? basis. This technology is prone to error in the presence of high protein or lipid levels in the blood. So we still need to be alert Henle & (looking at each other) No. for those, however, pseudohyponatremia does not seem to be the Glom problem here. Do you have a serum ethanol level from his initial laboratory examination in the emergency department? Nephron Regulatory volume decrease is the process by which cells adapt to swelling. In the brain, astrocytes do swell under hypotonic Glom Sure, it was 192 mg/dL. conditions, and neurons do not because they lack aquaporin 4, the water channel responsible for cerebral edema. Astrocytes Nephron Mmmm …. It seems we need to go over the concepts of osmolality achieve regulatory volume decrease by extruding osmoles to the and tonicity. Henle? extracellular compartment, therefore reducing intracellular tonicity to avoid further water entry. Initially, during the first 3 hours of Henle Tonicity is effective osmolality. Tonicity does not take into account this process, K+ and Cl- are the main osmoles extruded, but after the contributions of solutes that cross cell membranes and therefore that, organic osmoles, such as glutamate and myoinositol, take a do not exert an osmotic effect. Urea is one of these solutes. But the primordial role. Glutamate is the main excitatory neurotransmitter BUN is low in this patient? in the brain. It is hypothesized that glutamate released in large amounts during this process can cause excitotoxicity and neuronal Continued on page 20 20 | ASN Kidney News | March 2016

Detective Nephron

Continued from page 19 Nephron Yes. By the way, what are the sodium disorders?

Nephron Can you think of another solute that crosses cell membranes and Glom Mmm …. does not contribute to tonicity but does contribute to osmolality? Henle Hypovolemia and hypervolemia. Henle (jumps in) Ethanol! Nephron Excellent! Then an excess of solute-free water can develop as a Nephron Precisely, and this is what happened to this patient. The ethanol consequence of either increased water intake or decreased water level was high enough that it made the plasma osmolality normal, excretion. but if you discard its effects, the tonicity will still be low, roughly 228 mOsm/kg. This is really a hypotonic hyponatremia. Classically, Glom This is finally making more sense for me. this is seen in hospitalized ESRD patients with hyponatremia Nephron associated with normal osmolality. Let’s stop expensive workups Patients can ingest large amounts of water without developing looking for hypertriglyceridemia and multiple myeloma without hyponatremia because kidneys can handle huge water loads, but realizing that what makes osmolality normal in these patients is the there is a limit as to how much the kidneys can excrete… contribution of high urea levels. Pause… and the limit is about 18 liters per day. Glom (blushing) Thanks for telling me. I will cancel my orders for a SPEP and a lipid profile. So following the algorithm, then, this patient Glom I see. has hypotonic euvolemic hyponatremia. Nephron We said most hyponatremias are due to an increase in water Nephron You like algorithms, don’t you Glom? Clinicians use algorithms as compared to total exchangeable cations. We talked about increase a way of chunking separate pieces of information and to increase in water intake. What about decrease in renal water excretion? space in their working memory. That is a valid and effective What pathophysiological mechanisms do contribute to a decrease cognitive technique, but when algorithms are abused and used in renal water excretion? as cookbook medicine without understanding the underlying pathophysiology they fail miserably. There are several issues with Henle High antidiuretic hormone (ADH). the classic hyponatremia algorithm: first, clinicians’ assessment Nephron of volume status in hyponatremia has been studied and found to Yes! High ADH activity is the most common mechanism of have a low sensitivity and specificity. Second, the effectiveness of hypotonic hyponatremia. the classic algorithm only enables 10% of clinicians to correctly Nephron And what stimulates ADH to be released in large amounts? diagnose hyponatremia. Finally, the classic algorithm suggests you could arrive to a single diagnosis; however, hyponatremia is usually Glom Hypertonicity and hypovolemia. multifactorial. Nephron Hypertonicity is a well-known stimulus for ADH release, but Henle Understood. What is your approach then? remember true hyponatremia is hypotonic so this does not really apply here. Nephron In a series of pivotal studies done by Dr. Edelman and reported in a landmark paper published in the Journal of Clinical Investigation Glom What about hypovolemia? in 1958, he described what is known now as the Edelman equation by which the serum sodium concentration could be viewed as a Nephron To be more precise, you should say “decreased effective arterial function of total body contents of sodium, potassium, and water. + + blood volume.” Hypovolemia refers to decreased extracellular The equation goes like this: [Na ] = (NaE + KE)/TBW. Where [Na ] fluid (ECF) volume. Remember, extracellular fluid volume can is the plasma sodium concentration, NaE and KE are the total body be divided into 2 compartments, interstitial and intravascular. exchangeable sodium and potassium respectively, and TBW is total The intravascular compartment can also be divided into a venous body water. sub-compartment that contains 85% of the blood volume, and an arterial sub-compartment that contains only 15% of the blood Henle Exchangeable sodium and potassium? volume. The baroreceptors are located in the arterial portion of the intravascular space and sense changes in this compartment. When Nephron Exchangeable sodium and potassium represent the total body the volume of this compartment goes down, the baroreceptors sodium and potassium that exert an osmotic effect. For instance, are activated and the end result is the release of ADH from the bone tissue can store almost a third of total body sodium, but it is posterior pituitary. Baroreceptors do not sense changes in ECF non-exchangeable, meaning it does not exert an osmotic effect and volume. ECF volume changes can parallel changes in the arterial therefore does not contribute to plasma sodium concentration. It compartment such as in individuals who develop hemorrhage, is hypothesized that movement of sodium from bone to plasma vomiting, or diarrhea, the so-called hypovolemia, but sometimes during chronic hyponatremia is responsible for osteoclast activation not. That is why you could have patients with low effective arterial and subsequent osteoporosis. blood volume despite an expanded ECF volume. Can you think of Henle Very interesting. clinical scenarios where this happens? Glom Nephron Following the Edelman equation, then, hypotonic hyponatremia is Liver cirrhosis and heart failure. produced when total body water is increased relative to total body Nephron Very good! What about other non-physiological causes for ADH exchangeable sodium and potassium, or simply put, when there is release? excess solute-free water. Henle & Glom Is that why you always said hyponatremia is mainly a water Glom Mmm…. disorder, and not a sodium disorder? March 2016 | ASN Kidney News | 21

