August 2010 | Vol. 2, Number 8

CKD Patients Starting Dialysis “Late” Fare No Worse than Those Starting Early Inside

lanned early initiation of dialysis The IDEAL investigators reported does not improve survival for pa- that death from any cause—which was 6 Findings European Renal tients with stage 5 chronic kidney the primary study outcome—occurred Association--European disease,P a new study finds. in 152 (37.6 percent) of the 404 patients Dialysis and Transplant Early dialysis start times did not re- in the “early start” group and 155 (36.6 Association Congress sult in fewer cardiovascular, infectious percent) of the “late start” patients. In- disease, or dialysis-related complications cidence of infections and other compli- in the eight-year trial titled Initiating cations did not differ between the two Dialysis Early and Late (IDEAL). Re- groups. sults from the prospective, randomized Our results indicate that . . . trends 8 Journal View Monitoring avoids multicenter controlled clinical trial were toward early initiation of dialysis, which hyperkalemia from published by the New England Journal of have enough implications in terms of heart failure drug Medicine and presented at the European cost and infrastructure of dialysis serv- Renal Association-European Dialysis ices, are unlikely to improve clinical and Transplant Association 2010 Con- outcomes,” wrote IDEAL investigators gress in June. Bruce A. Cooper, PhD, of Royal North 11 Industry Spotlight The study population included 828 Shore Hospital and Sydney Medical patients over 18 years at 32 centers in School in Sydney, Australia, and the Australia and New Zealand. The pa- lead author of the NEJM paper. tients were randomly assigned to one of The trial’s findings highlight the im- 12 Fellow’s Corner two groups: “early start” and “late start.” portance of clinical symptoms and pa- The protocol for the “early start” group tient follow-up in determining the onset called for starting dialysis when the pa- of dialysis. tients’ estimated glomerular filtration “In our view, the IDEAL trial sup- 13 ASN News rate (eGFR) was 10–14 mL per minute. ports the currently recommended prac- Society announces In the “late start” group, dialysis was tice in which most nephrologists start 2010 grant recipients planned to occur when the eGFR fell to patients on renal replacement therapy 5–7 mL per minute. Continued on page 3 14 Policy Update Movement on multiple CMS Finalizes New ESRD Bundled Payment System chronic conditions, alleviating primary care shortage, and By Rachel Shaffer expanding preventive care access undamentally changing how Medi- services—including drugs and diagnostic provide renal dialysis services (see sidebar). care pays for dialysis services for pa- laboratory tests—to dialysis facilities for The QIP is the first pay-for-performance Ftients with end stage renal disease each dialysis treatment. Medicare current- program in a Medicare fee-for-service pro- 16 Dectective (ESRD), the Centers for Medicare and ly pays facilities a composite rate for most gram. Currently, facilities only report on Nephron Medicaid Services (CMS) released the items and services, while paying separately whether they have complied with quality A 65-year-old male Final ESRD Prospective Payment System for certain drugs, laboratory tests, and measures. Beginning in 2012, the extent presents with fatigue (PPS) Rule in late July. Under the new other services. to which dialysis facilities meet established and muscle weakness “bundled” payment system, effective Jan- Simultaneously, CMS issued a pro- performance standards will be reflected in uary 1, 2011, Medicare will provide a sin- posed rule that will establish a new quality their payment rates, with reductions of up gle payment that covers all renal dialysis incentive program (QIP) for facilities that to 2 percent. The new ESRD payment system is his- 18 Patient Safety Many errors result toric for two reasons: It is the first bun- from flawed systems, dled payment system of its kind CMS has rather than individuals’ implemented, and it marks the first time carelessness Medicare will vary payment based on the quality of care. These features—bundled Continued on page 4

August 2010 | ASN Kidney News | 3

Public Health. Becker also is physician- CKD Patients jnish Mehrotra, MD, who chairs ASN’s professor of medicine at UCLA’s David in-chief and head of the section of ne- Dialysis Advisory Group, and National Geffen School of Medicine and associ- Continued from page 1 phrology. Kidney Foundation President Bryan N. ate chief and of the division of nephrol- As a result, the mean eGFR at the on the basis of clinical factors rather than Becker, MD. ogy and Hypertension at Harbor-UCLA start of dialysis in the “late start” group numerical criteria such as the estimated “The IDEAL results provide several Medical Center. was 9.8 mL/min/1.73 m2. The median GFR alone,” wrote the authors of an lessons: delaying dialysis till the appear- “In my view, the single biggest aspect time to the initiation of dialysis was 7.4 editorial published along with the paper. ance of symptoms does no harm, contra- of the IDEAL trial was that because of months in this group versus 1.8 months Norbert Lameire, MD, PhD, and Wim ry to the previous nonrandomized stud- uremia, fluid overload, or other symp- in the “early start” group. The study pro- Van Biesen, MD, PhD, of the University ies; beginning dialysis early also does no toms, over 75 percent of the patients in tocol allowed patients assigned to “late Hospital Ghent, University of Ghent, harm; and the traditional clinical criteria, the “late start” group began dialysis when start” to begin dialysis early at the rec- Belgium, authored the editorial. patient monitoring and follow-up appear their GFR was above the study’s target ommendation of the treating physician, That clinical factors, not just apre- to be more important than the actual of 7.0 mL per minute,” said Becker, who was not required to discuss this determined GFR, should influence level of renal function in deciding when professor of medicine at the University decision in advance with the trial coor- decision-making was emphasized by Ra- dialysis should begin,” said Mehrotra, of Wisconsin School of Medicine and dinator. Becker applauded the extensive patient follow-up, repeated contact, and patient education provided to the chronic kidney disease patients in the IDEAL study, and noted that this high level of care may have influenced the similar outcomes of the “early start” and “late start” groups. “The vast majority of patients in the study were instructed about chronic kidney disease and the potential need for dialysis,” he said. “One manifesta- tion of the preparation was that dialy- sis access was already in place before it became evident that the patient would need dialysis.” IDEAL did not require the treating physicians to place a tem- porary catheter to avoid delaying the as- signed start time. Decisions about tem- porary placement were based on clinical judgment. In the real world of clinical medicine in the United States, nephrologists too often do not have the opportunity to educate and prepare patients well in ad- vance of initiating dialysis. “In the IDEAL study cohort, the patients were seeing a nephrologist for about two and one-half years before beginning dialysis,” Mehrotra said. “In the United States, over 40 percent of the 110,000 patients who begin dialysis each year have had no pre-dialysis care by a nephrologist.” The patient care provided to the IDEAL participants and to most U.S. chronic kidney disease patients differs in other respects, Mehrotra said. While 7 percent of U.S. patients are on peri- toneal dialysis, 57.7 percent and 54.9 percent of the “early start” and “late start” groups were on peritoneal dialy- sis, respectively. In the IDEAL study, a temporary dialysis catheter was used in 5 percent of the patients. About 80 percent of kidney disease patients begin dialysis with a catheter in the United States. The IDEAL results challenge the worldwide trend toward early renal re- placement therapy. From 1996 to 2005, the proportion of patients in whom di- alysis was initiated when the eGFR was greater than 10 mL per minute increased from 19 percent to 45 percent, accord- ing to the U.S. Renal Data System. Mehrotra noted that patients who begin dialysis when their eGFR is rela- tively high usually are “the sickest pa- tients. They are the most likely to be diabetic or have a history of congestive heart failure.” Continued on page 4 4 | ASN Kidney News | August 2010

