Removing a Kidney After Failed Transplant Can Yield Benefits

February 2010 | Vol. 2, Number 2

Removing a Kidney after Failed Inside

Transplant Can Yield Benefits 5 ASN News Help ASN By Tracy Hampton unearth nephrology idney transplants can be life- among this growing population of history by savers for many patients with high-risk patients with end stage renal playing chronic kidney disease. Still, disease,” the authors wrote. “Guess the Ka significant number of transplanted Nephrologist” kidneys are rejected or do not function Options after allograft failure properly over time. Physicians have been Patients with chronic kidney disease reluctant to remove these organs, but a often must wait years for a suitable recent study indicates that such a trans- 7 Special Section kidney transplant (and some die while Acute kidney injury is a plant nephrectomy can offer significant on the waiting list), but their return to major clinical problem. survival benefits for patients (Ayus JC, et health is not ensured once they receive Where are we now, and al. J Am Soc Nephrol 2010; 21:374–380). a donor kidney. A growing number of where should we go? While additional studies are needed, the patients are returning instead to di- results indicate that clinicians should re- alysis after a failed kidney transplant, think how they treat patients with failed where they face an increased risk of kidney allografts. complications and premature death. 18 World “Our results raise questions about The problem will likely become more Kidney the current clinical paradigm and sug- widespread, as the prevalence and in- Day gest that routine allograft nephrectomy cidence of end stage renal disease are in stable dialysis patients with a failed projected to increase substantially in renal allograft should be evaluated © Fotosearch the United States over the next several against current management strate- 18 Industry Spotlight Nephrectomy following failed kidney decades. transplant can yield significant benefits gies in a randomized trial as a possi- Salt in the spotlight for some patients. ble strategy for improving outcomes Continued on page 3 18 Haiti Relief ASN helps with dialysis, Researchers Discover Gene for Devastating other relief 20 Fellows Corner Kidney Disease What you need to know before you start Finding Could Lead to Better Diagnosis and Treatment of Patients with FSGS fellowship recent genetic discovery may provide Investigators have found that mutations tive director of the nonprofit NephCure A clues to the mysteries behind focal in the INF2 gene occur in a large num- Foundation, which helped fund the 22 Policy segmental glomerulosclerosis (FSGS), the bers of families with affected members study. Update second leading cause of kidney failure in and may be relevant for understanding These latest research findings could not come soon enough, as prevention Health care children and the most prevalent acquired how the disease originates. reform and kidney disease leading to transplanta- “We are hopeful these new findings and treatment options for patients with FSGS are sorely needed. Patients today Medicare tion among pediatric patients (Brown will impact future clinical studies and consultation codes patient care,” said Henry Brehm, execu- are treated with steroids, must undergo E, et al. Nature Genet 2010; 42:72–76). dialysis, and often require a kidney transplant. In 20 percent to 50 percent of transplant cases, the disease recurs in the 23 Journal View transplanted kidney, sometimes within Atherosclerotic hours. Over half of the patients with re- renovascular disease is current FSGS in their transplant will lose on the rise their kidney within five years. Continued on page 4

February 2010 | ASN Kidney News | 3

Failed Transplant ture transplant. with failed kidney allografts, Juan ney allograft failure, those who did not Others have questioned this rationale, Carlos Ayus, MD, FASN, director of Continued from page 1 have Medicare fee-for-service insur- however, and say that the benefits of ne- clinical research at Renal Consultants ance after the first 90 days following Physicians have wrestled with whether phrectomy outweigh its risks. They point of Houston, and his colleagues studied the return to dialysis, and those with- to remove failed kidney allografts in these to studies showing that a failed kidney information from all adults who un- out confirmed sequential transplants. patients, not knowing how such an exten- allograft acts as a focal point of immu- derwent a single kidney transplant or The primary outcome was death from sive surgery would affect the health and noreactivity that can perpetuate chronic two nonsequential kidney transplants any cause through December 31, 2004, survival of individuals receiving chronic inflammation, which is a major risk factor and returned to chronic dialysis after which was identified from USRDS files. dialysis. Many have assumed that the for cardiovascular death in patients receiv- kidney allograft failure between Janu- The mean follow-up was 2.93 ± 2.26 years. operation would be too risky and would ing chronic dialysis. ary 1994 and December 2004. Data increase patients’ immunoreactivity— were obtained from the U.S. Renal Among 10,951 transplant recipients who returned to chronic dialysis, 3451 presumably due to increased exposure to Outcomes following Data System (USRDS). The research- (31.5 percent) received an allograft ne- foreign antigens during the nephrectomy nephrectomy ers excluded patients in whom the kid- operation. The thought is that this in- ney allograft did not survive at least phrectomy during follow-up. These pa- creased immunoreactivity would decrease To investigate the costs and benefits three months, as well as those who tients returned to dialysis at a median time these patients’ chances of receiving a fu- of transplant nephrectomy in patients died within less than one day after kid- of 1.66 years (interquartile range: 0.73 to 3.02 years). The investigators found that 34.6 percent of these patients died during follow-up. Receiving an allograft nephrectomy was associated with a 32 percent lower risk for death from all causes after adjust- ing for sociodemographic characteristics, comorbidity burden, donor characteristics, interim clinical conditions associated with receiving allograft nephrectomy, and propensity to receive an allograft nephrectomy. Even after Ayus and his team performed six additional sensitivity analyses including or excluding specific patient subgroups, there were no clinically relevant differences in the estimated benefits associated with the nephrectomy. For patients who underwent a transplant nephrectomy, the rate of death within 30 days of the surgery was only 1.5 percent (53 deaths). The investigators also found that patients receiving a transplant nephrectomy were more than twice as likely to receive a second transplant during the follow-up period than those who did not undergo a nephrectomy of the initial failed allograft (10 percent versus 4.1 percent, p < 0.001). It is unclear why patients who received a transplant nephrectomy had an increased rate of repeat transplantation. The researchers suspect the increased transplantation rate may reflect better health in the nephrectomy group through either lower comorbidity or improved health status following nephrectomy due to reduced chronic inflammation. The investigators made several postula- tions after analyzing their findings. They suspect that patients with failed transplants experience higher death rates due to chronic inflammation. In addition, patients who retain a failed renal allograft routinely use low-dose immunosuppressive therapies after returning to dialysis, which may delay the need for ultimate nephrectomy and contribute to an increased risk of cardiovascular and infectious complications. Nephrectomy “spares the patients un- necessary immunosuppressive therapy and more importantly removes a source of chronic inflammation that predisposes to morbidity and mortality on dialysis,” said William Bennett, MD, who was not involved with the research. Bennett is medical director of kidney transplantation at Legacy Good Samaritan Hospital in Port- land, Oregon. According to Ayus, this is the first study to use a very sophisticated and large Continued on page 5 4 | ASN Kidney News | February 2010