Nephron What do you call the condition where ADH is secreted Nephron Have you heard of beer potomania? autonomously in the absence of a physiologic stimulus? Henle Oh yes! Henle SIADH (syndrome of inappropriate antidiuretic hormone secretion)! Nephron This condition occurs in alcoholics. They usually do not eat enough solute and therefore they have a limited capacity to excrete water. Nephron Exactly! Any other mechanism by which ADH could be high? On top of that, they drink beer all day and beer is 90% water. They usually end up retaining water and developing hyponatremia. I am Henle Adrenal insufficiency? afraid this is what is happening to this patient. How much does he drink? Does he eat enough solutes? Nephron Primary, secondary, or tertiary? Glom Yes, I asked him. He said he drinks 2 six packs of beer every day Henle I don’t know. and eats very little food. He looks very malnourished.

Nephron (surprised look) All! But by different mechanisms. Cortisol exerts Henle Yes, his BUN is only 3! a negative feedback loop on ADH release. So, in the absence of cortisol, ADH is uninhibited. This occurs in any adrenal Nephron Do you have a urine osmolality in this patient? insufficiency. In the specific case of primary adrenal insufficiency where the problem is the adrenal gland, aldosterone secretion Glom It is 79 mOsm/kg. is also compromised, and aldosterone regulates renal sodium excretion. In the absence of aldosterone, you have renal salt wasting Nephron That is very diluted urine with suppressed ADH, which can only and decreased effective blood volume causing ADH release as well. be explained by drinking in excess of the kidney’s ability to excrete water. You can see low urine osmolality in patients with primary Glom Fascinating! polydipsia who drink huge loads of water, or patients who drink a normal amount of water but their kidneys have a limited ability to Nephron What other mechanisms of decreased renal water excretion do you excrete water due to non-ADH mechanisms such as low GFR or know? low solute intake. Given his normal kidney function, the history of alcohol abuse, and his nutritional status, I say this is likely low- Henle Decreased GFR. solute-intake hyponatremia caused by beer potomania.