The study ended in 2008 and followed pa- CKD Patients tients for an additional year. Continued from page 3 Although the dialysis method was specified for each patient before randomi- Launched in 2000, IDEAL recruited zation, the treating physician and the pa- chronic kidney disease patients whose esti- tient ultimately determined the method mated GFR was 10–15 mL/min/1.73 m2 and regimen. of body-surface area, as calculated by us- “As the National Kidney Foundation ing the Cockcroft–Gault equation. The 32 goes through its traditional guideline as- centers included rural and urban, as well sessment, certainly we’ll want to see the as general and university hospital settings. IDEAL data represented,” said Becker. Editorial Staff Editor-in-Chief: Pascale H. Lane, MD, FASN Managing Editor: Dawn McCoy However, CMS will not add oral-only Design: Lisa Cain ESRD Bundled medications to the bundle until January Editorial Board: Payment System 1, 2014. Patients will continue to have Matthew D. Breyer, MD, FASN, access to these products under Medicare Eli Lilly and Company Continued from page 1 Wendy Weinstock Brown, MD, Jesse Brown VA Medical Center, Northwestern University Feinberg Part D until that date. School of Medicine, University of Illinois at Chicago This delay period will enable CMS to Teri Browne, PhD, MSW, University of South Carolina services and pay-for-performance—are address many of the concerns raised by Stephen Darrow, MD (fellow), University of Nebraska Medical Center likely to be increasingly prevalent within ASN in its comment on the Proposed Ira Davis, MD, Baxter Healthcare Corp. the Medicare reimbursement system in Rule about ESRD facilities’ ability to fur- Caroline Jennette, MSW, University of North Carolina Kidney Center coming years. Indeed, health reform legis- nish drugs formerly covered under Part D, Richard Lafayette, MD, Stanford University Medical Center lation instructs the Department of Health Edgar V. Lerma, MD, FASN, University of Illinois – Chicago /Associates in Nephrology, as well as the CMS’s ability to identify and SC and Human Services (HHS) to pilot mul- remediate any negative changes in avail- Teri J. Mauch, MD, FASN, University of Utah tiple versions of bundled payment systems. ability or quality of patient care. Among Victoria F. Norwood, MD, FASN, University of Virginia “The new payment system and quality in- other things, the delay will allow: Sheila M. O’Day, MSN, University of Nebraska Medical Center centive program for dialysis services have • CMS time to conduct additional analy- Matthew A. Sparks, MD,Duke University Hospital significant potential to improve patient sis regarding the ability of ESRD facili- Titte R. Srinivas, MD, Cleveland Clinic outcomes and promote efficient delivery ties to provide oral-only ESRD drugs. of health care services,” said CMS Admin- • ESRD facilities time to develop the ar- Advertising Sales: istrator Donald Berwick, MD. Demon- rangements or infrastructure necessary Scherago International, Inc. strating the effects of bundled payments 525 Washington Blvd., Suite 3310 to provide oral-only drugs and negoti- Jersey City, NJ 07310 for care of patients with chronic disease, ate prices with drug companies. 201-653-4777 phone implementation of the ESRD PPS may • CMS time for additional analysis of 201-653-5705 fax well act as a model for future health care ESRD facilities’ ability to provide oral- [email protected] payment reforms. only ESRD drugs. The ASN Public Policy Board, ESRD • CMS time to evaluate the need for ad- ASN Council: Task Force, and policy staff analyzed and ditional clinical indicators applicable to President: Sharon Anderson, MD, FASN commented extensively upon the ESRD the monitoring of certain patient con- President-elect: Joseph V. Bonventre, MD, PhD, FASN PPS Proposed Rule in 2009. The final ditions treated with oral-only drugs, Past-President: Thomas M. Coffman, MD, FASN rule addressed many of the concerns ASN such as bone loss and mineral metabo- Secretary-Treasurer: Donald E. Wesson, MD conveyed to CMS during the comment lism associated with the provision of Publications Committee Chair: Thomas M. Coffman, MD, FASN period. Creating separate payments for calcimimetics and phosphate binders. Councilors: Ronald J. Falk, MD, FASN; Jonathan Himmelfarb, MD, FASN; home dialysis training, preserving physi- This could assist in determining the Sharon M. Moe, MD, FASN; Bruce A. Molitoris, MD, FASN cian flexibility in ordering lab tests and impact of the fully bundled payment Executive Director: Tod Ibrahim medications, monitoring the bundle’s system—and any unintentional conse- Publications Manager: Robert Henkel influence on patient care and access, and quences that might ensue—on quality evaluating the effect of new copayments of care. ASN Kidney News is published by the American Society of Nephrology on patients are among the many revisions 1725 I Street NW, Suite 510, Washington, DC 20006. Phone: 202-659-0599 CMS made to its proposals following Scope of the bundle: oral drugs ASN’s comments. with an injectable equivalent www.asn-online.org Currently, these ASN groups are con- CMS will include oral drugs with an in- ducting an in-depth review of the final ASN Kidney News is the authoritative source for analysis of trends in medicine, industry, and policy jectable equivalent in the bundle begin- affecting all practitioners in nephrology. The statements and opinions expressed in ASN Kidney News rule, which is not open for public com- ning January 1, 2011. CMS classifies are solely those of the authors and not of the American Society of Nephrology (ASN) or the editorial ment. This summary presents an overview these products into five ESRD drug cat- policy of the editors. The appearance of advertisements in ASN Kidney News is not a warranty, of several of the most significant provi- egories based on mechanism of action, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or sions in the Rule. Over the coming weeks safety. The American Society of Nephrology disclaims responsibility for any injury to persons or and envisions that these categories will and months ASN will continue working property resulting from any ideas or products referred to in the articles or advertisements. provide flexibility to incorporate new to help members understand how medical products into the bundle as they become practice and patient care will be affected The American Society of Nephrology is organized and operated exclusively for scientific and available in the future. The final rule also educational purposes, including enhancing the field of nephrology by advancing the scientific by these changes. The society will also be delineates several drug categories expressly knowledge and clinical practice of that discipline through stimulation of basic and clinical working closely with CMS as a liaison excluded from the base rate, which CMS investigation, providing access to new knowledge through the publication of journals and the between the agency and the nephrology will continue to bill separately. These in- holding of scientific meetings, advocating for the development of national health policies to improve community. the quality of care for renal patients, cooperating with other national and international societies and clude drugs and biologicals classified as organizations involved in the field of nephrology, and using other means as directed immunosuppressant drugs, vaccines, and by the Council of the Society. Scope of the bundle: oral-only drugs chemotherapeutic drugs. The final rule, which is accessible on ASN’s website, con- Postmaster: Please send address changes to ASN Kidney News, c/o Customer Service, In the final rule, CMS finalizes its proposal tains a complete list of these drugs. American Society of Nephrology 1725 I Street NW, Suite 510, Washington DC 20006. to make a single bundled payment to di- Responding directly to ASN’s com- Publications mail agreement No. 40624074. Return undeliverable Canadian addresses to alysis facilities for each dialysis treatment ment that many nephrologists serve as PO Box 503, RPO West Beaver Creek, Richmond Hill ON L4B 4R6 that covers all dialysis-related drugs, diag- primary care providers for their patients nostic laboratory tests, equipment, sup- and in this capacity sometimes need to ASN Kidney News (ISSN print 1943-8044 and online 1943-8052) is an official publication of plies and staff time. For 2011, CMS sets prescribe non-ESRD-related drugs, CMS the American Society of Nephrology, 1725 I Street NW, Suite 510, Washington DC 20006, and the standardized base rate of the bundle ruled that nephrologists may continue to is published monthly. Application to mail as Periodicals Postage Pending at Washington, DC, at $229.63, which will be multiplied by order such products in the new payment and at additional mailing offices. Subscription rates: $12 per year. To order, please email patient and facility-level payment adjus- environment. The agency created a new [email protected]. Subscription prices subject to change. Annual ASN membership dues tors. As CMS proposed in 2009, the bun- modifier on the claim form for this pur- include $12 for ASN Kidney News subscription. dle will include erythropoiesis-stimulating pose. CMS also identifies a small number Copyright© 2009 All rights reserved agents (ESAs) and “oral-only ESRD-relat- of products that are sometimes ESRD-re- ed drugs and biologicals.” lated but are also often prescribed for other August 2010 | ASN Kidney News | 5 reasons. Facilities will be eligible to receive contributing to the increased cost of pro- in co-insurance under the current payment Table 1. Lab tests used to diagnose separate payment for these products, using viding care to certain groups. system and the new bundled payment sys- or monitor ESRD-related conditions the same new modifier to indicate the drug As it weighs decisions on the patient tem for an individual patient is directly re- that will be paid under the bundle was not administered for ESRD care. sex and race/ethnicity adjustors, CMS said lated to how their use of separately billable CPT HCPCS Short description it will continue to monitor for evidence of services compares to the average amount. Diagnostic laboratory tests decreased access to renal dialysis services— 82040 Assay of serum albumin a key activity ASN emphasized the agency 82108 Assay of aluminum CMS also addressed ASN’s concerns that Home dialysis conduct in the new payment environment. 82306 Vitamin D, 25 hydroxy nephrologists continue to be able to order As encouraged by ASN and others, CMS 82310 Assay of calcium laboratory values that are not related to re- Co-payments adopts a payment adjustor for home di- 82330 Assay of calcium, Ionized nal dialysis services. Allowing MCP neph- Under the ESRD PPS, the beneficiary’s alysis training for both hemodialysis and 82374 Assay, blood carbon dioxide rologists to order such laboratory tests min- coinsurance amount will be 20 percent of peritoneal dialysis (PD) modalities. The 82379 Assay of carnitine imizes patient discomfort, protects vascular the ESRD PPS bundled payment amount, agency will provide this add-on adjustment 82435 Assay of blood chloride access, and enables nephrologists to serve including applicable case-mix and facility- to facilities each time they conduct home 82565 Assay of creatinine as primary care providers. CMS adopted level adjustments and outlier payments. dialysis training, rather than accounting for 82570 Assay of urine creatinine ASN’s recommendation to identify non- Patients accessing care at facilities undergo- the cost of home training in the base rate 82575 Creatinine clearance test ESRD-related lab tests by using another ing the four-year transition period will pay applied to all facilities, as CMS originally separate modifier that allows for a separate 82607 Vitamin B-12 coinsurance on 20 percent of the blended proposed. However, facilities are not eli- payment for those tests. As such, CMS 82652 Vit D 1, 25-dihydroxy payment amount. compiled a list of 53 lab tests used to diag- gible to receive the home dialysis training 82668 Assay of erythropoietin Under the existing payment system, nose or monitor ESRD-related conditions add-on during the first four months after 82728 Assay of ferritin patients are not responsible to pay coin- (Table 1). Only tests included on this list initiating dialysis while the new-patient ad- 82746 Blood folic acid serum surance on laboratory services, but will will be paid under the bundle. CMS notes justor is in effect. 83540 Assay of iron become subject to the 20 percent coinsur- that the list was compiled based on tests 83550 Iron binding test ance obligation when the services are bun- most frequently identified by commenters Transition period 83735 Assay of magnesium dled into the set of renal dialysis services as ESRD-related, input from physicians at 83970 Assay of parathormone on January 1, 2011. Similarly, drugs being The final rule includes a four-year phase- the University of Michigan Kidney Epide- 84075 Assay alkaline phosphatase bundled that are currently payable under in (transition) of bundled payments, with miology and Cost Center, and a medical Medicare Part D—and currently subject to the phase-in occurring in equal increments 84100 Assay of phosphorus review by CMS physicians and other staff. a separate coinsurance structure—will be until 2014, when 100 percent of ESRD 84132 Assay of serum potassium 84134 Assay of prealbumin Patient-level adjustors subject to the 20 percent coinsurance part services will be covered under the bundle. of the set of bundled renal dialysis services. In 2011, 75 percent of the transition will 84155 Assay of protein, serum In the final rule, CMS adopts four patient- Importantly, however, oral-only ESRD be based on the payment rate under the 84295 Assay of serum sodium level case-mix payment adjustors—for age, drugs will not immediately be among the current basic case-mix adjusted compos- 84466 Assay of transferrin body mass index, body surface area, and products for which patients are responsible ite payment system and 25 percent based 84520 Assay of urea Nitrogen new patients—as well as six co-morbidity to pay coinsurance—CMS will continue to on the new bundled ESRD PPS payment 84540 Assay of urine/urea-N categories (listed below) for the co-morbid- pay these drugs under Part B until Janu- amount. In 2012, the balance will be 50- 84545 Urea-N clearance test ity case-mix adjustment. ary 1, 2014, when CMS adds them to the 50, and in 2013, 25 percent of the tran- 85014 Hematocrit • pericarditis (acute) bundle. ASN voiced concerns about the sition will be based on the payment rate 85018 Hemoglobin • bacterial pneumonia (acute) new financial burden created for patients under the current basic case-mix adjusted 85025 Complete (CBC), automated (HgB, Hct, RBC, • gastrointestinal tract bleeding with he- by adding drugs that were formerly payable WBC, and Platelet count) and automated morrhage (acute) under Part D to the bundle. In response, composite payment system and 75 percent differential WBC count • hemolytic anemia with sickle cell ane- CMS stated in the final rule that it plans to based on the new bundled ESRD PPS pay- 85027 Complete (CBC), automated (HgB, Hct, RBC, WBC, and Platelet count) mia (chronic) collect data on the oral-only ESRD drugs ment amount. Dialysis facilities have until • myelodysplastic syndrome (chronic) to assess the impact on beneficiaries and November 1, 2010, to make a one-time se- 85041 Automated RBC count • monoclonal gammopathy (chronic) facilities. The agency will address the im- lection to be excluded from the transition 85044 Manual reticulocyte count plementation of oral-only drugs in a future and paid entirely under the new fully bun- 85045 Automated reticulocyte count CMS originally proposed including notice of proposed rulemaking. dled system as of January 1, 2011. 85046 Reticyte/HgB concentrate an adjustor for patient sex and for race/ The new base rate reflects the average 85048 Automated leukocyte count ethnicity, but at this time is not finalizing cost for furnishing dialysis services to pa- Physician services 86704 Hep B core antibody, total its proposals for these characteristics. ASN tients. For this reason, CMS said, if pa- 86705 Hep B core antibody, Igm CMS states in the final rule that it does not, had expressed concern that the data em- tients today use less than the average of sep- 86706 Hep B surface antibody at this time, intend to modify payment for ployed to determine patient-level case-mix arately billable items and services (that is, 87040¹ Blood culture for bacteria physicians’ services. The agency is limiting adjustors may not be complete or may not items and services that were separately paid 87070¹ Culture, bacteria, other the scope of this rulemaking to payment for capture the most costly variables in patient under the current basic case-mix adjusted 87071¹ Culture bacteria aerobic other dialysis services, and notes that any changes care. Stating in the final rule that it is up- composite payment system), they can ex- 87073¹ Culture bacteria anaerobic in payment for physician services would be dating processes for collecting and validat- pect an increase in their co-insurance ob- 87075¹ Culture bacteria, except blood addressed in future rulemaking. ing patient-level data, CMS will continue ligation. However, if patients currently use 87076¹ Culture anaerobe ident, each studying patient sex and race/ethnicity. more than the average of separately billable 87077¹ Culture aerobic identify The agency also intends to perform addi- ASN thanks the members of the Policy Board items and services, they should pay less in 87081¹ Culture screen only tional studies to determine whether there co-insurance under the new bundled pay- and ESRD Task Force for their contributions 87340 Hepatitis B surface Ag, eia are underlying clinical or biological factors ment system. The amount of the difference on behalf of the society. G0306 CBC/diff WBC w/o platelet