The research makes several contribu- Gene Discovered tions to basic and clinical research, Pollak Continued from page 1 said: “It adds to the complexity of the genetic basis of FSGS, identifies a new gene Importance of the INF2 Gene and pathway as critical to the biology of Patients with FSGS excrete abnormally the podocyte, and adds to the ability to large amounts of protein in their urine make a correct etiologic diagnosis.” and may develop low blood protein lev- The findings could have important els as well as edema, especially in the clinical implications beyond diagnosis. feet and legs. Despite years of research “Understanding the function of INF2 and Editorial Staff and the discovery of several genes that the pathways in which it is involved in the Editor-in-Chief: Pascale H. Lane, MD, FASN play a role in the development of some cell will hopefully lead to better targets for Managing Editor: Dawn McCoy cases of FSGS, investigators have failed the prevention and treatment of FSGS,” Design: Lisa Cain to uncover the disease’s underlying Brown said. There is still much to learn about the Editorial Board: mechanisms or come up with effective INF2 Matthew D. Breyer, MD, FASN, Eli Lilly and Company treatments for patients. function of the gene and the pre- Wendy Weinstock Brown, MD, Jesse Brown VA Medical Center, Northwestern University Feinberg Many patients with familial FSGS do cise mechanism by which actin behav- School of Medicine, University of Illinois at Chicago not have mutations in the known FSGS- ior is disrupted in the presence of INF2 Teri Browne, PhD, MSW, University of South Carolina causing genes. To look closely at the herit- alterations. “Studying the way in which Stephen Darrow, MD (fellow), University of Nebraska Medical Center mutations in INF2 disrupt normal cell Nathan Hellman (fellow), Brigham & Women’s Hospital/Massachusetts General Hospital ability of FSGS, researchers led by Eliza- Ira Davis, MD, Baxter Healthcare Corp. beth Brown, MD, and Marin Pollak, MD, function can help us understand the role Caroline Jennette, MSW, University of North Carolina Kidney Center performed a genetic linkage analysis in two of INF2 in the podocyte. In addition, Richard Lafayette, MD, Stanford University Medical Center large families affected by the disease. The studying patients with INF2 mutations Edgar V. Lerma, MD, FASN, University of Illinois – Chicago /Associates in Nephrology, can help us better stratify patients with SC study was designed to identify new FSGS- Teri J. Mauch, MD, FASN, University of Utah causing genes in family members with FSGS for more personalized treatment Victoria F. Norwood, MD, FASN, University of Virginia autosomal dominant disease who were options,” said Brown. Sheila M. O’Day, MSN, University of Nebraska Medical Center negative for all known FSGS-causing gene Other researchers not involved with Titte R. Srinivas, MD, Cleveland Clinic mutations. Brown is associate physician in the work also anticipate that the find- medicine in the division of nephrology at ings could have a considerable impact on Advertising Sales: FSGS research and treatment. “The report Scherago International, Inc. Children’s Hospital, in Boston, and Pol- 525 Washington Blvd., Suite 3310 lak is assistant professor in medicine at by Brown et al. is yet another step forward Jersey City, NJ 07310 Brigham and Women’s Hospital and as- in our understanding the complexity of 201-653-4777 phone sociate professor in medicine at Harvard the genetics of podoctyes in health and 201-653-5705 fax disease,” said Frederick Kaskel, MD, PhD, [email protected] Medical School, also in Boston. The researchers’ analysis revealed that chief of the nephrology section at Chil- ASN Council: mutations in a region of chromosome dren’s Hospital at Montefiore, in Bronx, NY. “The fact that the newly identified President: Sharon Anderson, MD, FASN 14q were common in affected individu- President-elect: Joseph V. Bonventre, MD, PhD als. By sequencing the genes in this re- mutations are associated with proteins Past-President: Thomas M. Coffman, MD, FASN gion, the investigators detected various that maintain the stability of the podocyte Secretary-Treasurer: cytoskeleton opens the doors for further Donald E. Wesson, MD mutations, all of them in a gene called Publications Committee Chair: Thomas M. Coffman, MD, FASN investigations aimed at targeting these INF2. Next, they sequenced the INF2 Councilors: Ronald J. Falk, MD, FASN; Jonathan Himmelfarb, MD, FASN; mutations in health and disease in an at- gene in 91 additional families and un- Sharon M. Moe, MD, FASN; Bruce A. Molitoris, MD tempt to halt the progression of the po- covered nine different INF2 mutations docytopathy.” Kaskel noted that it will be Executive Director: Tod Ibrahim in 11 of the 93 total families. INF2 gene interesting to search other familial FSGS Publications Manager: Robert Henkel mutations were found in more families databases to confirm the latest findings. than either of the previously identified ASN Kidney News is published by the American Society of Nephrology autosomal dominant disease-associated 1725 I Street NW, Suite 510, Washington, DC 20006. Phone: 202-659-0599 Need for new treatments genes, actinin-4 and TRPC6. The INF2 www.asn-online.org gene mutations caused substitutions According to the NephCure Founda- tion, more than 20,000 people currently ASN Kidney News is the authoritative source for analysis of trends in medicine, industry, and policy in highly conserved amino acids in the affecting all practitioners in nephrology. The statements and opinions expressed in ASN Kidney News INF2 protein (a formin protein), and the live with end stage renal disease due to are solely those of the authors and not of the American Society of Nephrology (ASN) or the editorial mutations segregated with disease within FSGS. Chronic kidney disease sufferers policy of the editors. The appearance of advertisements in ASN Kidney News is not a warranty, the affected families. None of the gene in various stages of FSGS number in endorsement, or approval of the products or services advertised or of their effectiveness, quality, or mutations were found in healthy con- the tens of thousands, at the least. More safety. The American Society of Nephrology disclaims responsibility for any injury to persons or people in the United States suffer from property resulting from any ideas or products referred to in the articles or advertisements. trols. In addition, the INF2 gene mutations were all located in the same region, FSGS than from cystic fibrosis, accord- The American Society of Nephrology is organized and operated exclusively for scientific and which encodes a domain that is thought ing to NephCure. The organization esti- educational purposes, including enhancing the field of nephrology by advancing the scientific mates that 1117 kidney transplants were to be involved in the regulation of the knowledge and clinical practice of that discipline through stimulation of basic and clinical performed on FSGS patients in 2007 INF2 protein. investigation, providing access to new knowledge through the publication of journals and the alone. In addition, young African Amer- holding of scientific meetings, advocating for the development of national health policies to improve The formin protein encoded by the ican males are diagnosed with FSGS five the quality of care for renal patients, cooperating with other national and international societies and INF2 gene regulates actin. Abundant times more frequently than young Cau- organizations involved in the field of nephrology, and using other means as directed in the podocytes of the kidney, actin is by the Council of the Society. casian males. important for creating and maintaining “FSGS is a very serious condition Postmaster: Please send address changes to ASN Kidney News, c/o Customer Service, the cells’ architecture, namely their cy- and one that affects thousands world- American Society of Nephrology 1725 I Street NW, Suite 510, Washington DC 20006. toskeleton. The researchers believe that wide. There are few effective treatments mutations in the INF2 protein in po- for FSGS and its recurrence posttrans- Publications mail agreement No. 40624074. Return undeliverable Canadian addresses to docytes compromise the cells’ structure plant is devastating to patients and PO Box 503, RPO West Beaver Creek, Richmond Hill ON L4B 4R6 and, hence, their ability to filter toxins. families,” said the NephCure Founda- “This is the second actin binding protein ASN Kidney News (ISSN print 1943-8044 and online 1943-8052) is an official publication of tion’s Brehm. He hopes that the Pollak the American Society of Nephrology, 1725 I Street NW, Suite 510, Washington DC 20006, and described that, when mutated, can cause team’s findings will encourage other is published monthly. Application to mail as Periodicals Postage Pending at Washington, DC, FSGS,” said Brown. “Both of these pro- FSGS investigators to step up the pace and at additional mailing offices. Subscription rates: $12 per year. To order, please email teins are ubiquitous; however, the kidney of their research. “This is the kind of [email protected]. Subscription prices subject to change. Annual ASN membership dues appears to be the primary organ affected tangible progress that creates the kind include $12 for ASN Kidney News subscription. by the genetic mutations, reinforcing the of momentum we need. The most excit- Copyright© 2009 All rights reserved importance of the podocyte architecture ing part is that the research is just get- in the development of FSGS.” ting started,” he said. February 2010 | ASN Kidney News | 5

tation when in fact our study shows for the after transplant failure. “This is indeed an transplant nephrectomy and increased sur- Failed Transplant first time that in the group of patients who important article addressing a difficult vival,” he said. “Until the randomized study Continued from page 3 underwent transplant nephrectomy, the management point in transplantation is done (if ever), this information is the rate of re-transplantation was significantly management,” Bennett said. “The paper strongest evidence that physicians could database to suggest a significant survival higher compared with the non-nephrec- gives us clear guidance on the preferability use to improve survival in patients who re- advantage with transplant nephrectomy tomy group,” he said. This finding argues of allograft nephrectomy for failed grafts.” turn to dialysis with a failed allograft.” and a very low mortality with this type of against withholding a transplant nephrec- While this study is the largest and most Ayus said he hopes that additional rig- operation. tomy due to a presumed reduced chance of rigorous thus far, it is not a randomized orous studies are performed to provide “More importantly, the study has dis- repeat transplantation, the authors wrote. clinical trial, which is the gold standard in more definitive information on the value pelled the notion that transplant nephrec- The research results challenge the tradi- epidemiology, Ayus said. “Our study only of transplant nephrectomy following failed tomy reduces the chance for re-transplan- tional practice of retaining kidney allografts indicates a very strong association between kidney allografts.

ASN News New Archives Effort Will Document ASN and Nephrology History

n honor of ASN’s 50th anniversary in 2016, asn-online.org or call her at 202-416-0658 to the society is developing an archives pro- discuss your potential contributions. Igram to document important milestones in ASN will underwrite the costs of copying the history of ASN and nephrology. and shipping material that we do not already ASN seeks volunteers to assist the society possess and that needs to be added to the in identifying pivotal moments in ASN history archives. and the most important advances in kidney We have included some images of ASN at- treatment and research. Please let us know tendees during past Renal Week meetings if you are interested in participating and con- and encourage you to guess who they are. tributing to our archiving efforts. You will find the key on page 23 to help you One way you may wish to contribute is by find out if you were right. sharing materials you have from ASN meet- ASN invites our members to contribute to ings, publications, or other activities. If you this exciting endeavor. As we look toward the have material you think may be of interest, future with the arrival of 2010, let us celebrate please contact Shari Leventhal at archives@ the past by building our archives program!

Guess the Nephrologist

February 2010 | ASN Kidney News | 7

Acute Kidney Injury: The Road to Recovery

Patients with AKI, presently recognized any benefit on the course of this disease. 1. Cosentino F. Risk factors influencing by increasing serum creatinine values or ol- Presently, there is great uncertainty as to survival in ICU acute renal failure. Ne- iguria, have unacceptably high rates of com- how best to diagnose this process or to get phrol Dial Transplant 1994; 9S4:179– plications demonstrated by increased costs, an early and full appreciation of risk. Fur- 182. prolonged ICU stays, and hospitalization, thermore, once identified, there is no clear 2. VA/NIH Acute Renal Failure Trial Net- as well as the frequent need for dialysis sup- intervention to help the kidney recover work: Intensity of Renal Support in port. Most notably, hospital mortality rates more quickly or completely or to assure Critically Ill Patients with Acute Kidney range from 30 to 80 percent for sustained, that the patient suffers fewer complica- Injury. New Engl J Med 2008; 359:7– dialysis-dependent AKI, depending on the tions. We continue to be uncertain of the 20. setting (1,2). Recently, there has been in- appropriate time to intervene with dialysis 3. Lo LJ, et al, Dialysis-requiring acute re- creased attention to the fact that survivors or with which modality or intensity to sup- nal failure increases the risk of progres- of AKI continue to suffer long-term ad- ply renal replacement therapy (2). sive chronic kidney disease. Kidney Int verse events, including progression to renal In this special issue of ASN Kidney News, 2009; 76:893–899. failure and increased mortality (3). we are fortunate to have the viewpoints of 4. Nash K, Hafeez A, Hou S. Hospital-ac- In our hospitals, the incidence of AKI is several leaders in the field of acute kidney in- quired renal insufficiency. Am J Kidney increasing, reaching rates as high as 7 per- jury. They provide evidence that nephrology Dis 2002; 39:930–936. cent of all admissions (4). This is associated is trying to develop better, more effective 5. Hsu, C-Y, et al. Community-based in- with an aging population, sicker inpatients, ways to deal with the diagnosis, treatment, Richard Lafayette cidence of acute renal failure. Kidney Int and more aggressive care for serious ill- and support of patients with AKI. Ranging 2007; 72:208–212. cute renal failure, increasingly nesses, including cardiovascular disease and from efforts to verify novel biomarkers of cancer. The community-based risk of AKI injury through enhanced basic science un- 6. Nicoara A, et al: Mortality trends associ- Abeing called acute kidney in- is also apparently growing, now as high as derstanding of pathophysiology, to specific ated with acute renal failure requiring di- jury (AKI), is a devastating event, 5.2 cases per 1000 patient-years (5). issues in patient care in terms of fluid sup- alysis after CABG surgery in the United most typically occurring in hos- There are some indications that overall port and nondialytic and dialytic treatment States. Blood Purif 2009; 28:359–363. 7. Chertow GM, et al. Mortality after pitalized patients. While we teach outcomes may be improving slightly either in the hospital, these insights should pave due to better reporting of cases or to true the way to new avenues of investigation and acute renal failure: Models for prognos- our students to look for easily re- improvements in overall supportive care clinical care. We certainly must hope for im- tic stratification and risk adjustment. versible causes such as pre-renal (6). It is also encouraging that there are clear provement in the care and outcome of this Kidney Int 2006; 70:1120–1126. and obstructive causes of AKI, or efforts at getting better definitions of disease very devastating event. 8. Bellomo R, et al. Acute renal failure, treatable interstitial nephritis or and of the measures of outcome to set the definition, outcome measures, animal stage for future discovery (7,8). Unfortu- Richard Lafayette, MD, is clinical chief, ne- models, fluid therapy and informa- glomerulonephritis, it often fol- nately, to date, most studies of specific ther- phrology, and associate professor of medicine tion technology needs. Crit Care 2006; lows a progressive course. apies and interventions have failed to show at Stanford University Medical Center. 8:R204–R212.