Nephron Very well. This is a very common problem in our AKI, CKD, and Glom What is the treatment? ESRD patients. They don’t need to drink 18 L of water to develop hyponatremia. With much less water intake they will be in trouble Nephron Increase his solute intake, give him a hamburger! I mean, give him because their kidneys cannot excrete the extra water load. When regular hospital food. you see an anuric ESRD patient with hypotonic hyponatremia, it is almost always due to this. Don’t do a million dollar workup Henle Any other recommendations? looking for another cause. Nephron I am glad you asked. Patients with low-solute-intake Nephron Any other mechanisms of decreased renal water excretion? hyponatremia will overcorrect once dietary solute is increased. These patients usually start having a brisk urine output due to Glom I don’t know any other. massive water diuresis, so the primary team needs to be aware of this and ready to act. Nephron Low solute intake. The amount of solutes excreted in the urine, also known as urine solute load, determines the volume of urine being Glom Act? produced. Under steady state conditions, the amount of solutes you eat is equal to the urine solute load. So, if you eat a low solute Nephron (with confidence) Overcorrection of hyponatremia is a medical diet, then you will excrete a small urine solute load and therefore emergency. Overcorrection is the main risk factor for osmotic your urine volume will be low, and with low urine volumes the demyelination syndrome. ability to excrete water will be limited. Glom OK, I will tell them the correction rate should be 0.5 mEq/L/h. Glom (confused) What is considered a low solute intake? Nephron That is the classic teaching in medical school but there is actually Nephron The normal diet contains 600 to 900 mOsm per day of solutes. not much evidence to support the notion of correction rates. There are, however, correction limits that when you cross put Glom I must be eating a good amount of solute because I love spaghetti. your patient at risk for osmotic demyelination syndrome. The limits have traditionally been 10–12 mEq/L in 24 h. The 0.5 Nephron That is a common misconception; carbohydrates do not produce mEq/L/h is an extrapolation of this, i.e., 12 mEq/L divided by 24 any meaningful solutes. Most solutes are derived from either h. The absolute magnitude of correction is more important than proteins because they metabolize to urea, or salt. the rate. You could theoretically correct the sodium by 10 in the first hour as long as you keep the sodium the same in the next 23 Henle I guess this occurs in the so-called tea and toast diet? hours. There are animal studies that support this concept.

Nephron Exactly. These patients eat toast, which is mainly carbohydrates, Henle So, should we tell the team our goal is no more than 10 mEq/L in with very little solute intake, and drink tea all day, which is mainly 24 h? water, exceeding the capacity of their kidneys to excrete water. Any other clinical scenarios? Nephron No. 10 mEq/L in 24 h is a limit, not a goal. When you use digoxin or phenytoin, you do not aim for one minus the toxic Henle Not sure. dose, right? You aim for a smaller level that is effective but also Continued on page 22 22 | ASN Kidney News | March 2016

Detective Nephron

Continued from page 21 a state of artificial SIADH and avoiding water diuresis, which is the main state responsible for overcorrection. In that way, they are able to correct the hyponatremia very nicely without complications.