G0307 CBC without platelet

1 Only ESRD-related when testing is related to the dialysis access site. CMS Proposes Quality Incentive Program Besides implementing a bundled payment system for ESRD care, CMS outlined its vi- Facilities have already been reporting these measures on claims, and the results for sion for a Quality Improvement Program (QIP) in a Proposed Rule, released the same each facility are publicly available on the CMS Dialysis Facility Compare website. day as the ESRD Final Rule. The QIP will be the first pay-for-performance program in Having finalized the quality measures for the QIP in the ESRD Final Rule, CMS ad- a Medicare fee-for-service payment program and will go into effect on January 1, 2012. dresses other aspects of the QIP in the proposed rule. Besides selecting performance The proposed rule is open for comment until September 24, 2010. standards against which facilities will be judged, the agency proposes a sliding scale for Intended to improve outcomes for ESRD patients, the QIP will adjust dialysis fa- reducing payment rates based on a total performance score that reflects all three measures. cility payments based on facilities’ performance across three quality measures—with a Although the payment reductions will not take place until January 2012, CMS states that reduction of up to 2 percent for facilities that do not meet or exceed the standards. the performance period must occur before that date to allow for claims processing. CMS The three quality measures are: proposes a performance period for the entire calendar year of 2010. • hemodialysis adequacy: Achieved urea reduction ratio of 65 percent or more ASN has formed a QIP Task Force to analyze the proposed rule and provide com- • anemia management: Controlled anemia, as shown in two measures: ment to CMS, in conjunction with the ASN Public Policy Board. In the coming days o percentage of patients at a facility whose hemoglobin levels were less than 10 and weeks the Task Force will provide a detailed explanation of the proposed rule to help g/dL members understand how CMS’ proposals may affect nephrology care. Please visit ASN’s o percentage of patients at a facility whose hemoglobin levels were greater than ESRD bundling webpage to get the latest information on the QIP at http://asn-online. 12 g/dL org/policy_and_public_affairs/esrd-bundling.aspx. Findings European Renal Association--European Dialysis and Transplant Association Congress

Atoarvastatin Beats Rosuvastatin in Protecting Kidneys in Diabetic and Nondiabetic Patients

wo related trials investigating the effects excretion and renal function in hypercho- nine ratio. LDL cholesterol to about the same degree, tof statins on urinary protein excretion lesterolemic patients with moderate pro- For PLANET I, De Zeeuw said, “Ator- and all were well tolerated in both trials. and kidney function found atorvastatin teinuria. vastatin significantly reduces the proteinu- He concluded from these findings that (ATV) protective and rosuvastatin (RSV) PLANET I enrolled 325 patients with ria in these patients on top of ACE/ARB in diabetic or nondiabetic patients with nonprotective or possibly harmful in dia- type 1 or 2 diabetes, and PLANET II therapy with around 15 percent reduction proteinuria, using optimal therapy, in- betic or nondiabetic patients. High-dose involved 220 patients without diabetes. in proteinuria, whereas with rosuvastatin cluding ACE inhibitors and ARBs: Patients had urinary protein/creatinine ra- both 10 and 40 mg had no significant ef- ATV significantly reduced proteinuria and • ATV 80 mg/day significantly reduced did not affect renal function. RSV, on the tios of 500–5000 mg/g and fasting LDL fect at all on proteinuria.” The effect of cholesterol ≥90 mg/dL. They had used ATV was evident by week 26. proteinuria by about 20 percent other hand, was associated with a signifi- ACE inhibitors or ARBs for at least three In PLANET II, “we see a similar pat- • RSV 10 or 40 mg/day had no effect on cant decline in function and had no effect months prior to screening. tern, even more pronounced,” he said. proteinuria on proteinuria. • RSV 40 mg/day was associated with a In diabetic and nondiabetic patients, After an eight-week lead-in period, pa- ATV reduced proteinuria by >20 percent tients were put on drug. The patients rand- at 26 and 52 weeks, but there was no sig- significant decline in eGFR of about 8 proteinuria is a risk factor for further loss omized to receive RSV 40 mg/day or ATV nificant effect with either dose of RSV. mL/min/1.73 m2/year of kidney function and progression to end 80 mg/day took half the daily dose for the For eGFR, De Zeeuw said the re- • ATV 80 mg/day had no effect on stage renal disease, even when ACE in- first four weeks and then escalated to full sults were “very surprising” in that the eGFR hibitors or angiotensin receptor blockers doses. Patients with severe renal disease, PLANET I patients on RSV lost more • ATV 80 mg/day had a clear advantage (ARBs) are used to lower blood pressure. defined as an estimated glomerular filtra- kidney function over 52 weeks than did over RSV 40 mg/day in terms of renal Experimental results have suggested that 2 tion rate (eGFR) of <40 mL/min/1.73 m , the ATV group. Patients on ATV lost protection or renal damage the use of statins may reduce proteinuria or in PLANET I with a hemoglobin A1c about 1–2 mL/min/1.73 m2 over 52 Multiple clinical trials have led clini- and preserve kidney function. >11 percent, were excluded from the study, weeks, the group on RSV 10 mg/day At the XLVII European Renal Associ- as were people with active liver disease. lost about 4 mL/min/1.73 m2, and the cians to view most statins as fairly simi- ation-European Dialysis and Transplan- The primary endpoint of the studies RSV 40 mg/day group lost close to 8 lar, a so-called “class effect” for this class tation Association conference, Dick De was the change in urinary protein/creati- mL/min/1.73 m2. of drugs. De Zeeuw said this trial “sort of Zeeuw, MD, PhD, a clinical pharmacolo- nine ratio from baseline to week 52 or to In nondiabetic patients (PLANET II) dismembers the class effect,” at least for gist at the University Medical Center in the last on-treatment observation carried the effects of the treatments on kidney the parameters studied here. “I think this Groningen, The Netherlands, reported on forward. The patients in the three treat- function were slightly less pronounced. ‘class’ discussion is going to be extremely the PLANET trials. These randomized, ment arms were fairly well matched within There was a significant decline in eGFR important,” he added, and advised, “If you double blind, multinational trials tested each trial for their baseline characteristics, with RSV 40 mg/day but not in the other are considering putting such a patient on the effects of ATV 80 mg/day or RSV 10 including mean eGFRs, mean protein/ two treatment arms. a statin, you should not put them on ro- mg/day or 40 mg/day on urinary protein creatinine ratio, and mean albumin/creati- All the treatments lowered total and suvastatin.”

Allopurinol Reduces Left Ventricular Hypertrophy in CKD

igh-dose allopurinol treatment Xanthine oxidase as a target Stage 3 CKD patients were ran- compliance and the LV afterload,” she caused regression of left ven- domly assigned to an allopurinol arm h One source of oxidative stress is the said. tricular hypertrophy (LVH) and im- (n = 27) or to a placebo arm (n = 26). There were no differences between purine degradation pathway, in which provement of endothelial function The allopurinol group received the the two arms of the trial in terms of xanthine oxidase converts hypoxan- in patients with stage 3 chronic kid- drug at 100 mg/day for two weeks, blood pressure, renal function, or the thine to xanthine, with the release ney disease (CKD). Allopurinol is which was increased to 300 mg/day prevalence of adverse events. Serum of free radical byproducts, leading an inhibitor of the enzyme xanthine if it was well tolerated and did not uric acid levels were lower in the al- to oxidative stress. Thus, inhibiting oxidase and acts as an anti-oxidant by adversely affect kidney function. All lopurinol group (but did not corre- xanthine oxidase should block the preventing the formation of free radi- baseline characteristics were similar late with the changes in LVM index generation of some free radicals. Kao cals from the action of the enzyme. between the two groups except that seen). reported that xanthine oxidase inhibi- Patients with even mild to moder- the allopurinol arm had a slightly “We found for the first time that ate kidney disease are at greatly elevat- tion has been shown to improve en- lower diastolic blood pressure (70 ± 8 allopurinol can regress LVH in man. ed risk of cardiac morbidity and mor- dothelial function in diabetics, smok- mm Hg vs. 75 ± 8 mm Hg). Patients And we also found that allopurinol tality, including LVH, said Michelle ers, hypercholesterolemic patients, were well matched for LVM, and can improve both endothelial dys- Kao, MBChB, a clinical research fel- and those with congestive heart fail- most were already on an angiotensin- function and arterial stiffness in pa- low at the University of Dundee, UK, ure. But it has never been investigated converting enzyme inhibitor or an an- tients with CKD,” Kao concluded. “Increasingly, people are beginning to in patients with CKD. giotensin receptor blocker. She said yet to be tested is whether appreciate that oxidative stress plays So she tested the effect of high- “We found that those patients these effects translate into improve- a major part in this poor overall out- dose allopurinol on endothelial func- on allopurinol had regression of the ments in hard clinical endpoints, such come in patients with advanced renal tion and LVH in patients with CKD. LV [left ventricular] mass after nine as cardiac events or death. She has disease,” she said. Using cardiac magnetic resonance im- months [-1.42 ± 4.67 g/m2] compared blood samples and will test them for She told an audience at the Euro- aging, she measured left ventricular to progression for those patients in markers of oxidative stress to confirm pean Renal Association-European Di- mass (LVM) at baseline and at nine the placebo group [+1.28 ± 4.45 g/ whether the changes seen correlate alysis and Transplantation Association months in a randomized, double- m2],” Kao reported. “We also found with the level of oxidative stress. congress that studies have indicated blind, placebo-controlled trial. LVH a trend toward improvement in end- David Harris, MD, of the Uni- that oxidative stress manifests as LVH was determined by echocardiography. diastolic volume for those patients on versity of Sydney in Australia, com- and endothelial dysfunction. LVH is Endothelial function was determined allopurinol.” mented that if this study is confirmed a strong cardiac risk factor because it by ultrasound measurement of flow- Endothelial function, as indicated by larger ones, it could change clini- is arrhythmogenic and reduces coro- mediated dilatation (FMD) of the by FMD, improved for the allopuri- cal practice “because it’s the first trial nary perfusion reserve, leading to di- brachial artery after release of artery nol group. “This suggests to us that that’s shown a reduction in left ven- astolic heart failure and to left atrial occlusion with a cuff. The degree of perhaps some of the beneficial effects tricular mass with allopurinol, [and] dilatation, a precursor of atrial fibril- reactive dilatation is an indication of seen on the LV mass index were due I think that’s a very important out- lation and embolic stroke. arterial stiffness. to an improvement in the vascular come.” August 2010 | ASN Kidney News | 7