Fluid Administration in Pediatric AKI: When Is a Patient Being Overdosed? By Stuart Goldstein

ecent and important advances in complex supportive measures of fluid Can fluid be a toxic concept of a deleterious degree of posi- acute kidney injury (AKI) research resuscitation, vasoactive medication medication? tive fluid accumulation, or fluid over- R dose, has received no systemic evaluation have focused primarily on: ( i) deriva- administration, and decisions as to All physicians are taught about fluid and certainly has not been defined. For tion and validation of multidimen- timing of renal replacement therapy and electrolyte homeostasis in medi- example, neither of the two most recent, sional AKI definitions and classifica- (RRT). cal school and early in postgraduate comprehensive, randomized, and con- tion systems, e.g., RIFLE (Risk, Injury, Clinical research in adults with training, with an emphasis on how to trolled trials comparing small solute dose and Failure (1), pRIFLE (2), or the sepsis and acute respiratory distress respond to pathological homeostatic of RRT has reported to date the positive Acute Kidney Injury Network (AKIN) syndrome has also focused primarily disorders such as SIADH or diabetes fluid balance in their patient cohorts (3) definitions; (ii) demonstrating that on the benefits of early and aggressive insipidus. In these instances, physi- even small serum creatinine increases goal-directed fluid resuscitation to re- at the time of RRT initiation (12–14). cians become quite adept at managing (e.g., > 0.3 mg/dL) can be associated store end-organ provision. Recently Given that these patients had oligoanuric fluid composition and volume rates to with increased patient mortality (4); attention has been given to conserva- AKI and that disordered fluid homeos- correct or minimize the electrolyte de- and (iii) discovery and validation of tive late fluid management strategies tasis is a primary indication to initiate rangements that accompany these syn- novel urinary biomarkers that can de- to limit fluid administration (8–9). RRT, our collective ignorance regarding dromes. In fact, much controversy has tect AKI earlier than serum creatinine However, it has been pediatric stud- the fluid balance status in patients with arisen recently regarding the potential changes with the hope that earlier de- ies that have examined the concept of AKI is perplexing. dangers of prescribing hypotonic solu- tection may provide clinicians with the fluid accumulation in the critically ill Why has cumulative fluid balance tions to any hospitalized patient (10– opportunity to intervene to prevent child with AKI. received such short shrift? I suggest that or at least mitigate the effects of AKI Children with AKI provide an in- 12). Clearly the concept that certain we and AKI investigators have assumed (5–7). Although these advances will formative population for study, as their fluid compositions in particular settings that patients are getting the amount of undoubtedly lead to improved patient care is usually not complicated by co- may be toxic is not new. fluid they need (and maybe too little, care by prompting clinicians to be vigi- morbidities found in adults such as In the setting of AKI, physicians are but rarely too much), and since it is lant for early AKI development, they atherosclerotic heart disease, diabetes, very cognizant to limit the dose of po- usually of a relatively isotonic composi- may provide little benefit once patients or chronic obstructive pulmonary dis- tentially harmful electrolytes (potassium, tion (e.g., normal saline or Ringer’s lac- have already developed AKI. ease. The purpose of this article is to phosphorus) provided in exogenous flu- tate) and can be removed by RRT, fluid Care for the critically ill patient introduce the concept of “fluid over- ids, but the concept of a fluid volume can’t really be overdosed. However, les- with sepsis and AKI is further com- dose” in the critically ill patient with dose has been limited for the most part sons from the pediatric AKI literature plicated by the need to manage multi- AKI based on pediatric studies from to an acute dose to treat hypotension challenge these assumptions. organ system failure, often requiring the past decade. (e.g., 10 mL/kg of normal saline). Yet the Continued on page 8 Acute Kidney Injury: The Road to Recovery

Fluid Administration mean CVP was two- to threefold above tar- Table 1 get recommendations, it is difficult to sup- Continued from page 7 port the notion that patients received only Author Cohort (n) Outcome p the fluid volumes they needed and not an Lessons from the pediatric Goldstein Single center (22) Survivors 16% FO 0.03 excess amount of fluid. intensive care unit Nonsurvivors 34% FO Limitations and potential The lessons from pediatric nephrologists rationale Gillespie Single center (77) % FO>10% with OR death 0.002 and intensivists emanate from two prac- 3.02 tice perspectives ingrained into pediatri- The observational and focused nature of Foland Single center (113) 3 organ MODS patients 0.01 cians—disease prevention and medication the studies mentioned above cannot be dosing based on patient size. I am not sug- overemphasized. These studies just high- Survivors 9% FO gesting that these perspectives are unique light a potential association between fluid Nonsurvivors 16% FO to pediatrics and absent in internal medi- overdose and mortality, yet do not prove cine, but they are more common in pedi- causality. In addition, the studies only in- 1.78 OR death for each atric training and everyday practice. cluded children who ultimately received 10% FO increase In the area of pediatric AKI and RRT, CRRT at the discretion of the local physi- a concept of relative fluid accumulation cian; CRRT initiation was not directed by Goldstein Multicenter (116) 2+ organ MODS patients 0.002 (percent fluid overload) based on ICU ad- a protocol in any of these studies. Finally, Survivors 14% FO mission weight and timing of renal replace- since these studies involved only CRRT co- Nonsurvivors 25% FO ment based on percent fluid overload and horts, the ability to generalize the findings not BUN concentration has driven exten- to patients without AKI who don’t need <20% FO: 58% survival sive pediatric research in the past decade. RRT is hampered. >20% FO: 40% survival Critically ill children often require ag- Nonetheless, the observations generate gressive fluid and inotropic support to some potential provocative hypotheses to Hayes Single center (76) Survivors 7% FO 0.001 maintain adequate perfusion. Substantial explain the associations. For instance, in Nonsurvivors 22% FO single-center and multicenter pediatric pediatric practice, almost all medications study over this past decade demonstrates are prescribed to patient size, in terms OR death 6.1>20% FO that increasing degrees of relative fluid of body weight or surface area. One can accumulation, or percent fluid overload, imagine a scenario in which a child with Data from over 400 critically ill children demonstrate increased risk at the time of RRT initiation in children gram negative sepsis treated with a third- of mortality at > 10% fluid overload (FO) at CRRT initiation with AKI is independently associated generation cephalosporin dosed on ICU with mortality (Table 1) (15–19). Per- admit weight or historical dry weight is 2004; 8:R204–12. case for using isotonic saline. Pediatr cent fluid overload is calculated by total- actually underdosed as a result of a severely 2. Akcan-Arikan A, Zappitelli M, Loftis 2003; 111:227–30. ing fluid volumes from ICU admission increased volume of drug distribution from LL, Washburn KK, Jefferson LS, Gold- 11. Moritz ML, Ayus JC. Hospital- to RRT initiation using the following excessive fluid accumulation. In this exam- stein SL. Modified RIFLE criteria in acquired hyponatremia: why are equation: ple, it is possible that the antibiotic con- critically ill children with acute kidney there still deaths? Pediatr 2004; %FO = [ ( Fluid Input (L) – Fluid Out- centration is below the pharmacodynamic injury. Kidney Int 2007; 71:1028–35. 113:1395–6. put (L) ) / Patient ICU admission weight profile to eradicate the organism. Another 3. Mehta RL, Kellum JA, Shah SV, et al. 12. Ayus JC, Arieff AI. Postoperative hy- (kg) ] obvious potential hypothesis would posit Acute Kidney Injury Network: report ponatremia. Ann Intern Med 1997; an association between excessive fluid ac- of an initiative to improve outcomes 126:1005–6. In all of these studies, estimated GFR, cumulation and impaired oxygenation or in acute kidney injury. Crit Care 2007; 13. Palevsky PM, Zhang JH, O’Connor patient age and size, urine output, diuretic other pulmonary mechanics, especially in 11:R31. TZ, et al. Intensity of renal support in use, and severity of illness did not differ be- patients with capillary leak syndromes such 4. Chertow GM, Burdick E, Honour critically ill patients with acute kidney tween survivors and nonsurvivors. Analysis as sepsis. M, Bonventre JV, Bates DW. Acute injury. N Engl J Med 2008; 359:7– of different percent thresholds from these Final thoughts kidney injury, mortality, length of 20. studies suggests mortality increases from stay, and costs in hospitalized patients. 14. Bellomo R, Cass A, Cole L, et al. In- 40 percent to 60 percent in children with This article promotes a concept of fluid J Am Soc Nephrol 2005; 16:3365–70. tensity of continuous renal-replace- >10–20 percent fluid overload at RRT ini- overdose in critically ill children with AKI. 5. Mishra J, Dent C, Tarabishi R, et ment therapy in critically ill patients. tiation, independent of patient severity of Inherent in this concept is the importance al. Neutrophil gelatinase-associated N Engl J Med 2009; 361:1627–38. illness (Table 1). Thus, the pediatric com- of regarding fluid as a medication with lipocalin (NGAL) as a biomarker for 15. Foland JA, Fortenberry JD, Warshaw munity now has data from over 400 chil- respect to both composition and volume acute renal injury after cardiac surgery. BL, et al. Fluid overload before con- dren in five studies that consistently show (dose). Future investigation will require Lancet 2005; 365:1231–8. tinuous hemofiltration and survival a potential fluid overdose threshold at >20 prospective evaluation of different fluid 6. Zappitelli M, Washburn KK, Arikan in critically ill children: a retrospec- percent positive accumulation from ICU dosing strategies beyond the initial resus- AA, et al. Urine neutrophil gelatinase- tive analysis. Crit Care Med 2004; admission to CRRT initiation. citation effort to optimize care for all criti- associated lipocalin is an early marker 32:1771–6. The Prospective Pediatric Continuous cally ill patients. of acute kidney injury in critically ill 16. Gillespie RS, Seidel K, Symons JM. Renal Replacement Therapy (ppCRRT) children: a prospective cohort study. Effect of fluid overload and dose of re- Registry Group recently conducted an Stuart Goldstein, MD, is associate professor of Crit Care 2007; 11:R84. placement fluid on survival in hemo- analysis of its entire 340-patient cohort us- pediatrics at Baylor College of Medicine and 7. Waikar SS, Bonventre JV. Biomark- filtration. Pediatr Nephrol 2004. ing a tripartite classification for percent flu- medical director, Renal Dialysis Unit and ers for the diagnosis of acute kidney 17. Goldstein SL, Currier H, Graf C, Co- id overload (FO) at CRRT initiation: < 10 Pheresis Service, Texas Children’s Hospital. injury. Nephron Clin Pract 2008; sio CC, Brewer ED, Sachdeva R. Out- percent FO, 10–20 percent FO, and > 20 He is also founder and principal investigator 109:c192–7. come in children receiving continuous percent FO (Sutherland S. et al, accepted of the Prospective Pediatric Continuous Renal 8. Wiedemann HP, Wheeler AP, Ber- venovenous hemofiltration. Pediatr for publication in Am J Kidney Dis). Replacement Therapy (ppCRRT) Registry in nard GR, et al. Comparison of two 2001; 107:1309–12. One could still potentially argue that Houston, Texas. fluid-management strategies in acute 18. Goldstein SL, Somers MJ, Baum MA, the patients actually “needed” the fluids lung injury. N Engl J Med 2006; et al. Pediatric patients with multi- they received. However, in a published References 354:2564–75. organ dysfunction syndrome receiving multicenter study from the ppCRRT, the 1. Bellomo R, et al. Acute renal fail- 9. Rivers E, Nguyen B, Havstad S, et continuous renal replacement therapy. mean central venous pressure (CVP) for ure—definition, outcome measures, al. Early goal-directed therapy in Kidney Int 2005; 67:653–8. survivors was 16.5 + 6.1 mm H2O versus animal models, fluid therapy and in- the treatment of severe sepsis and 19. Hayes LW, Oster RA, Tofil NM, 21.2 + 6.6 mm H2O for nonsurvivors (18). formation technology needs: the Sec- septic shock. N Engl J Med 2001; Tolwani AJ. Outcomes of critically Current recommendations for early goal- ond International Consensus Con- 345:1368–77. ill children requiring continuous re- directed fluid resuscitation advocate fluid ference of the Acute Dialysis Quality 10. Moritz ML, Ayus JC. Prevention of nal replacement therapy. J Crit Care administration until a CVP of 8. Since the Initiative (ADQI) Group. Crit Care hospital-acquired hyponatremia: a 2009; 24:394-400. DecemberFebruary 20092010 | ASN Kidney News | 9