safe. The same happens in hyponatremia. We do not aim for 10 Glom I will also tell them to replace the potassium of 2.5 mEq/L. mEq/L; 10 mEq/L is our limit. Case series have demonstrated that correcting the sodium concentration by 6 mEq/L in any Nephron Hold on! You have to be very careful about replacing potassium in 24-h period is a safe and effective goal. patients with hyponatremia. Following the Edelman equation, any addition to the total body potassium will increase serum sodium Glom OK, so aim for 6 mEq/L but definitely no more than 10 mEq/L? concentration. In other words, correcting hypokalemia will also correct hyponatremia. So, I will try to minimize the potassium Nephron (in teaching mode) Also incorrect. 10 mEq/L is the limit for patients correction for now unless the patient has arrhythmias or muscle with average risk of osmotic demyelination syndrome. Patients weakness until the sodium concentration is at a safer level. with liver cirrhosis, malnutrition, alcoholism, and hypokalemia Henle are at high risk of osmotic demyelination syndrome and the limit (yawning) It looks like I might need to be awake all night to should be no more than 8 mEq/L. monitor the sodium concentration in this patient. Nephron Glom What happens if the sodium corrects too fast? What can we do? That is a good idea Henle but also it is part of being a good nephrologist. We always do the best for our patients. Make sure Nephron They need to carefully monitor his urine output and once they see you bring your coffee with you Henle, as you will need it! an increase in urine output or a rapid elevation of serum sodium concentration they need to relower the serum sodium. Relowering Special thanks to Dr. Helbert Rondon, Assistant Professor of Medicine, Renal- serum sodium concentrations has been proven to be an effective Electrolyte Division at the University Of Pittsburgh School Of Medicine (writer and prevention strategy to avoid osmotic demyelination syndrome in submitter for this case). case series and animal studies. I recommend using D5W at 3 mL/ The concept of Detective Nephron was developed by Kenar D. Jhaveri, kg IV over 1 hour and repeat sodium right after. We can also add MD, Associate Professor of Medicine at Hofstra North Shore LIJ School desmopressin 2–4 µg subcutaneously if it seems that D5W is not of Medicine and an Attending nephrologist at North Shore University and enough. Some clinicians follow a protocol where they start with Long Island Jewish Medical Center in Great Neck, NY. Send correspondence NaCl 3% along with desmopression Q8h from the get-go, creating regarding this section to [email protected] or [email protected].

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Closing Date & Cancellations: FURTHER YOUR EDUCATION WITH CME COURSES Copy must be received four weeks in advance of the month in which the PROMOTE AN UPCOMING CONFERENCE ad is to appear. Cancellation requests must be made in written form by fax, e-mail or postal mail and will be honored for the earliest applicable issue.

These plus more opportunities available when you contact Contact: All Ads Rhonda Truitt Rhonda Truitt Must be PrePAid [email protected] [email protected] P: 443-512-8899 x. 106 F: 443-490-4003 443-512-8899 x 106

Early Programs 2015 Online The online version of several Early Programs from ASN Kidney Week 2015 are now available. Access key content from: • Critical Care Nephrology: 2015 Update • Kidney Transplantation • Diagnosis and Management of Disorders of • Maintenance Dialysis Acid-Base, Fluid, and Electrolyte Balance: • Polycystic Kidney Disease: Translating Challenging Issue for the Clinician Mechanisms into Therapy • Glomerular Disease Update: Diagnosis and Therapy 2015

These online Early Programs are complimentary to fully paid Early Program participants or are available for purchase. For more information, www.asn-online.org/learningcenter. Please note that CME, CNE, and CPE credits are not available for this activity.

Early Programs Ad 9.5x3.28.indd 1 3/1/16 12:16 PM

Index to Advertisers Baxter ...... Pages 12-13 Keryx ...... Pages 6-8 Mount Sinai Health System ...... Page 5 Relypsa ...... Page 3 Spectra ...... Back page If you’re looking for a trusted laboratory partner, don’t just take our word for it. The proof is in the numbers.

Servicing over 237,000 patients Performing over 65 million tests annually Performing 4,000+ on-site clinical inservices per year Processing over 11.5 million specimens per year Servicing over 3,190 clinics

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www.spectra-labs.com bicoastal operations in: © 2016 Fresenius Medical Care Holdings, Inc. All rights reserved. Milpitas, CA • Rockleigh, NJ Spectra® and the Spectra logo are trademarks of Fresenius Medical Care Holdings, Inc.

2016 Mar Numbers MagGlassAd ASN.indd 1 3/1/16 11:23 AM