Adynamic Bone Disease Raises Risk of Vascular Calcification By Daniel Keller

he field of adynamic bone disease disease,” he said. Among the reasons are disease have more bone pain, and the reversible in a substantial number of thas moved quickly in the past decade increased awareness and diagnosis, more risk of fractures is increased, probably patients. Bover recommended: from consideration of the kidney-bone dialysis of elderly and diabetic patients, because the bone has a diminished ca- • stopping aluminum exposure and axis, with concern about renal osteodys- high calcium load from dialysis solu- pacity to repair microdamage. “The initiating chelation treatment (de- trophies and the impact of kidney disease tions, vitamin D overtreatment, patients most important association of ady- feroxamine) on bone, to a concept of chronic kidney on peritoneal dialysis being at slightly namic bone disease is the presence reducing the calcium load disease (CKD) and its relation to min- more risk, the presence of malnutrition- of arterial or coronary calcifications • reducing vitamin D overload eral and bone disorders (CKD-MBD). inflammation syndrome, hypogonad- or the association with calcemic ure- • The latter is a broader clinical syndrome ism, and treatment with bisphospho- mic arteriolopathy, such as calciphy- • restoring PTH activity with the encompassing not only bone abnormali- nates. laxis,” Bover said. Calciphylaxis is a new pharmacologic compounds ties but also laboratory abnormalities Finally, low levels of parathyroid syndrome of vascular calcification, • changing from calcium-containing and vascular calcification and has been hormone (PTH) or bone resistance to thrombosis, and skin necrosis. phosphate binders to sevelamer or associated with increased mortality in the PTH can lead to adynamic bone disease. Abnormal calcium balance makes lanthanum dialysis population. “Skeletal resistance to the action of PTH it hard for the body to incorporate • decreasing the calcium content in Characterized by reduced bone turn- has been known for many, many years,” calcium into bone, and the highest dialysate for patients with diag- over, adynamic bone disease is increas- Bover said and compared it to resistance aortic calcification scores have been nosed adynamic bone disease ingly recognized as the most common to several other hormones, such as insu- associated with low bone turnover. form of renal osteodystrophy. Adynamic lin and growth hormone in the uremic Similarly, low bone turnover has been Bover concluded that adynamic bone disease is particularly common in state. shown to increase coronary artery bone disease is increasingly found in peritoneal dialysis populations. Constant calcification and progression. “This Although bone biopsy is the defini- patients with CKD and is associated exposure to calcium in dialysate fluids is one of the reasons we are trying tive method to diagnose adynamic bone with an increased risk of vascular cal- leads to episodic hypercalcemia, suppres- to underline the importance of this disease, other less invasive approaches cification. There is a need for better sion of parathyroid levels, and therefore, “neo” bone-vascular axis,” Bover em- can also be used. However, none of the noninvasive biomarkers of bone activ- adynamic bone. The bone has normal phasized. biochemical markers has reached a suffi- ity as well as of risk for cardiovascular mineralization and low or normal bone He showed data indicating that cient level of diagnostic accuracy. Bover calcification. He said nephrologists volume but few or no osteoblasts or os- patients with high or low levels of need to be aware of the PTH assay teoclasts. said low serum levels of intact PTH iPTH are at increased risk of death. kit they are using to be able to keep Jordi Bover, MD, PhD, of the neph- (iPTH, <100 pg/mL) are associated The lowest mortality risk occurred patients in the optimal range. Normal rology department at Fundació Puigvert with adynamic bone disease. High levels when iPTH, calcium, and phosphate in Barcelona, Spain, spoke at the XLVII of bone alkaline phosphatase “virtually levels were within the KDOQI (Kid- PTH levels are probably not desir- European Renal Association-European exclude adynamic bone disease,” he told ney Disease Outcomes Quality Initia- able in nondialysis or dialysis CKD Dialysis and Transplantation Association the audience. tive) ranges. patients. Although many patients in conference, about the “bone-vascular Although the management of ady- the KDOQI-recommended range Risk of vascular calcification axis” in adynamic bone disease. “During namic bone disease has not been in- also suffer from ADB, these patients the last decades…we have observed an A diagnosis of adynamic bone disease vestigated well and randomized trials are the ones with the highest survival, increased prevalence of adynamic bone is important since patients with the are absent, adynamic bone disease is Bover said.

Restless Legs Syndrome More Prevalent Among Hemodialysis Patients, Correlates With CRP Levels By Daniel Keller

estless legs syndrome (RLS) affects pa- MD, professor of nephrology at the Uni- the chronic hemodialysis patients without ders, we reduce a cardiovascular risk factor rtients on chronic hemodialysis about versity of Udine and S.M. Misericordia RLS, CRP levels were about three times the because CRP is a possible cause of increased four times as often as it does the gen- University Hospital in Udine, Italy, found upper limit of normal in the general public, cardiovascular risk.” Besides CRP levels, eral population. An Italian research team a prevalence of RLS of 21.4 percent. RLS Romano said. the levels of transferrin saturation, another showed an association of RLS with blood patients were defined as those who experi- Looking at a variety of other common marker of inflammation, were different be- levels of C-reactive protein (CRP) in chron- enced symptoms at least twice a week. laboratory parameters, the researchers tween patients with or without RLS. ic hemodialysis patients at the European The 12 patients with RLS in this study found a significant difference between pa- Antiparkinson drugs have been used to Renal Association-European Dialysis and took much longer to fall asleep, slept less tients with or without RLS only for serum relieve RLS. So the next step, according to Transplant Association Congress. at night, took longer naps, and had more iron and for percent transferrin saturation. Romano, is to work with his colleagues in RLS interferes with sleep by causing pa- insomnia and daytime sleepiness com- There were no significant differences be- the neurology department to treat the RLS tients an urge to move the legs when at rest. pared with 46 hemodialysis patients with- tween the groups in regard to hemoglobin, patients with such drugs to see if reducing Patients may complain of insufficient and out RLS. hematocrit, urea, creatinine, albumin, or nighttime leg movements and restoring non-restorative sleep and of daytime sleepi- Among RLS patients on chronic hemo- parathyroid hormone levels, nor to Kt/V, sleep lowers CRP levels, and eventually, car- ness and diminished functioning. People dialysis, “the interesting conclusion of our indicating that under-dialysis was not the diovascular risk. with RLS also have a higher prevalence of work is that there is a correlation between cause of the RLS. Although cardiovascular events (e.g., anxiety and depression. restless legs syndrome and an increase of Several studies have shown that increased nonfatal and fatal heart attacks) are associ- The “primary” form of RLS affects inflammatory cytokines and the increase of inflammation is associated with elevated ated with elevated levels of CRP and are about 5 percent of the general population CRP,” Romano said. The total sleep time cardiovascular risk in patients on chronic the main cause of death among hemodial- and does not appear to have an underlying correlated negatively with the level of se- hemodialysis, Romano said. There is also ysis patients, it would make sense to look cause. Another form is secondary to other rum CRP. The higher the CRP, the shorter evidence that sleep disorders induce elevat- at other markers of inflammation as well. medical conditions or treatments, such as the sleep time was. The group of patients ed levels of proinflammatory cytokines. “We have to find out all risk factors,” said hemodialysis. with RLS had a serum CRP level of 43.96 “We think that if patients have some Nageswara Reddy, MD, assistant profes- From a study of 58 chronic hemodialysis ± 23.71 mg/L versus 15.24 ± 3.94 mg/L for sleep disorders, they evoke inflammation,” sor of nephrology at Manipal University patients, lead investigator Giulio Romano, the non-RLS patients (p = 0.04). Even in he said, “and so if we treat the sleep disor- in India. 8 | ASN Kidney News | August 2010 Journal View

No Clear Benefit of mTOR Inhibitors for ADPKD Monitoring Avoids Hyperkalemia from Spironolactone

Everolimus and sirolimus do not appear early-stage ADPKD—average total kid- With attention to serum potassium talization for heart failure who were effective in the treatment of autosom- ney volume approximately 1000 mL— and creatinine levels, increased use of receiving an angiotensin-converting al dominant polycystic kidney disease were randomly assigned to sirolimus or spironolactone for heart failure does enzyme inhibitor, the rate of spironol- (ADPKD), according to a pair of clinical standard care. At 18 months, the median not lead to a higher rate of hospital ad- actone use increased from 19.8 per 100 trials presented at the 70th Scientific Ses- increase in total kidney volume was about missions for hyperkalemia, according to patients in early 1999, to 70.1 per 100 sions of the American Diabetes Associa- 100 percent in both groups. There was a study in the British Medical Journal. patients in late 2001, to 61.3 per 100 tion and published by The New England also no significant difference in glomeru- National Health Service records for patients in 2007. At the same time, the Journal of Medicine. lar filtration rate, but the sirolimus group Tayside, Scotland, were reviewed to rate of outpatient potassium measure- The trials evaluated the effects of the had a higher urinary albumin excretion track trends in prescribing of spironol- ments showing hyperkalemia (serum two mammalian targets of rapamycin rate. actone and hospitalizations for hyper- potassium level over 6 mmol/L) de- (mTOR) inhibitors on relevant clinical The results are disappointing in light kalemia from 1994 to 2007. The goal creased from 9.9, to 6.9, to 2.9, respec- was to assess the impact of the 1999 tively, per 100 patients. outcomes in patients with ADPKD. In of promising experimental and observa- the larger of the two trials, 433 patients Randomized Aldactone Evaluation Previous reports linked the increased tional studies. An accompanying edito- with ADPKD and stage 2 or 3 chronic Study (RALES), which found that use of spironolactone in response to rial discusses the implications for future kidney disease were randomly assigned to spironolactone improves outcomes in RALES to an increased rate of severe studies, highlighting the urgent need for two years of treatment with everolimus or severe heart failure. hyperkalemia. But the experience in “better tools for assessing the effects of placebo. All patients had an average base- Prescriptions for spironolactone rose Tayside suggests that with increased line renal volume greater than 1500 mL. our interventions on renal function in sharply after the publication of RALES: serum potassium and creatinine moni- Everolimus was associated with a humans.” [Walz G, et al. Everolimus in from about 2800 prescriptions in the toring, hospitalizations for hyperka- smaller increase in total kidney volume: patients with autosomal dominant poly- first half of 1999 to 6600 in the second lemia remain low—despite increased 203 mL at two years, compared to 301 cystic kidney disease. Published at www. half of 2001. There were significant spironolactone prescribing. The re- mL in the placebo group. Yet there was nejm.org June 26, 2010 (10.1056/NEJ- and parallel increases in the number of searchers write, “Spironolactone pre- no associated improvement in kidney Moa1003491); Serra AL, et al: Sirolimus serum creatinine and potassium meas- scribing seems to be safe in the setting function—mean decrease in estimated and kidney growth in autosomal domi- urements performed. These trends were of the NHS, probably owing to care- glomerular filtration rate was 8.9 and 7.7 nant polycystic kidney disease. (10.1056/ not limited to patients with heart fail- ful monitoring of electrolytes and renal mL/min/1.73 m2, respectively. Patients NEJMoa09074190); Watnick T, Ger- ure. Hospital admissions for hyperkale- function.” [Wei L, et al. Spironolac- in the everolimus group had more drug- mino GG: mTOR Inhibitors in Poly- mia remained very low throughout the tone use and renal toxicity: population specific adverse events. cystic Kidney Disease. (10.1056/NE- study period. based longitudinal analysis. BMJ 2010; In the other trial, 100 patients with JMe1006925)]. Among patients with recent hospi- 340:c1768].