Optimizing Therapeutic Options in Acute Renal Failure—An Ever Elusive Goal By Orfeas Liangos and Bertrand Jaber

he main therapeutic intervention portant to note, however, that the minimal has become popular among nephrologists ARF would be helpful. This question of Tfor treatment of acute renal failure effective dose of RRT required to optimize and intensivists due to its superior tolera- course, as simple as it may seem, has been (ARF), extracorporeal renal replacement survival in ARF is not yet known. bility and capacity for volume and solute difficult to answer, because patients who therapy (RRT) was introduced over half a control, especially in critically ill patients typically require CRRT, and therefore century ago. RRT has changed the natural Continuous RRT (CRRT) versus with circulatory compromise. CRRT re- are set to benefit most from it, are those history of this disorder from a devastating intermittent RRT (IRRT) quires high resource and personnel uti- who cannot tolerate IRRT, namely the condition that almost invariably led to the The importance of CRRT as a modality lization and there is a high mortality in hemodynamically unstable, making it patient’s demise, to a manageable compli- for the treatment of critically ill patients patients chosen to receive CRRT. Com- impossible to randomize such patients to cation. Unfortunately, further improve- with ARF is presented in detail by Tol- paring in a controlled fashion the effects IRRT. On the other hand, patients who ment in survival rates among patients wani in this issue. (see page 12). CRRT of CRRT versus IRRT on mortality in Continued on page 10 with ARF have at best been incremental, with mortality rates remaining unacceptably high (1–3). Optimization of RRT carries the promise of improving clinical outcomes. Sever- al treatment characteristics have been the subject of clinical investigations, including RRT intensity and type of modality. Two recently published trials addressed dialysis intensity and were unprecedented in scale and quality to any previously published work related to ARF (4,5). Unfortunate- ly, the results of these trials were negative, finding no improvement in survival with higher treatment intensity. Previous, smaller scale trials addressing questions of modality and timing were similarly unre- vealing. In addition to understanding the reasons why these characteristics of RRT seemingly have no effect on the survival of patients with ARF, this brief review raises the question of timing of dialysis as a new frontier with the potential for substantially improving the outcome of patients with ARF and for advancing the field of critical care nephrology further.

Intensity of RRT It is logical to assume that increasing the intensity or dose of therapy would improve outcome in patients with ARF, i.e., the more therapy is administered, the better the correction of electrolyte and acid base disturbances, as well as the control of extracellular fluid volume and removal of uremic retention solutes, which in turn, leads to improved outcomes. However, it has been difficult, if not impossible, to demonstrate such a cause-and-effect relationship. Several small, single-center studies on this topic have reported conflicting results and great heterogeneity of patient population, RRT modality, and design (6–11). Moreover, to date, there are no well-established and validated methods to measure intensity of RRT in ARF. Clearly, well designed and executed, adequately powered multicenter, randomized controlled trials have been lacking until two such trials were recently published demonstrating no measurable benefit in the higher intensity treatment arms (4,5). Despite these negative results, it has recently been argued that tools for quality assurance and performance improvement should be adopted for RRT rendered to patients with ARF, to ensure that the therapy delivered is at least as intensive as that provided in the lower-intensity groups of these two trials (12). It is im- Acute Kidney Injury: The Road to Recovery