FGF23 Affects Bone Metabolism in Pediatric CKD TMP-SMX Linked to Hyperkalemia in Elderly— With or Without β-Blockers Fibroblast growth factor 23 (FGF23)— low estimated glomerular filtration rate a predictor of cardiovascular complica- were the factors most strongly related to The increased risk of hyperkalemia in older related to hyperkalemia risk. tions of chronic kidney disease (CKD) in FGF23. adults taking trimethoprim-sulfamethoxa- Analysis of a cohort of non-β-blocker adults—has an important impact on bone Fibroblast growth factor 23, which zole (TMP-SMX) is unrelated to concom- users included 1349 hyperkalemia cases metabolism in children with CKD, reports regulates renal phosphate reabsorption, is itant β-blocker treatment, according to a and 5378 controls. The results showed a a study in Kidney International. increased in adults with CKD, in whom it study in the Clinical Journal of the Ameri- similar increase in hyperkalemia requiring The cross-sectional study included 69 has been linked to cardiovascular morbid- can Society of Nephrology. hospital admission among TMP-SMX us- children with CKD of various causes, repre- ity. There are very few data on the levels Linked Ontario health data were used to ers. senting all stages of renal dysfunction. Lev- and effects of FGF23 in pediatric CKD. assess the relationship between TMP-SMX The TMP-SMX combination, one of els of FGF23 and other biochemical vari- The new results show that, in children use and hospital admission for hyperkale- the most widely prescribed antibiotics in ables of bone metabolism were assessed. as in adults with CKD, FGF23 levels in- mia among older adults taking β-blockers. North America, decreases the kidney’s Mean FGF23 level increased from 47 crease gradually with disease stage. Even at The analysis included nearly 300,000 pa- ability to eliminate potassium. It has been ng/L in children with stage 1–2 CKD, to an early stage of CKD in children, FGF23 tients, aged 66 years or older, receiving suggested that simultaneous use of TMP- 144 ng/L for those in stage 3, 313 ng/L in appears to have an important impact on β-blockers between 1994 and 2008. In SMX and β-blockers may confer a high stage 4, and 734 ng/L in stage 5. Thus sig- calcium and phosphate homeostasis and this cohort, 189 patients were hospitalized risk of hyperkalemia. nificant elevation of FGF23 was already vitamin D metabolism. “FGF23 is a nov- within 14 days after receiving a prescrip- The new results confirm the increased present before the development of hyper- el and important biomarker in children tion for antibiotics commonly used for risk of hospitalization for hyperkalemia in phosphatemia in stage 4 CKD. with chronic renal failure,” the investiga- the treatment of urinary tract infections: older adults taking TMP-SMX, regardless The increases in FGF23 were positive- tors conclude. They call for further stud- TMP-SMX, amoxicillin, ciprofloxacin, of concomitant β-blocker therapy. Measur- ly correlated with parathyroid hormone ies of its effect on bone disease, growth norfloxacin, or nitrofurantoin. ing blood potassium in patients prescribed and phosphate levels and negatively cor- failure, and cardiovascular morbidity [van Of case patients admitted for hyperkale- TMP-SMX could potentially decrease the related with 1,25-dihydroxyvitamin D, Husen M, et al: Fibroblast growth factor mia, 51.9 percent were taking TMP-SMX, risk of hyperkalemia associated with TMP- estimated glomerular filtration rate, and 23 and bone metabolism in children with compared to 19.5 percent of matched con- SMX, the authors suggest [Weir MA, et al. tubular phosphate reabsorption. On mul- chronic kidney disease. Kidney Int 2010; trols without hyperkalemia. On adjusted Beta-blockers, trimethoprim-sulfamethox- tivariate analysis, hyperphosphatemia and 78:200–206]. analysis, TMP-SMX was associated with a azole, and the risk of hyperkalemia requir- fivefold increase in the risk of hospitaliza- ing hospitalization in the elderly: a nested tion for hyperkalemia compared to amoxi- case-control study. Clin J Am Soc Nephrol cillin. None of the other antibiotics was 2010 doi: 10.2215/CJN.01970310]. Letters ASN Kidney News accepts letters to the Be in tune with your field. editor in response to published articles. Find more articles on important findings in clinical nephrology at www.asn-online.org/publications/. Please submit all correspondence to Literature review by [email protected] NephrologyNow.com PLO0026 Look Again NNI DR 3/8/10 12:49 PM Page 1

Think you know all about phosphate binders? Look again. CARE Study In the 8-week CARE Study, PhosLo® (calcium acetate) achieved the K/DOQI guidelines for mean serum phosphorus and Ca x P product control faster while sevelamer never reached these guidelines.1

CARE-2 Study The CARE-2 study demonstrated NO significant difference in the progression of coronary artery calcification following equivalent lipid control in the PhosLo and sevelamer treated groups.2 DCOR Study DCOR, a Genzyme-sponsored study, failed to achieve both primary and secondary endpoints, demonstrating NO mortality benefits with sevelamer when compared to calcium-based phosphate binders.3 DOPPS II Study DOPPS II showed NO survival benefit of sevelamer over calcium-based phosphate binders.4

PhosLo is well tolerated with limited GI side effects.5 PhosLo has not been associated with metabolic acidosis.6 PhosLo offers potential cost-savings for patients.7 Care to know more

PhosLo® is indicated for control of hyperphosphatemia in end-stage renal failure. Patients with higher-than-normal serum calcium levels should be closely monitored and their dose adjusted or terminated to bring levels to normal. PhosLo® is contraindicated in patients with hypercalcemia. No other calcium supplements should be given concurrently with PhosLo.® Nausea, hypercalcemia and pruritus have been reported during PhosLo® therapy. BRIEF SUMMARY OF PRESCRIBING INFORMATION CONTRAINDICATIONS: Patients with hypercalcemia. INDICATIONS AND USAGE: For the control of hyperphosphatemia in end-stage renal failure.WARNINGS: Patients with end-stage renal failure may develop hypercalcemia when given calcium with meals. No other calcium supplements should be given concurrently with PhosLo. Progressive hypercalcemia due to overdose of PhosLo may be severe as to require emergency measures. Chronic hypercalcemia may lead to vascular calcification, and other soft-tissue calcification.The serum calcium level should be monitored twice weekly during the early dose adjustment period.The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 66. Radiographic evaluation of suspect anatomical region may be helpful in early detection of soft-tissue calcification. PRECAUTIONS: Excessive dosage induces hypercalcemia; therefore, early in the treatment during dosage adjustment serum calcium should be determined twice weekly. Should hypercalcemia develop, the dosage should be reduced or the treatment discontinued immediately depending on the severity of hypercalcemia. Do not give to patients on digitalis, because hypercalcemia may precipitate cardiac arrhythmias. Always start PhosLo at low dose and do not increase without careful monitoring of serum calcium. An estimate of daily calcium intake should be made initially and the intake adjusted as needed. Serum phosphorus should also be determined periodically. Information for the Patient: Inform the patient about: 1) compliance with dosage, 2) adherence to diet instructions and avoidance of nonprescription antacids, and 3) symptoms of hypercalcemia. Drug Interactions: PhosLo may decrease the bioavailability of tetracyclines. Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed. Pregnancy:Teratogenic Effects: Category C. Animal reproduction studies have not been conducted. It is not known whether PhosLo can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Give to a pregnant woman only if clearly needed. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of subjects in clinical studies of PhosLo (n = 91), 25 percent were 65 and over, while 7 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS: In clinical studies, patients have occasionally experienced nausea during PhosLo therapy. Hypercalcemia may occur during treatment with PhosLo. Mild hypercalcemia (Ca>10.5 mg/dl) may be asymptomatic or manifest itself as constipation, anorexia, nausea and vomiting. More severe hypercalcemia (Ca>12 mg/dl) is associated with confusion, delirium, stupor and coma. Mild hypercalcemia is easily controlled by reducing the PhosLo dose or temporarily discontinuing therapy. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing PhosLo therapy. Decreasing dialysate calcium concentration could reduce the incidence and severity of PhosLo induced hypercalcemia.The long-term effect of PhosLo on the progression of vascular or soft-tissue calcification has not been determined. Isolated cases of pruritus have been reported which may represent allergic reactions. OVERDOSAGE:Administration of PhosLo in excess of appropriate daily dosage can cause severe hypercalcemia (see ADVERSE REACTIONS). For more information on PhosLo®, please contact Fresenius Medical Care at 800-323-5188. Manufactured for and distributed by: Fresenius Medical Care North America,Waltham, MA 02451

1. Qunibi WY,Hootkins RE, McDowell LL, et al.Treatment of hyperphosphatemia in hemodialysis patients:The calcium acetate renagel evaluation (CARE Study). Kidney International 65:1914-1926, 2004. 2. Qunibi WY,Moustafa M, Kessler P,et al. Coronary artery calcification in hemodialysis patients: Preliminary results from the calcium acetate renagel evaluation-2 (CARE-2) study. Poster session presented at the International Society of Nephrology/World Congress of Nephrology Meeting in Rio de Janeiro, Brazil:April 21-25, 2007. 3. Suki WN, Zabaneh R, Cangiano JL, et al. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney International Aug 29, 2007. 4.Young EW,Albert JM,Akizawa T,et al. Sevelamer vs. calcium-containing phosphate binders and mortality in the dialysis outcomes and practice patterns study (DOPPS). J Am Soc Neph.16:Abstract, 2005.American Society of Nephrology Renal Week. Pennsylvania Convention Center, Philadelphia, PA. November 8-13, 2005. 5. PhosLo [prescribing information]. Fresenius Medical Care,Waltham, MA: January 2007. 6. Mehrotra R, Kopple JD,Wolfson M. Metabolic acidosis in maintenance dialysis patients: clinical considerations. Kidney International 64(suppl 88):S13-S25, 2003. 7. Drug Topics Redbook (Montvale, NJ:Thomson Healthcare), 2007.