Therapeutic Options 3. Waikar SS, et al. Declining mortality in patients with acute renal fail- Continued from page 9 ure, 1988 to 2002. J Am Soc Nephrol are able to tolerate either of the modali- 2006; 17:1143–50. ties, and thus would be good candidates 4. Palevsky PM, et al. Intensity of renal for randomization, are not likely to ben- support in critically ill patients with efit from CRRT, which is more invasive acute kidney injury. N Engl J Med and more prone to untoward effects than 2008; 359:7–20. IRRT. This dilemma is underscored by 5. Bellomo R, et al. Intensity of con- the lack of a mortality benefit for CRRT tinuous renal-replacement therapy compared with IRRT in prospective ran- in critically ill patients. N Engl J domized controlled trials as discussed by Med 2009; 361:1627–38. Tolwani in this issue. 6. Paganini EP, et al. Establishing a di- In summary, CRRT, once a promis- alysis therapy/patient outcome link ing new method that allowed for the first in intensive care unit acute dialysis time the administration of effective RRT for patients with acute renal failure. and correction of metabolic and volume Am J Kidney Dis 1996; 28:S81– derangements in the most severely ill, S89. did not prove superior to IRRT in di- 7. Ronco C, et al. Effects of different rect comparison. However, CRRT will doses in continuous veno-venous continue to have an important place in haemofiltration on outcomes of the treatment armamentarium for criti- acute renal failure: a prospective cally ill patients in whom IRRT is not randomised trial. Lancet 2000; an option. 356:26–30. 8. Bouman CS, et al. Effects of early Timing of RRT high-volume continuous venovenous Timely institution of RRT in ARF is fun- hemofiltration on survival and re- damental to achieving treatment goals, covery of renal function in intensive namely solute clearance and fluid bal- care patients with acute renal failure: ance, while awaiting recovery of kidney a prospective, randomized trial. Crit function. Currently indisputable indica- Care Med 2002; 30:2205–11. tions for RRT include persistent hyper- 9. Tolwani AJ, et al. Standard versus kalemia, severe metabolic acidosis, and high-dose CVVHDF for ICU-relat- hypervolemia unresponsive to conserva- ed acute renal failure. J Am Soc Ne- tive measures; uremic serositis; bleed- phrol 2008; 19:1233–8. a prospective need for RRT—might be ing diathesis; and severe encephalopa- This systematic review suggested that 10. Schiffl H, Lang SM, Fischer R. more valid inclusion criteria. thy (13). Beyond these indications and early institution of RRT might have a Daily hemodialysis and the outcome Finally, a large observational study to when azotemia is the sole abnormality, it beneficial effect on survival of patients of acute renal failure. N Engl J Med further characterize practice patterns and is unclear when RRT should be started. with ARF. Besides the design and meth- 2002; 346:305–10. variation in RRT care internationally “Early” or “prophylactic” RRT histori- odological concerns of the studies includ- 11. Saudan P, et al. Adding a dialysis might help identify more robust criteria cally described the initiation of dialysis ed, the most commonly used criterion dose to continuous hemofiltration for timing of RRT, which in turn, might therapy before nitrogenous waste prod- for “early” versus “late” initiation of RRT increases survival in patients with possibly help develop best practices of ucts reached some arbitrary predefined was an arbitrary cutoff of blood levels of acute renal failure. Kidney Int 2006; care. In summary, after completion and “critical” blood value, regardless of other retention solutes, rather than an objective 70:1312–7. publication of two definitive, large-scale indications. Older reports suggested that time variable from onset of renal failure 12. Palevsky PM. Renal support in clinical trials addressing RRT intensity early initiation of RRT might improve to RRT. This represents a fundamental acute kidney injury—how much and modality in ARF, a case is made survival (14,15), but this has not been design flaw since not only the time, but is enough? N Engl J Med 2009; for the next “RRT frontier” that might confirmed in recent years. also the velocity of uremic retention sol- 361:1699–701. promise improvement in outcomes, i.e., We performed a comprehensive re- ute accumulation such as urea, related in 13. Teehan G, Mehta R, Chertow G. the timing of RRT initiation. Based on view of all available data on this topic part to the degree of protein catabolism, Dialytic management for acute renal the results of a recent systematic review, by conducting a systematic review and determine its blood level. failure, in Chronic Kidney Disease, we argue in favor of designing and car- meta-analysis to examine the effect of Overall, these findings require confir- Dialysis and Transplantation: A Com- rying out a large-scale, definitive clinical early initiation of RRT on survival (16). mation by a large multicenter randomized panion to Brenner and Rector’s The trial on timing of RTT initiation in ARF, Again, the heterogeneity of the individu- controlled trial primarily designed to as- Kidney, B Pereira and P Blake, eds. while avoiding potential pitfalls and al studies was formidable. They included sess the effect of timing of RRT on surviv- Elsevier Saunders: Philadelphia, PA. study design flaws. randomized controlled trials, trials with al in ARF. A trial designed to answer this 2005; 807–822. sequential treatment assignment, and question should be adequately powered. 14. Salisbury P. Timely versus delayed prospective and retrospective compara- If one conservatively assumes an overall Orfeas Liangos, MD, FASN, and Ber- use of the articial kidney. Arch Intern tive cohort studies. In addition, the stud- hospital mortality rate of 25 percent in trand Jaber, MD, FASN, are with the De- Med 1958; 101:690–701. ies spanned more than four decades. In patients with ARF regardless of dialysis partment of Medicine, Division of Neph- 15. Parsons FM, et al. Optimum time the primary analysis, which included requirement (3,17) and a hypothesized 36 rology, St. Elizabeth’s Medical Center, in for dialysis in acute reversible renal four randomized controlled trials and percent mortality risk reduction derived Boston. Liangos is also with the Division failure. Description and value of an one quasi-randomized controlled trial from the aforementioned meta-analysis of Nephrology, Klinikum Coburg, Coburg, improved dialyser with large surface totaling 270 patients, early RRT was as- (16), a sample size of approximately Germany. area. Lancet 1961; 1:129–134. sociated with a 36 percent mortality risk 1100 would be required to achieve 90 16. Seabra VF, et al. Timing of Renal References reduction (relative risk = 0.64; 95% con- percent power, which is a feasible goal. Replacement Therapy Initiation in fidence interval = 0.40, 1.05; p = 0.08). Much more thought and deliberation, 1. Levy EM, Viscoli CM, Horwitz RI. Acute Renal Failure: A Meta-analy- In a secondary, more inclusive analysis however, must be spent on selecting the The effect of acute renal failure on sis. Am J Kidney Dis 2008; 52:272– comprising 18 comparative cohort stud- appropriate patient population and entry mortality. A cohort analysis. J Am 284. ies and totaling 2108 patients, early RRT criteria. Clearly, an arbitrary cutoff value Med Assoc 1996; 275: 1489–94. 17. Liangos O, et al. Epidemiology and was associated with a 28 percent mortal- for urea or similar retention solutes will 2. Xue, JL, et al. Incidence and mortal- Outcomes of Acute Renal Failure ity risk reduction (relative risk = 0.72; not suffice. Other measures—including ity of acute renal failure in Medicare in Hospitalized Patients: A Na- 95% confidence interval = 0.64, 0.82; p novel urinary or blood markers confer- beneficiaries, 1992 to 2001. J Am tional Survey. Clin J Am Soc Nephrol < 0.001). ring prognostic discrimination toward Soc Nephrol 2006; 17:1135–42. 2006:43–51. ASNKidneyNow-ynhhad2010:Layout 1 1/11/10 2:12 PM Page 1

Neera Dahl, MD, PhD, and Rex Mahnensmith, MD, examine a CT scan from a PKD patient.

The genetics behind kidney disease are intricate and multifac- eted. Only a few medical institutions in the country have the commitment to understanding and treating inherited kidney diseases and the resources to house the prestigious George M. O’Brien Kidney Research Center and a Polycystic Kidney Disease (PKD) Research Center, all supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We are one of those centers.

Our researchers have discovered over fifteen genes for human diseases affecting the kidney and blood pressure. These discov- Research Excellence, eries cover the gamut from rare disorders of blood pressure regulation through sodium and potassium handling such as Clinical Leadership and Liddle’s syndrome, pseudohypoaldosteronism type II and Bartter’s and Gittelman’s syndromes to such common inherited kidney diseases as polycystic kidney disease (PKD). While our a Commitment to Our researchers are now seeking to translate these findings to treatments for PKD and other disorders, our nephrologists are Patients using these discoveries to help our patients lead healthy and fulfilling lives.

Being at the forefront of clinical research and treatments means that our physicians and surgeons are furthering the current understanding of kidney disease. Most importantly, it means they are positioned to provide the best care possible to our patients.

Yale-New Haven Hospital is the primary teaching hospital of Yale School of Medicine and is ranked among the nation’s best hospitals by U.S.News & World Report. www.ynhh.org Acute Kidney Injury: The Road to Recovery

Another concern is that any difference in hemodynamics between ing patients who received an adequate trial the study only required the two modalities. Uehlinger et al. (4) re- of therapy with no crossover (92.3 percent Continuous Renal achieving a mean urea ported a similar frequency of hypotension versus 59.4 percent; p < 0.01). concentration of 84 mg/ between IRRT and CRRT. Two recent large epidemiologic studies dL or less, which is a low The VA/NIH Acute Renal Failure Trial have also reported increased rates of renal target according to cur- Network (ATN) study by Palevsky et al. recovery in patients on CRRT. In the Be- Replacement Therapy: (5) aimed to determine the optimal inten- ginning and Ending Supportive Therapy rent standards. This resulted in metabolic con- sity of renal replacement therapy (RRT) in (BEST) kidney trial (7), a multinational, trol not being achieved critically ill patients with AKI and at least prospective, epidemiologic study of AKI Modality of Choice in the any better with CRRT one other failing organ or sepsis. The study in the ICU including over 30,000 patients than with IRRT. Finally, compared two strategies for the manage- in 23 countries, 1218 patients received patients crossed over ment of RRT in critically ill patients with RRT. Although no mortality difference Intensive Care Unit? from CRRT to IRRT due AKI. Both treatment strategies employed was detected between patients treated with to inadequate metabolic both conventional IRRT in patients whose CRRT compared to IRRT, dialysis inde- control from technical blood pressure was stable and either sus- pendence at hospital discharge was higher By Ashita Tolwani issues such as inability tained low-efficiency dialysis (SLED) or after CRRT (85.5 percent versus 66.2 per- to keep the circuit patent CRRT in patients who were hemodynami- cent; p < 0.0001). cute kidney injury (AKI) is a frequent and complications of anticoagulation. cally unstable. Bell et al. (8) retrospectively studied Acomplication in critically ill patients Multiple published meta-analyses of In one strategy, IRRT and SLED were 2202 patients treated with RRT for AKI and is associated with a high mortality RCTs comparing CRRT with IRRT in provided three times per week, and CRRT from 32 ICUs in Sweden. CRRT was rate. Continuous renal replacement thera- ICU patients with AKI also have not dem- was dosed to provide a clearance of approx- used for 1911 patients and IRRT for 291. py (CRRT) represents a spectrum of dialy- onstrated a survival benefit with CRRT. imately 20 mL/kg/h. In the other treat- Ninety-day mortality was not significantly sis modalities developed in the 1980s spe- However, the validity of the data from ment arm, IRRT and SLED were provided different between the two groups. Among cifically for the management of critically ill the studies is dubious because of issues six times per week and CRRT was dosed survivors, 8.3 percent treated with CRRT patients with AKI who could not tolerate related to study design, such as exclusion to provide a clearance of approximately 35 became dialysis dependent compared to traditional intermittent renal replacement of patients with hemodynamic instability, mL/kg/h. Overall, there was no significant 16.5 percent treated with IRRT. Multi- therapy (IRRT). Over the years, CRRT improper randomization, differences in improvement in patient outcomes with variate analysis showed that the adjusted has found widespread use and acceptance baseline characteristics between arms, and the more intensive treatments. Notably, odds ratio (OR) of dialysis dependence due to its ability to provide effective vol- high crossover rates between modalities. only 4.6 percent of treatments performed in IRRT was 2.60 compared with CRRT. ume and metabolic control in hemody- Finally, no trial standardized the dose de- in hemodynamically unstable patients Moreover, in patients who did develop namically unstable patients. livered or the timing of initiation. Notably, were SLED. This low utilization of SLED chronic dialysis dependence, the subse- Despite its physiologic benefits, rand- even though the meta-analysis by Bagshaw in hemodynamically unstable patients oc- quent survival rate was significantly lower omized controlled trials (RCTs) have not et al. (2) found no statistical difference in curred despite physicians’ ability to pre- in patients treated with HD compared to shown a mortality benefit of CRRT over survival between the two modalities, there scribe either SLED or CRRT in the study. CRRT-treated patients. IRRT. Vinsonneau et al. performed the was a higher occurrence of hemodynamic Moreover, hypotension was a more serious In the ATN trial by Palevsky et al. (5), largest RCT comparing the effect of IRRT instability and greater cumulative fluid complication among patients treated with over 70 percent of patients in both treat- IRRT. Approximately 1.7 percent of all ment strategy arms (intensive and less in- IRRT treatments required discontinuation tensive) had no recovery of kidney function of therapy due to hypotension compared by 28 days and were dialysis dependent. to only 0.7 percent of CRRT/SLED treat- This is quite high compared to other tri- ments. These differences were observed de- als, given that patients with CKD were spite the fact that the IRRT patients were excluded. It is important to realize that the considered hemodynamically stable. two arms consisted of a mix of patients on The rate of renal recovery at hospital dis- CRRT, SLED, and IRRT. In the RENAL charge was substantially lower in the ATN Replacement Therapy Study of dose inten- study than what has been reported previ- sity (9), patients were randomized to CV- ously, even with the exclusion of patients VHDF at 25 mL/kg/h versus CVVHDF with moderate to severe CKD. A possible at 40 mL/kg/h. explanation is that the high rate of severe In contrast to the ATN trial, the RE- hypotension in the IRRT patients may NAL investigators reported 14 percent of have contributed to the relatively low rate patients were dialysis dependent in both of renal recovery. Finally, fluid removal was treatment arms by 28 days. Unlike the much less aggressive in the IRRT patients ATN trial, the two intensity arms only in- (approximately 6–9 L/week) compared to cluded patients on CRRT, and not on oth- that in the CRRT patients (greater than 20 er modalities. Moreover, unlike the ATN L/week). These findings support CRRT as trial, the RENAL study included patients the standard of care for hemodynamically with CKD. This finding supports the no- and CRRT on patient survival in 360 pa- balance in the IRRT groups. unstable patients with AKI. tion that CRRT leads to higher rates of tients at several French institutions (1). Al- If current studies cannot demonstrate renal recovery. though the investigators found no signifi- a survival benefit of CRRT compared to Renal recovery Fluid management cant difference in patient survival, several IRRT, are there other outcome benefits for Renal recovery is another important out- aspects of the study limit the applicability CRRT? come for patients with AKI and may be In critically ill patients, nutritional require- of the results to general clinical practice. affected differently by RRT modality. Fail- ments and the use of intravenous medi- Hemodynamic stability First, patients with pre-existing chronic ure to recover renal function after AKI has cations necessitate the administration of kidney disease (CKD) were excluded. Sec- Hypotension is one of the most common both short- and long-term implications large amounts of fluid, resulting in exces- ond, for unclear reasons, survival progres- complications associated with IRRT, oc- with respect to morbidity and health care sive volume overload. Excessive fluid ad- sively increased in the IRRT group while curring in approximately 20 percent to costs. Multiple observational studies and ministration can cause pulmonary edema, it remained constant in the CRRT group, 30 percent of all treatments. This compli- one randomized study support greater hypoxia, and the need for mechanical ven- suggesting systematic changes occurred in cation can lead to further organ ischemia rates of renal recovery in patients with tilation. In addition, excessive fluid accu- the delivery of IRRT. Third, maintaining and injury. Several observational studies AKI requiring CRRT compared to IRRT. mulation can impair cardiac function and hemodynamic stability in the IRRT group and randomized studies have demonstrat- Mehta et al. randomized 166 patients in renal perfusion. required longer sessions with a mean IRRT ed better hemodynamic stability associated four centers to receive CRRT or IRRT Several observational studies have treatment duration of 5.2 h per session. with CRRT. In a small RCT, Augustine et and demonstrated no difference for hos- shown a direct relationship between fluid As such, the applicability of the IRRT al. (3) reported a significant reduction in pital mortality using multivariate logistic accumulation and mortality in critically ill results to the “real world,” where IRRT mean arterial pressure (MAP) during IRRT, regression analysis (6). However, CRRT patients. The Acute Respiratory Distress treatment times are significantly less than which was not observed during CRRT. On was associated with a significantly higher Syndrome (ARDS) clinical trial network this on a routine basis, is questionable. the other hand, others have not reported rate of complete renal recovery in surviv- (10) demonstrated that a more liberal fluid DecemberFebruary 20092010 | ASN Kidney News | 13 administration regimen (to CVP of about Internationally, the multinational epi- AKI. This is due to the recognition by its centre randomised trial. Lancet 2006; 12 cm H2O) resulted in greater lung func- demiologic BEST Kidney Study (7) re- users of the advantages of CRRT in vol- 368:379–385. tion impairment than a more conserva- ported that CRRT was the initial modality ume management and hemodynamic sta- 2. Bagshaw SM, Berthiaume LR, Dela- tive approach (target CVP of about 8 cm used in 80 percent of AKI treatments in bility in the critically ill patient. ney A, Bellomo R. Continuous versus H2O). Although survival at 60 days was the ICU, followed by IRRT (17 percent). intermittent renal replacement thera- not significantly different between the two Finally, a recent survey of an international Ashita Tolwani, MD, is associate professor of py for critically ill patients with acute groups, ventilator-free days and ICU-free multidisciplinary cohort of renal practi- medicine in the division of nephrology at the kidney injury: a meta-analysis. Crit days were both significantly lower in the tioners showed that CRRT had become University of Alabama at Birmingham. Care Med 2008; 36:610–7. conservative group. Moreover, the per- the standard for AKI support outside of 3. Augustine JJ, Sandy D, Seifert TH, centage of patients requiring dialysis in the the United States (15). References Paganini EP: A randomized control- conservative group (10 percent) was lower In summary, although there is a call for 1. Vinsonneau C, et al. Continuous led trial comparing intermittent with than in the liberal group (14 percent). more outcomes-based RCTs, mounting venovenous haemodiafiltration versus continuous dialysis in patients with In the Program to Improve Care in evidence published in the last decade has intermittent haemodialysis for acute ARF. Am J Kidney Dis 2004; 44:1000– Acute Renal Disease (PICARD) database propelled CRRT to become the preferred renal failure in patients with multiple- 1007. (11) of critically ill patients with AKI modality of choice in the ICU patient with organ dysfunction syndrome: a multi- Continued on page 14 in whom nephrology consultation was sought, volume overload in patients with AKI was independently associated with increased mortality. Fluid overload was defined as a percentage of fluid accumulation >10 percent over baseline weight at hospital admission. In 542 patients in whom fluid data were available, those with a >10 percent accumulation had a significantly higher risk of death at 30 and 60 days of enrollment. Within the group requiring RRT, those with greater fluid accumulation at dialysis initiation had worse outcomes with an OR for death (adjusted for severity of illness and dialysis modality) of 2.07 (95 percent CI 1.27–3.37). Patients who remained fluid overloaded had a higher mortality rate that was proportional to the degree of fluid accumulation. Volume control was significantly better in those treated with CRRT versus IRRT. Importantly, the correction of volume accumulation had a positive effect on survival, making this an important therapeutic target in critically ill patients with AKI. Prospective randomized studies with different regimens of fluid administration are necessary to know their effects on mortality and the outcome of AKI in critically ill patients. Augustine et al. (3) compared net fluid balance provided by IRRT and CRRT in an RCT. Even over a relatively short three- day period, significant differences were ob- BRCU Online served. In the CRRT group, a net loss of 4005 mL (approximately 4 kg) occurred, ASN Distance Learning for CME while the IRRT group sustained a net gain of 1539 mL (approximately 1.5 kg) on an average basis. Although RCTs have not been consistent in this area, these data are Access online version of the corroborated by other studies and general ASN Board Review Course & Update 2009 clinical practice and represent one of the benefits of CRRT over conventional IRRT. The capacity to adjust fluid balance on an Download presentations or view them with streaming video hourly basis, even in hemodynamically unstable patients, is largely responsible for the growing popularity of CRRT. In a survey by the National Kidney Learn more and register at www.asn-online.org Foundation 10 years ago, IRRT was de- termined to be the preferred modality for renal support for AKI, used in more than 75 percent of cases by most nephrologists (12). More recently, a survey of intensivists and nephrologists who participated in the multicenter ATN study revealed that CRRT accounted for 36 percent of prescribed RRT treatments (13). In the multicenter PICARD study (14), 60 percent of dialyzed patients had received CRRT for some or all of their renal support. Acute Kidney Injury: The Road to Recovery