Fresenius Medical Care, the triangle logo and PhosLo are registered trademarks of Fresenius Medical Care Holdings, Inc., and/or its affiliated companies. 100738-01 Rev.01 02/08 AmericAn Society of nephrology Renal Week 2010 Renal Week 2010: November 16 – 21 Exhibit Dates: November 18 – 21

colorado convention center Denver, colorado

Register online at www.asn-online.org August 2010 | ASN Kidney News | 11

Industry Spotlight

GlaxoSmithKline’s Avandia Found to Increase Heart Disease and Stroke

The type 2 diabetes drug Avandia (rosiglitazone; The European Medicines Agency will con- heart attacks and heart failure in patients who manufactured by GlaxoSmithKline [GSK]) is duct a review of Avandia in a manner similar used the drug. in the news again. Two separate and dissimilar to that of the FDA’s review. The agency could Avandia can present several challenges, in- studies found Avandia increased the risk of heart then revoke or change marketing authorization cluding heart-related adverse events such as attack and other conditions. for the drug in Europe. fluid retention and congestive heart failure. The These studies set the stage for a public de- One of the American studies was published in drug is monitored per FDA directives for these bate within the U.S. Food and Drug Adminis- the Journal of the American Medical Association and other events. tration (FDA) advisory panel, which convened by David Graham, a drug safety researcher at Overall, shares of GSK have fallen 13 percent to discuss the safety of Avandia in July. After the U.S. Food and Drug Administration (FDA). in the past year, according to Bloomberg Busi- hearing the evidence and many presentations, Graham and his colleagues analyzed insurance nessweek. To date, more than 4000 lawsuits have most of the 33 panel members recommended records of 227,571 patients who took either been filed against GSK because of Avandia’s the continued sale of Avandia with new usage Avandia or Actos and found that Avandia in- effects on the heart and circulatory system. In restrictions or warnings on the drug’s labeling. creased both the risk for heart attack and stroke. May, the company agreed to pay $60 million in Twelve panel members said the drug should be Avandia patients were 27 percent more likely to the first settlements of the litigation, according fully withdrawn. have a stroke, 25 percent more likely to develop to sources familiar with the agreement, Bloom- The panel’s general conclusion was that al- heart failure, and 14 percent more likely to die. berg Businessweek reported. though Avandia does increase the chance of a There was an 18 percent increased risk for all Avandia’s use fell sharply after Nissen’s first heart attack, its chances of increasing the risk three outcomes, in addition to heart attack. study, but the medicine is still widely prescribed, of mortality are very small. According to the The other study, by outspoken and long-time with sales of $1.2 billion in 2009, Reuters re- Boston Herald, most panel members felt it was Avandia opponent Steve Nissen of the Cleve- ported. It loses patent protection in 2012. important to keep Avandia on the market as an land Clinic, found a 39 percent higher chance The Graham study convinced epidemiolo- alternative to Actos (pioglitazone; manufactured of heart attack in patients who used Avandia. gist Corinne de Vries of the University of Bath, by Takeda Pharmaceuticals, Osaka, Japan), an- Nissen’s results were published in the Archives United Kingdom, of the drug’s problems. “I other drug for type 2 diabetes, because not eve- of Internal Medicine in an updated study on can’t fault it, and I suspect it might be the nail ryone will have an effective course of treatment Avandia; in 2007, Nissen and his research team in the coffin for rosiglitazone,” she said in a with Actos. found and reported a similar increased risk of news report for the journal Nature.

CORPORATE SUPPORTERS ASN gratefully acknowledges the Society’s Diamond, Platinum, and Gold Level Corporate Supporters for their contributions in 2009.

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Astellas Pharma US, Inc. Otsuka America Pharmaceutical, Inc. Watson 12 | ASN Kidney News | August 2010 Fellows Corner How to Formulate a Research Question By Nathan Hellmann

ll renal fellows are required tial mentors in anticipation of the bally interesting to the field of ne- to perform some type of re- upcoming research years. Talking phrology. Someone who hopes to search during the course of directly with current and former fel- stay in research may choose to tackle Atheir training. For some, this re- lows about a given mentor can also an ambitious, long-term project— search will be a stepping stone to a be invaluable in identifying poten- think something along the lines of career in academic nephrology. For tial conflicts or mismatches before “developing an animal model to de- others, the research years will be a they occur. termine the permeability factor re- brief sojourn into a different realm Although some fellows may feel sponsible for FSGS,” for example. for a year or two, until private prac- uncomfortable making such deci- Someone who prefers to restrict his tice beckons. Out of the myriad op- sions so early on in their fellowship, or her time in the lab to only one to tions available, how does one choose a case can be made that it justly forc- two years and a guaranteed publica- a worthy research question? es fellows to ask themselves essential tion or two might decide instead to Choosing a research mentor is questions about where they see their mine existing patient databases for intimately linked to choosing a re- career evolving. The choice of men- factors that predispose toward CKD search question. Except for the few tor may be very different depend- in a specific patient subpopulation. brave souls who are already inde- ing on whether or not an individual Regardless of the scope, asking the pendently minded (and independ- wants to stay within academics or following questions can be useful in ently funded) coming into fellow- begin their clinical practice career. honing in on a research focus: ship, nephrology fellows will need to A large, 30-plus person labora- find a mentor, someone who will not tory studying mechanisms of trans- 1. Is the question I’m asking im- only help develop the research ques- plant immunobiology may not be portant? Even for basic science MD, a nephrologist at Brigham and tion into a full-fledged independent the best fit for an individual with- types, in the current funding Women’s Hospital who has published project, but also provide career ad- out much research experience who climate it is often necessary to several important papers regarding vice and allow fellows to build upon simply wants to develop a clinical justify a project based on its rel- the epidemiology of hypertension, previous discoveries and techniques practice after completing fellowship. evance to human disease. started his fellowship research in a developed by the lab. Large labs tend to favor individuals 2. Is the project doable in the allot- basic research lab before switching Finding the right mentor and with an ability to carry out a project ted amount of time? More ambi- to a clinical research pathway after a the right project can be a challenge, independently. This is not to say tious, long-term projects should full year of research. particularly when nephrology fel- that fellows who do not anticipate be embarked on only by those “I found that at the end of the day, lows are required to commit to a staying within research should au- with the stomach for a long- I would be much more interested in specific laboratory very early on, tomatically rule out the possibility term research career. Knowing talking about clinical research ques- usually during the notoriously dif- of trying a basic science lab. In the what tools are available to you tions than basic research questions, ficult clinical year during which free right scenario with good one-on-one is essential for answering this and I realized that I could be very time can be hard to come by. Fellows mentoring, a rewarding research ex- question. happy pursuing a career in clinical are typically asked to commit to a perience can be achieved. 3. Is my research question specific research,” Forman said. given “track”—basic science, clini- For individuals who think they enough? Generally speaking, the Having to change one’s research cal research, and clinician-educator want to have a career predominantly more specific, the better. It’s not focus is not altogether uncommon, are common choices—that allows in research, the decision as to which enough to say, “I want to study especially in light of the difficul- fellowship programs to plan for the mentor and research question to dialysis access.” Instead, ask a di- ties of grant writing or experimental future and ensure a healthy balance choose are even more critical. Should rected question such as, “I want planning during the clinical year. In of research and clinical fellows. one choose the department head who to study the incidence/preva- terms of formulating an appropri- “I think in general you need to has 258 publications to his name, lence rates of AV fistula use in ate research question, Forman noted choose the best combination of access to exciting scientific reagents this subpopulation of the ESRD the importance of having the fel- mentor and project that fits with or databases, but will only be able to population using this particular low choose the actual question with your individual needs,” said Jonath- meet individually with fellows once database and using these partic- guidance from the mentor, rather an Bazeley, MD, a recent graduate of every three months? Or should one ular statistical techniques.” than simply being handed a research the University of Michigan nephrol- choose the up-and-coming junior 4. Will I be funded? Many neph- project. “You’ve got to pick some- ogy fellowship program. “Something faculty member who is able to pro- rology programs have a training thing that you can do in a relatively which really helped [in our nephrol- vide lots of individual attention and grant that can guarantee fellow short period of time with the re- ogy fellowship program] was that quality mentoring but may be un- funding for research. Howev- sources available to you,” he said. renal fellows have a protected two- able to provide guaranteed funding er, not all fellows (particularly Although formulating the re- week block of time halfway through for the duration of the project? Ulti- those from abroad) are eligible search question may seem intimidat- the clinical fellowship intended for mately, the decision comes down to for these grants. Many programs ing to the early nephrology fellow, fellows to go around and interview the individual, but most would agree strongly encourage individuals many find it among the most use- with the faculty of the nephrol- that a good rapport with the mentor to apply for their own funds. ful lessons of fellowship and see the ogy division to discuss potential should exist prior to joining the lab. It’s much better to know about process as an essential part of their projects.” these policies ahead of time. education. Narrowing down the focus Not all nephrology fellowship programs have such blocks, so most Key to a good research question is Finally, it’s important to realize that Renal fellow Nathan Hellman, MD, would agree that fellows will need to how to narrow down the focus to a nothing is set in stone. The research passed away February 13, 2010. Hell- set aside some time to discuss pos- question specific enough to obtain question a fellow investigates can man had been a member of the ASN sible experimental ideas with poten- meaningful conclusions, but glo- evolve dramatically. John Forman, Kidney News editorial board. August 2010 | ASN Kidney News | 13 ASN News

Society Announces Grant Recipients

ASN is pleased to announce grant recipients for 2010.