CRRT 6. Mehta RL, et al. A randomized clinical 10. Wiedemann HP, Wheeler AP, Ber- nephrologists. The National Kidney trial of continuous versus intermittent nard GR, Thompson BT, Hayden D, Foundation Council on Dialysis. Am Continued from page 11 dialysis for acute renal failure. Kidney deBoisblanc B, Connors AF Jr, Hite J Nephrol 1999, 19:377–82. 4. Uehlinger DE, et al. Comparison of Int 2001, 60:1154–1163. RD, Harabin AL: Comparison of 13. Overberger P, Pesacreta M, Palevsky continuous and intermittent renal 7. Uchino S, et al. Acute renal failure in two fluid-management strategies in PM, et al. Management of renal re- replacement therapy for acute renal critically ill patients: A multinational, acute lung injury. N Engl J Med 2006, placement therapy in acute kidney in- failure. Nephrol Dial Transplant 2005, multicenter study. J Am Med Assoc 354:2564–2575. jury: a survey of practitioner prescrib- 20:1630–1637. 2005, 294:813–818. 11. Bouchard J, Soroko SB, Chertow ing practices. Clin J Am Soc Nephrol 5. VA/NIH Acute Renal Failure Trial 8. Bell M, et al. Continuous renal re- GM, Himmelfarb J, Ikizler TA, Pa- 2007, 2:623–30. Network, Palevsky PM, Zhang JH, placement therapy is associated with ganini EP, Mehta RL; Program to 14. Mehta RL, Pascual MT, Soroko S, et O’Connor TZ, Chertow GM, Crow- less chronic renal failure than inter- Improve Care in Acute Renal Dis- al. Spectrum of acute renal failure in ley ST, Choudhury D, Finkel K, mittent haemodialysis after acute re- ease (PICARD) Study Group. Fluid the intensive care unit: the PICARD Kellum JA, Paganini E, Schein RM, nal failure. Intensive Care Med 2007, accumulation, survival and recovery experience. Kidney Int 2004, 66: Smith MW, Swanson KM, Thomp- 33:773–80. of kidney function in critically ill pa- 1613–21. son BT, Vijayan A, Watnick S, Star 9. The RENAL Replacement Therapy tients with acute kidney injury. Kidney 15. Ricci Z, et al. Practice patterns in the RA, Peduzzi P. Intensity of renal sup- Study Investigators. Intensity of con- Int 2009; 76:422–7. management of acute renal failure in port in critically ill patients with acute tinuous renal replacement therapy 12. Mehta RL, Letteri JM. Current sta- the critically ill patient: an interna- kidney injury. N Engl J Med 2008; in critically ill patients. N Eng J Med tus of renal replacement therapy for tional survey. Nephrol Dial Transplant 359:7–20. 2009, 361:1627-38. acute renal failure. A survey of US 2006, 21:690–6. Biomarkers of Acute Kidney Injury: Dawning of a New Era By Joseph Bonventre

he kidney community has devoted a jury rather than a secondary consequence tinued exposure to the agent in question. ker of kidney injury. Urine has the advan- Tgreat deal of effort to building consen- of injury—a reduction in GFR, as manifest It is also likely that some of these biomar- tage of being readily available noninvasively sus regarding the definition of acute kidney by an increase in SCr. kers will be useful not only for AKI, but and amenable to straightforward testing by injury (AKI). This has resulted in RIFLE In commenting on a major initiative of also to monitor severity and progression of both health care professionals and patients classification and AKI network (AKIN) the FDA that focuses on biomarkers, Janet glomerular or tubular-interstitial disease in themselves. Given its normally low protein criteria focused on changes in serum cre- Woodcock, MD, deputy commissioner for patients with chronic kidney disease. content, there is also less interaction in the atinine (SCr) and rate of urine production. operations and head of FDA’s Critical Path Over the years, a large number of bi- biomarker assay with proteins. On the oth- These changes in SCr are important and Initiative, said: “Most researchers agree that omarkers of kidney injury have been sug- er hand, large variations in physical chemi- have been shown to be predictive of out- a new generation of predictive biomarkers gested, yet for various reasons, none have cal properties of urine may affect reliability come in a number of studies. SCr changes, would dramatically improve the efficiency been routinely accepted in animal or clini- of the test for the biomarker and/or stabil- however, can be affected by a large number of product development, help identify cal studies. In some cases, the biomarker ity of the analyte. of things unrelated to kidney injury, in- safety problems before a product is on the was felt to be too sensitive, not sensitive Given the importance to the clinical, cluding drug interference with secretion market (and even before it is tested in hu- enough, or too nonspecific. In other cases, pharmaceutical, and regulatory commu- of creatinine into the tubule, muscle mass, mans), and facilitate the development of the biomarker was unstable with storage. nities motivated by early intervention and gender, age, and renal reserve, a measure of new types of clinical trials that will pro- More recently, however, there have been a safer therapies, there has been a great deal how much the kidney can compensate for duce better data faster” (2). The FDA has number of advances in the application of of activity devoted to examining the role of injury. provided guidance that a biomarker can be biomarkers to AKI. various potential biomarkers of kidney in- Kidney injury, which leads to a reduc- considered “valid” if (i) it is measured in an jury in both animals and humans. Biomar- tion in GFR, is not immediately followed analytical test system with well established Promising biomarkers kers have been proposed to reflect injury to by an increase in SCr. This lag time greatly performance characteristics and (ii) there is A limited number of biomarkers are cur- various parts of the nephron or to reflect impedes the early diagnosis of AKI, delays an established scientific framework or body rently being evaluated by a number of interstitial disease (5), although in many therapy, and impairs our ability to test new of evidence that elucidates the physiologic, groups, and clinically useful reagents have cases the specificity for particular nephron therapies early in the course of the disease pharmacologic, toxicologic, or clinical sig- been developed. Some of the most prom- sites has not been sufficiently studied. when AKI is much more likely to be ame- nificance of the test result (3). ising urinary biomarkers for AKI include: Ischemia/reperfusion injury and most nable to interventions that might alter its We need better biomarkers to diagnose microalbuminuria, kidney injury mole- tubular toxins have as their primary site of natural history. SCr concentration can AKI earlier, to predict outcome in a patient cule-1 (KIM-1), N-acetyl ß-D glucosami- injury the proximal tubule. If in some cases also increase due to functional decreases in with AKI with standard therapy, and to nidase (NAG), neutrophil gelatinase as- the primary site of injury is more distal GFR that are not associated with tubular identify who will respond to an interven- sociated lipocalin (NGAL), cystatin C, along the nephron, the proximal tubule is injury. This is the case in prerenal azotemia. tion and whether the intervention is work- L-fatty acid binding protein (L-FABP), and often also secondarily involved. Although It has thus been recognized for a number of ing. In addition, better biomarkers will interleukin-18 (4). there are some important exceptions to years that new biomarkers of injury would permit better stratification of patients for Translational biomarkers that can be this generalization, such as lithium, whose be very desirable. A “kidney troponin,” for clinical trials and potentially lead to defi- measured in blood or urine in both experi- toxicity is predominantly distal nephron- example, would allow for the identification nition of new therapeutic targets for AKI. mental animals and humans are of particu- related, in general a biomarker sensitive of true injury to the kidney as troponin A good predictive biomarker will have a for proximal injury will be useful for many lar interest. It may be possible to draw on does for the myocardium. significant effect on evaluation of potential clinical scenarios as well as very useful in the experimental information obtained for A biomarker is defined as a characteristic therapies because it will enable the identi- safety monitoring and assessment. that can be objectively measured and evalu- fication of subgroups of patients who will such biomarkers in animals to help guide the use and interpretation of biomarker ated as an indicator of normal biologic or have a high incidence of kidney injury Kidney biomarkers in drug studies in humans. Biomarkers that have pathogenic processes of pharmacological and hence reduce the number of patients approval responses to a therapeutic intervention (1). needed to study in order to test potential been well studied and characterized as very Examples of biomarkers are proteins; lip- therapeutic strategies. sensitive biomarkers of injury in animals, if The importance of the identification of ids; genomic, metabolomic, or proteomic A clinically useful new kidney biomar- they function similarly in man, may make kidney injury biomarkers for patient safe- patterns; imaging determinations; electri- ker will improve the sensitivity and spe- it possible to monitor safety and efficacy ty was manifest quite clearly in July 2008 cal signals; and cells present on a urinalysis. cificity for the detection of renal injury and in clinical trials when the ability to obtain when the FDA and the European Medi- Having a biomarker that directly reflects discriminate renal injury, which may have kidney tissue is severely constrained and cines Agency (EMEA) agreed to accept injury and is easily measured from fluid long-term consequences, from adaptive re- when the severity of the injury early on is data for seven kidney toxicity biomarkers that is easily obtained, such as blood or sponses that may be reflected by transient insufficient to result in an increase in SCr. as part of the drug approval process. This urine, would introduce a new paradigm in BUN/creatinine increases that return to Blood and urine are two convenient flu- was the first time that a single application which we would be directly monitoring in- pre-elevated levels over time, even with con- ids in which to measure a particular biomar- was submitted to both regulatory agencies. DecemberFebruary 20092010 | ASN Kidney News | 15