The following three grants provide funding for University of Texas Southwestern Medical Center Student Scholar Grants enable selected medical young faculty to foster evolution to an independ- Three recipients were named for the M. James students with an interest in either basic or clinical ent research career by providing transition funding Scherbenske Grant. The purpose of this grant is research to spend from 10 to 52 weeks engaged toward successful application for an RO1 grant. to provide bridge funding for investigators from in continuous full-time research. The mentor must Applicants must be within seven years of initial RO1 to RO1 whose application was not funded. be an ASN member and must submit a program faculty appointment and may be in the last two Applicants are eligible only during the period of of study for the applicant. An award period can be years of a mentored award. Applicants must be first revision of R01. a summer, semester, academic year, or any other able to show evidence of progress toward capabil- 10- to 52-week period of continuous full-time ity to oversee an independent research project or M. James Scherbenske Grant Recipients research. Applicant must be completing research its equivalent. in a nephrology lab. Melissa A. Cadnapaphornchai, MD University of Colorado School of Medicine Carl Gottschalk Research Scholar Student Scholar Grant Recipients Recipients Mary E. Choi, MD Narae Ko Vivek Bhalla, MD, FASN Harvard Medical School, Brigham and Women’s Yale University School of Medicine Stanford University School of Medicine Hospital Dhruti Patel David M. Charytan, MD Leonidas Tsiokas, PhD Brigham and Women’s Hospital Brigham and Women’s Hospital University of Oklahoma Health Sciences Center Krupa Patel Paolo Fiorina, MD, PhD University of Maryland School of Medicine Children’s Hospital Boston Harvard Medical School Shannon Nees Columbia University College of Physicians and Akio Kobayashi, PhD Surgeons Brigham and Women’s Hospital Stacy Rosenberg Vladimir Pech, MD Tulane University School of Medicine Emory University School of Medicine Ryan Reichert Timo M. Rieg, MD Medical University of South Carolina College University of California, San Diego School of of Medicine Medicine Amy Zhang Simone Sanna-Cherchi, MD University of Maryland School of Medicine Columbia University College of Physicians and Surgeons

John Merrill Grant in Transplantation Recipient Joshua D. Mezrich, MD University of Wisconsin School of Medicine and Public Health

Norman Siegel Research Grant Recipient Massimo Attanasio, MD

Index to Advertisers

Amgen ...... Back Cover

Fresenius Renal Pharmaceuticals ...... 9

Genzyme ...... 2–3 14 | ASN Kidney News | August 2010

Policy Update

New Funds to Help Alleviate Primary Care Shortage and Expand Preventive Care Access By Rachel Shaffer

trengthening and expanding cian assistants and other providers. Recognizing the need to reverse • Establishing new nurse practi- the primary care workforce is Increasing access to primary and this trend, the first Prevention and tioner-led clinics: Supporting a pivotal component of recent preventive care to prevent disease, Public Health Fund allocation funds the operation of 10 nurse-man- Shealth reform legislation, and the five key initiatives—outlined below— improve outcomes, and shrink health aged health clinics which assist in Department of Health and Human care costs is a tenet of the health reform to attract, train, and support 500 new the training of nurse practition- Services (HHS) recently announced bill—but cannot be achieved without primary care physicians (PCPs) and ers. These clinics are staffed by a key step toward that goal: the alleviating the current and growing other providers. HHS dedicates a nurse practitioners, who provide availability of $250 million in new majority of the funds toward bolster- workforce funding. Intended to shortage of primary caregivers. The comprehensive primary health American Association of Medical Col- ing the ranks of primary care physi- care services to populations liv- help meet the growing demand for cians, but also supports training of primary care workers, the funding— leges (AAMC) has estimated that if ing in medically underserved over 1000 physician extenders. For part of a new Prevention and Public trends continue, the United States will communities. a complete funding allocation break- Health Fund—will help train thou- face a deficit of approximately 21,000 • Encouraging states to plan for down, see Table 1. sands of new doctors, nurses, physi- primary care physicians in 2015. and address health professional workforce needs: $5 million for • Creating additional primary states to plan and implement in- care residency slots: Training novative strategies to expand their more than 500 new primary care primary care workforce by 10 to physicians by 2015. 25 percent over ten years to meet • Supporting physician assist- increased demand for primary ant training in primary care: care services. Supporting the development of more than 600 new physician as- “These new investments will sistants, who practice medicine strengthen our primary care work- as members of a team with their force to ensure that more Americans supervising physician, and can be can get the quality care they need to trained in a shorter period of time stay healthy,” said HHS Secretary compared to physicians. Kathleen Sebelius. “Primary care pro- • Increasing the number of nurse viders are on the front line in helping practitioners trained: Train an Americans stay healthy by preventing additional 600 nurse practition- disease, treating illness, and helping ers, including providing incen- to manage chronic conditions.” tives for part-time students to be- While new funding will not di- come full-time and complete their rectly add to the supply of nephrolo- education sooner. gists nationwide, it nonetheless offers benefits for patients with or at risk Table 1. Funding for primary care initiatives for kidney disease. Many people with kidney disease are unaware they have it, and as more of these individuals are able to access routine care and screen- ings they may be considerably more capable of preventing the progression of their condition. “Expanding access to preventive care by growing the primary care workforce is a significant step toward earlier detection and better manage- ment of kidney disease,” said ASN Chronic Kidney Disease Advisory Group Chair Thomas DuBose, MD, FASN. “Increasing Americans’ ac- cess to routine kidney function tests and timely referrals to a nephrologist through a PCP will translate to better renal health nationwide. However, it will be even more important for us as nephrologists to work closely with the primary care community in educat- ing these new providers about iden- tification and care of chronic kidney disease.” August 2010 | ASN Kidney News | 15

HHS Strategizes to Improve Care of Patients with Multiple Chronic Conditions By Rachel Shaffer

he Department of Health with multiple chronic conditions, external stakeholders. Figure 1. and Human Services according to HHS (Figure 1). Responding to HHS’ request Percentage of Americans with (HHS) recently launched Medicare spends $42 billion an- for public feedback on the draft multiple chronic conditions anT initiative to address increasing nually to treat people with CKD framework, ASN President Sha- versus total spending on concerns about the public health alone—yet it remains the ninth ron Anderson, MD, FASN, sub- multiple chronic conditions. impact of the growing number of leading cause of death (1,2). mitted a comment letter on behalf Americans with multiple chronic Given the increasing costs of the society, drafted in conjunc- U.S. Health Care Spending: conditions. of, poor outcomes among, and tion with the Public Policy Board Multiple Chronic Conditions Approximately 75 million complexity of managing care for and ASN staff. In its comments, Americans have multiple chronic people with multiple chronic the society applauded HHS’s ini- 66% conditions, including kidney dis- conditions—and the leading role tiative of improving the health ease, heart disease, and diabetes. HHS plays in health research and quality of life for individuals 44% Nearly 30 million Americans—13 and payment for and delivery of with concurrent chronic condi- percent of the population—have health care services—HHS re- tions, but emphasized the impor- chronic kidney disease (CKD). cently organized a workgroup on tance of including kidney disease. CKD is a common co-morbid individuals with multiple chron- The initial draft did not include condition among patients with ic conditions. This workgroup, mention of CKD or end stage re- other chronic conditions, particu- which included representatives nal disease.

larly hypertension, cardiovascular from nearly every HHS operat- The ASN Public Policy Board Health care spending on people with disease, congestive heart failure, ing division, drafted a “Strategic looks forward to collaborating with multiple chronic conditions Health care spending on people with diabetes, and peripheral vascular Framework on Multiple Chronic HHS in its efforts to improve out- one or no chronic conditions disease. As a patient’s number of Conditions (MCC).” Intended comes for patients with multiple chronic conditions increases, so to help the department prevent chronic conditions—including kid- 27% 73% too does his or her risk of unnec- and improve quality of life for ney disease—and will continue to essary hospitalizations, duplicate individuals with multiple chronic advocate for recognition and inclu- tests, conflicting medical advice, conditions, the draft framework sion of kidney disease throughout and mortality. Today, 66 percent identified opportunities for HHS the department’s divisions. Read Americans with Multiple Americans with one or of all health care spending is di- to take a more coordinated, com- ASN’s comment letter online at Chronic Conditions no chronic conditions rected toward care for the approx- prehensive approach to care in- http://www.asn-online.org/policy_ imately 27 percent of Americans ternally and in collaboration with and_public_affairs/.

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16 | ASN Kidney News | August 2010

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 presents a new case to the master consultant.

Henle I have a case for us. Metabolic alkalosis. Henle I am getting to that point. You can have a low volume state with diuretic use and have a high urine chloride. So Nephron Excellent. don’t assume that just because the urine chloride is high, it’s not low eff ective volume yet. Henle, prepared A 65-year-old male was just seen recently for fatigue and muscle weakness and found to have a serum bicarbonate Nephron You are both correct. Fascinating. So now what do we level of 39 mEq. need to do? Find out if he is on a diuretic or taking any endogenous medications that might be increasing his Nephron, chuckling Give me a break, apprentice, this is a cake walk. Give HCO load? some hydration and send him home. 3 Tubule He refused to take any of the drugs you mention. Henle, with a curious ey tried that for three days. Perhaps you want to know look that his pre- and posthydration urine chloride values are Nephron Are you sure? Go back and check again. It’s very on or about 80 mEq/L important to make sure. Nephron, confused Ahhah!, this is going to be fun! Tubule and Henle exit and Detective Nephron resumes drinking his coffee. Henle He has recently diagnosed prostate cancer, with metastatic disease to the liver and the bone. He was treated with leuprolide, and recently with cisplatin and Nephron (to himself) Henle and Tubule really were having a very powerful etoposide. discussion. I love their passion for the subject.

The detective listens. Henle returns to the of ce. All of a sudden, a knock is heard, and a medical student in a nicely ironed short white coat enters the room. Nephron You’re back. She appears frightened. Henle, very excited No diuretics. Nephron Who are you and what do you want? Nephron Good! Henle, smirking She is a medical student who has been involved with this case. She wanted to join us today with our discussion. Henle But we noticed a few more things: worsening Her name is Ms. Curious Tubule. hypokalemia (2.9 mmol/L) and hypernatremia (147 mmol/L), and this has been getting worse for the past Nephron Hello, Ms. Tubule, so here we have a case of metabolic month. alkalosis or alkalemia? Nephron Stop right there! So now you are telling me we have Tubule He did get an arterial blood gas that revealed a ph of a case of a chloride-resistant hypokalemic metabolic

7.57 and pC02 of 41 mm Hg. e bicarbonate was 38. alkalosis? is suggests a case of mixed respiratory and metabolic alkalosis. Henle Yes, you are correct.

Nephron How so? Nephron, with I assume normal renal function. con dence Henle His primary problem appears to be metabolic alkalosis,

and to compensate, his pC02 should have been lower, Henle Yes, as usual you are correct. at least 0.5 mm Hg for every rise of bicarbonate of 1 mEq/L. Hence, there is a respiratory alkalosis as well. Nephron, looking Where is your friend, Ms Tubule? around Nephron Great job, let’s move on. Let’s discuss the causes of this patient’s metabolic alkalosis. Can either of you tell me Henle She is gathering some more data for us. I asked her to get why this patient’s plasma bicarbonate level rose to 39? the blood pressure readings for the last few months. Henle Two possibilities: either there was decreased eff ective They pause as Tubule enters. extracellular volume or there was an exogenous or endogenous source of increased extracellular volume content. Nephron Let me guess, recent onset of hypertension as well?

Tubule at is so confusing. But wouldn’t the urine chloride The detective pauses to see their response. be helpful here? Since it’s high, I don’t think it’s a low volume state. Tubule Yes, you are correct.

August 2010 | ASN Kidney News | 17

Nephron When the urine chloride is not zero, you asked if he was Henle Dr. Nephron, his prostate cancer is producing ACTH. taking a diuretic; you said he wasn’t. So now we are left e octeotride scan and immunohistochemistry staining with the question of whether he has hypertension or for ACTH on the prostate biopsy confi rmed it. He is no hypertension. If he has no hypertension, you enter responding very well to the therapy. His hypertension, the world of “Bartter’s and friends.” You also confi rmed diabetes, alkalosis, and hypokalemia all resolved with normal renal function, another possibility if there was the treatment. no hypertension. Nephron Remember, this patient presented with Cushing’s like Henle e presence of hypertension is important because syndrome. In patients with the classic form of ectopic it might be the only clue to a diagnosis of primary ATCH syndrome, the degree of ACTH and urinary hyperaldosteronism, renal artery stenosis, or production cortisol and hypokalemia is much greater than classic of endogenous compounds in the body that can Cushing’s disease (pituitary cause). Usually ACTH raise blood pressure and have profound metabolic ectopic production is classically seen in small cell and derangements. non-small cell lung cancer, but there are cases of thyroid cancer, prostate cancer, and ovarian carcinoid that have Tubule So you think he has a primary aldosteronism or been reported with ectopic ACTH production. something like that? Tubule In ectopic ACTH production, is the hypertension more profound? Nephron, pleased Excellent. By the way, does he have elevated blood sugars? Nephron, smiling Good question. Cushing’s syndrome is the cause of hypertension in approximately one in 400 Henle As a matter of fact, he did mention that he was hypertensives. Among patients with Cushing’s diagnosed recently by his oncologist with type II syndrome, hypertension is very common, aff ecting diabetes mellitus and he has been gaining weight. He some 80 percent of patients. e number of patients had normal blood glucose levels as of last year and he with ectopic ACTH production who are hypertensive sees a primary care physician regularly. is usually lower than in other forms of Cushing’s syndrome. is is likely due to the shorter duration of Tubule Is that a recent onset diabetes? at is strange? the disease or the underlying cancer. No one knows really. As you saw, this patient had hypernatremia, Henle So we have a chloride-resistant, hypertensive metabolic hypokalemia, and initial sodium retention. You see alkalosis with hyperglycemia and hypokalemia. Could this when there is excess glucocorticoid eff ect. ere he have Cushing’s syndrome or disease? is increased urinary retention leading to increased extracellular volume, and there is volume-mediated Nephron, with a smirk Again, my dear apprentices, I have a diagnosis for you! hypertension. e plasma renin activity will be low. Perhaps you are correct. Cortisol, a classic glucocorticoid hormone, might have some mineralocorticoid activity and hence raise Henle His plasma renin and serum aldosterone levels were blood pressure through its hypertensinogenic activity. low. His urinalysis revealed >1000 glucose, and urine ese are the two mechanisms usually that can lead to potassium was 45 mmol/L for a serum potassium of 2.9 hypertension in ACTH elevations—but again, usually mmol/L. He is having renal losses of potassium. lower chances in ectopic ACTH than in primary Cushing’s disease. Tubule Perhaps he is producing too much ACTH? Or too much cortisol? Henle He is doing very well. His cancer is stable with no further progression. Nephron What are you waiting for, you want to check Nephron the levels? I shall see you in a few days. Again, my dear apprentices, from a diagnosis of metabolic Tubule and Henle exit and Detective Nephron starts reading ASN Kidney alkalosis, you made a News. A few days later… diagnosis of a life-threatening systemic disorder. Always be a good detective. Observe, Nephron My coff ee is good, less sweet than usual. think, read, and apply. If it doesn’t cross your mind, you Tubule Sweet is the key word. ACTH level was signifi cantly will never diagnosis it. Great elevated with a 24-hour urinary cortisol level in the case, Henle. astronomical range. Detective Nephron was developed by Kenar Jhaveri, Henle So this patient is producing ACTH? Where? MD, assistant professor of medicine at Hofstra Medical Nephron Did you see his prostate biopsy? He probably has School and an attending nephrologist at North Shore neuroendocrine features and is producing ACTH. I University and Long Island Jewish Medical Center would start ketoconazole soon. Perhaps his ACTH in Great Neck, NY. e column was inspired by production could be a marker of his cancer. Muthukumar angamani, MD, and Alan Weinstein, MD, both of Cornell University, and Mitch Halperin, Tubule Fascinating! MD, of the University of Toronto. Send correspondences regarding this section to [email protected] or kdj200@ A few weeks later… gmail.com. 18 | ASN Kidney News | August 2010 Patient Safety: General Principles and the Role of the Nephrologist By Henry Crevensten and Robert Wachter

s medical professionals, the last thing individuals has been extraordinarily helpful errors among patients with kidney disease, “no blame”with accountability in patient we want is for patients to come to to promoting safety, there are some areas nephrologists have a critical role in develop- safety. N Engl J Med 2009; 361:1401–6. harm because they came to us for of patient safety in which our systems are ing and implementing safety systems, and 6. Seliger SL, Zhan M, et al. Chronic Acare. Sadly, this happens with alarming mature yet problems remain. In these areas, ensuring that such systems help meet the kidney disease adversely influences pa- regularity. An estimated 44,000 to 98,000 we do rely on individual performance. One specific needs of their patients and settings tient safety. J Am Soc Nephrol 2008; patients die each year as a result of prevent- example is infection control. Many health of care. 19:2414. able medical errors (1). Thankfully, we as a care organizations have done a good job profession are starting to come together to of improving the systems to support hand Henry Crevensten, MD, is assistant professor Additional Resources improve our systems of care in the name of hygiene. In many hospitals, there are now in the department of medicine and Robert Internet patient safety. ubiquitous hand-washing stations and Wachter, MD, is professor and chief of the di- 1. The Joint Commission (www.jointcom- This article provides an overview of sev- posters of leading clinicians cleaning their vision of hospital medicine at the University of mission.org) eral philosophies of patient safety and sug- hands. Computerized screen savers graphi- California, San Francisco. 2. Keeping Kidney Patients Safe, a resource gests methods for incorporating these ideas cally illustrate serious health care-associated of the Renal Physicians Association into daily practice. infections. Yet despite these interventions References (www.kidneypatientsafety.org) Until the patient safety movement, most and associated provider education, only 1. Kohn LT, Corrigan JM, Donaldson MS, 3. Institute for Health Care Improvement errors were approached as manifestations of about 70 percent of providers consistently Institute of Medicine. To Err is Human: (www.ihi.org) individual carelessness. Such errors were wash their hands before touching patients Building a Safer Health System, National 4. Agency for Health Care Research and dealt with by finger pointing and blaming (3). The concept of “just culture” delineates Academy Press, Washington D.C. 2000. Quality (www.ahrq.gov) the individual, or “name and shame.” One “blameless acts” (innocent mistakes made 2. Leape LL. Error in medicine. JAMA of the first concepts to emerge in quality by competent providers) versus “blame- 1994; 272:1851–7. Publications improvement and patient safety was the worthy acts” (willful violations of safety 3. Gawande A. On washing hands. N Engl 1. Wachter RM, Shojania KG. Internal idea of “systems thinking”—recognizing rules, such as hand hygiene) (4). The pa- J Med 2004; 350:1283–6. Bleeding: The Truth Behind America’s that most errors result from faulty systems tient safety field is increasingly focusing on 4. Marx D. Patient Safety and the “Just Terrifying Epidemic of Medical Mistakes. rather than flawed individuals (1). how to ensure a systems focus for blameless Culture”: A Primer for Health Care Ex- New York: Rugged Land, 2004. Reason’s “Swiss cheese model” has pro- acts while creating accountability when ap- ecutives. Trustees of Columbia Univer- 2. Gawande A. Better: A Surgeon’s Notes on vided a useful mental model for thinking propriate (5). sity, 2001. Performance. New York: Metropolitan about systems versus individuals: while an Nephrologists may see patients through- 5. Wachter RM, Pronovost PJ. Balancing Books, 2007. error chain may involve a slip by an in- out hospitals and outpatient settings, but dividual, detailed analysis of most errors they also work in a special area—the di- Figure 1. Reason’s “Swiss cheese” model of error (often called “root cause analysis”) dem- alysis center. Particular patient safety issues onstrates that errors reach patients because here include proper identification of the pa- multiple layers of potential protection fail. tient, proper use of dialysis orders, adhering In the analogy, the error makes it through to infection control standards (particularly holes in Swiss cheese (see Figure 1). important given the number of procedures The Swiss cheese model is helpful be- and the frequency of serious infections in cause it forces us to focus on tightening this population) and using checklists when the system rather than trying to get people inserting dialysis catheters. They also care to be perfect. Examples of a systems focus for a special patient population: those include developing checklists and other with chronic kidney disease. Patients with memory aides, building in double checks chronic kidney disease are 19 percent more and other redundancies, standardizing likely to suffer a preventable medical error practice settings, and implementing com- than other patients (6), likely as a result puterized decision support or pre-written of their high rates of hospitalization, pro- orders (2). Providers can help by using such cedures, and medications. Nephrologists systems and becoming involved in their de- should at least be aware that their patient velopment. population is especially susceptible to errors Because our health care system has and be sure to develop and use systems to Figure 2. As settings of care become more and more complex, the become so complex, teamwork and com- prevent them. importance of creating safe systems grows. munication are vital to the delivery of safe Lastly, you cannot improve what you medical care. Teamwork can involve ensur- do not measure. Most health care systems ing accurate patient identification (such as have some sort of medical error reporting using two patient identifiers, helping to system. This should be used for all types of prevent the errors that occur when one says incidents, not just those that caused harm. “bring the patient in 23A down to inter- The ideal purpose of reporting errors is not ventional radiology”—what if the patient only to respond to errors but ultimately to in 23A had been moved?), writing clear help prevent their occurrence. For example, orders (using computerized order entry if a large number of reports of mislabeled available), verifying orders (using bar-cod- specimens may indicate a systematic prob- ing systems), verifying patient medications, lem in specimen handling that needs to be or clearly discussing discharge instructions addressed. (a major source of error). The patient safety field recently marked In the face of work hour restrictions for its 10th anniversary: the Institute of Medi- residents and more shift work by practic- cine Report on safety (“To Err is Hu- ing physicians, thorough handoff commu- man”) was released in late 1999. Over the nication has become vital to ensuring safe past decade, we have made considerable care. Physicians can help by participating progress in developing and implementing or starting teams that collaborate in patient safety systems, in research in patient safety, care. Ideally, these teams will be multidis- and in creating a policy environment in ciplinary, including nurses, pharmacists, which organizations and individual caregiv- Photo courtesy MD, of PhD Michael Gropper, technicians, and dieticians. ers are pushed to focus on delivering safe, While the focus on systems rather than high-quality care. Given the high risk for NephSAP

A Resource for CME and MOC*

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Volume 9 • Number 1 • January 2010

Renew diagnostic and NephSAP ® therapeutic skills. Nephrology Self-Assessment Program Refresh clinical knowledge.

Earn CME credits and MOC points. Transplantation Co-Editors: Access in both print and podcast John P. Vella, MD, and (Audio NephSAP) formats. David J. Cohen, MD

� Editor-in-Chief: Stanley Goldfarb, MD � Deputy Editor: Jeffrey S. Berns, MD

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