These important additions to the drug ap- disease. This will add to the armamen- Partners Healthcare to Johnson and Johnson, Center for Devices and Radiological proval process resulted from a historic col- tarium of personalized medicine by better Inc., and Genzyme Corp. Health (CDRH): Guidance for Indus- laboration among pharmaceutical compa- informing interventional, diagnostic, and References try. Pharmacogenomic data submis- nies, academia, and regulatory agencies, therapeutic decision-making to minimize 1. Group BDW. Biomarkers and surro- sions. 2005; 1–22 comprising the Predictive Safety Testing kidney injury and optimize interventional gate endpoints: preferred definitions 4. Vaidya VS, Ferguson MA, Bonventre Consortium (PSTC). The seven biomar- strategies. I am convinced that better kid- and conceptual framework. Clin Phar- JV. Biomarkers of acute kidney injury. kers found in urine—KIM-1, albumin, ney injury biomarkers will provide us with macol Ther 2001; 69:89–95. Annu Rev Pharmacol Toxicol 2008; total protein, ß2-microglobulin, cystatin better tools that will result in better out- 2. FDA. FDA Unveils Critical Path Op- 48:463–93. C, clusterin, and trefoil factor-3—were comes for our patients. portunities List Outlining Blueprint 5. Dieterle F, et al. Monitoring kidney deemed indicative of drug-induced dam- To Modernizing Medical Product De- safety in drug development: emerging age to kidney cells and hence “qualified” Joseph Bonventre MD, PhD, is with the Renal velopment by 2010. Biomarker De- technologies and their implications. for used in rat studies. The PSTC is cur- Division, Department of Medicine, Brigham velopment and Clinical Trial Design Curr Opin Drug Discov Devel 2002; rently working to obtain sufficient evi- and Women’s Hospital, Harvard Medical Greatest Areas for Impact. FDA News. 11:60–71. dence for the FDA and EMEA to qualify School, Harvard Institutes of Medicine, in P06-39, March 16, 2006. 6. Vaidya VS, et al. A rapid urine test for some or all of these markers for human Boston. Bonventre declares that he is co-in- 3. FDA. Center for Drug Evaluation early detection of kidney injury. Kid- studies. ventor on KIM-1 patents that are licensed by and Reseach (CDER) CfBEaRC, and ney Int 2009; 76:108–14. Much of the development of biomarkers has grown out of kidney safety and drug toxicity studies. The information obtained from these studies will go far to inform the use of these biomarkers— and potentially others—for patients with sepsis, ischemia, and other drug and nondrug-related forms of injury. Understanding the performance of kidney injury biomarkers, however, is much more straightforward in animals than it is in humans. In animals there is a very good “gold standard”: renal pathology. In humans, pathology is infrequently available. Novel approaches must be developed because comparisons to SCr are not satis- factory for the reasons already mentioned. A change in SCr, especially if it is transient and reasonably modest, does not necessarily imply kidney injury. A biomarker may be increased without a change in SCr but that does not impugn the biomarker necessarily since there may be significant Grants and Funding injury that is not sufficient to produce an increase in SCr. On the other hand, SCr may be increased and a biomarker not in- Opportunities creased when there is no injury but rather a hemodynamic change that results in an elevation in SCr. There is a strong tendency in the growing literature on this topic to compare ASN recognizes the need to support the clinical and basic science biomarkers to SCr as a gold standard. research of its members. The Society offers grants to assist researchers Under certain circumstances SCr is a very reasonable metric since it provides insight at various points in their careers. into GFR; however, the inadequacies of SCr as a gold standard represent barriers to understanding of the true perform- Grants & Funding Opportunities Available: ance of the biomarker to diagnose injury. Patient outcome is a “hard endpoint.” t $BSFFS%FWFMPQNFOU(SBOUTGPS/FX*OWFTUJHBUPST Patients are quite complicated, however, t *OUFSJN'VOEJOH(SBOUTGPS&TUBCMJTIFE*OWFTUJHBUPST with many things contributing to long- t (SBOUTGPS.FEJDBM4UVEFOU3FTFBSDI term outcome. It has been suggested that multiple biomarkers will be more useful t 5SBWFM4VQQPSU than one and this, I believe, may be true if we really understand what each biomark- For more information regarding ASN Grants and Funding, please contact er is telling us. Point-of-care technologies, including dipsticks, will be very useful in [email protected] or visit www.asn-online.org. making the biomarkers more available for routine clinical use (6). The recognition of the inadequacy of kidney injury biomarkers that have been used for 50–100 years (BUN and creatinine) has led to intense interest in finding and validating new biomarkers. New biomarkers will enable us to diagnose kidney injury earlier and provide better information about the status of ongoing injury in patients with chronic kidney

Grants Ad_Journal_KN.indd 1 1/22/10 12:30:34 PM Acute Kidney Injury: The Road to Recovery

Pharmacological Treatment of Acute Kidney Injury: Where Are We and Where Are We Going? By Mark Okusa

ver the past few years, and for ap- that ARF includes a spectrum of clinical with eGFR <15 mL/min/1.73 m2. Biomarkers of AKI Opropriate reasons, the field of acute conditions from subclinical injury and Although no drug has been shown to Serum creatinine is a poor biomarker of kidney injury (AKI) has evolved at a rapid prerenal azotemia to acute tubular necro- be beneficial in the prevention of AKI, un- AKI. Although both the RIFLE and AKIN pace. Even the name acute renal failure sis. This all-inclusive terminology of AKI derstanding that CKD increases the risk of criteria use serum creatinine in their stag- (ARF) was changed to AKI, and ICD-9 has been adapted and has been used with AKI should lead physicians to use caution ing, it is hoped that sensitive biomarkers codes adopted AKI in October 2008. increasing acceptance worldwide. in this high risk group. Avoidance of non- will be employed in the future. There is The primary reason for the change in no- The literature indicates that for a single steroidal anti-inflammatory drugs, avoid- a considerable amount of injury that may menclature was the repeated observation procedure, such as cardiac surgery, there ance of contrast imaging studies, and using occur without a change in GFR. At the that pharmacological therapy of AKI has are over 30 definitions for AKI leading isosmolar contrast agents or avoiding inva- same time there may be changes in GFR been unsuccessful despite proven benefits to highly variable incidence of AKI of sive procedures are critical measures in the without a change in tubular injury (prere- seen in preclinical studies. Prevention and 1–31 percent. With such high variability prevention of AKI. nal). Furthermore, there is a delay in the treatment of AKI are indeed important one cannot compare studies to determine rise in serum creatinine so that by the time Acute kidney injury increases clinical issues, as the incidence and mor- whether drugs are efficacious or not. Se- a change is observed, intervention may be risk of chronic kidney disease tality in patients with AKI, especially in verity of injury may be highly variable be- too late. Lastly, a number of factors affect and ESRD critically ill patients, remains alarmingly tween studies. serum creatinine independent of a change high despite substantial advances in tech- Recently, two classification schemes Although the high mortality associated in GFR, including but not limited to nu- niques of resuscitation and renal replace- have been described: RIFLE (Risk, Inju- with AKI has long been recognized, only trition, muscle mass, infection, edema ment therapy. ry and Failure) and Acute Kidney Injury recently have the long-term effects of AKI (which affects the volume of distribution), Recognizing the importance of AKI Network (AKIN) Staging (I, II, III) based on renal outcomes been demonstrated. Is- and drugs such as n-acetyl cysteine, which and mortality, investigators over the past upon graded levels of rise in serum cre- hani et al. demonstrated for the first time may alter the metabolism of creatinine. few decades have identified many com- atinine and/or decrease in urine output that patients with AKI and preexisting Over the past several years, a concerted pounds and drugs that have benefited ani- effort has been made to identify the “kid- (4,10). In 2000, the ADQI was established CKD had an increased risk for progres- mals, but none so far that have been use- ney troponin.” Biomarkers may be used to to develop an evidence-based assessment sion to ESRD, an observation suspected ful in humans. So why have we failed to identify, early in the course of AKI, differ- and consensus guidelines to standardize but not previously demonstrated (16). In identify a “silver bullet,” or even a bronze ent forms of AKI, and they may predict care and direct further research (11). The this study, a 5 percent random sample of one, in the prevention and treatment of Medicare beneficiary claims data from the the severity and prognosis of patients with ADQI group classified ARF based upon AKI? The answer may be simply that these Centers for Medicare and Medicaid Serv- AKI. A number of biomarkers have been creatinine and urine output. A growing therapeutic agents may be effective, but a ices (CMS) and the ESRD incidence da- identified, and prominent among these number of studies have validated this clas- number of barriers exist that preclude fa- tabase from the United States Renal Data are kidney injury molecule 1 (KIM-1), sification scheme of AKI (12,13). vorable outcomes. Thus a large number of System (USRDS) was used. The risk for neutrophil gelatinase associated lipoca- investigators began a more coordinated ef- In light of recent studies indicating that developing ESRD was greatest in patients lin (NGAL), interleukin-18 (IL-18), and fort at reappraising the barriers to progress even a small rise in creatinine was associat- with AKI and CKD with a hazard ratio liver fatty acid binding protein (LFABP) in human AKI. ed with an increase in mortality, the AKIN of 41.2 [95% confidence interval (CI) to name a few. group proposed the AKIN staging (I, II, The value of biomarkers as diagnostic A reappraisal of the field of 34.6 to 49.1] compared to AKI without III). These studies highlight the important CKD, 13.0 (95% CI 10.6 to 16.0) and tools and predictors of clinical course will acute kidney injury effects of a small decline in GFR on the with CKD without AKI, 8.4 (95% CI 7.4 depend on their individual performance. Recently, concerted effort has been made overall outcome of critically ill patients. to 9.6). Therefore, AKI in older patients Given the heterogeneity of causes of AKI, to determine and understand gaps in our Even the least severe category of RIFLE, with CKD poses a significantly increased background conditions, and age, it is like- knowledge. With better understanding of “R,” or AKIN stage I, was associated with risk for ESRD, and AKI may accelerate a ly that a panel of biomarkers will be most these deficiencies, progress might be made a mortality rate of 30.9 percent or 30.7 progressive decline in renal function. effective. A highly sensitive, high-through- in reducing the morbidity and mortality percent, respectively (14). Recent studies put method that can be performed within of AKI. There have been a number of con- indicate that both classification systems Distant organ effects of AKI 3-4 h has been developed by Bonventre’s sensus conferences from different groups, group and uses a multiplex microbead perform well. Thus, these new classifica- Recent studies have focused on the obser- including the Acute Dialysis Quality Ini- technology capable of simultaneously tion systems will allow future studies to be vation that a small increase in creatinine tiative (ADQI), the Acute Kidney Injury measuring multiple biomarkers within a done using a single definition of AKI. is an independent predictor of increased Network (AKIN), the Acute Kidney In- single well (18). Another high-through- mortality. What is becoming increasingly jury Advisory groups to the American So- put, easy to use immunochromatographic Chronic kidney disease evident is that AKI is a complex and mul- ciety of Nephrology, and the International assay developed for KIM-1 is sensitive and increases risk of AKI tisystemic condition, which is thought to Society of Nephrology, as well as the Na- specific and will permit rapid (within min- lead to a distant organ dysfunction syn- tional Kidney Foundation and Kidney Most recently, in population-based stud- utes) point-of-care detection of urinary drome contributing to fatality in such pa- Disease: Improving Global Outcomes ies, there is evidence that strongly suggests biomarkers in humans with AKI (19). We tients. Experimental studies provide some (KDIGO) groups. an important and growing role of AKI in are hopeful that a rapid “dipstick” method insight into the mechanism by which Two important barriers to advance- the global epidemiology of chronic kidney or multiplex technology will lead to early isolated events leading to the loss of GFR ment are: i) lack of a definition of AKI disease (CKD) and end stage renal disease diagnosis of AKI where therapies may be can lead to distant organ effects, including and ii) lack of an accurate way to detect (ESRD). A recent study highlights the instituted early in the course of disease to circulating factors such as cytokines and AKI early in its course. This recognition important association between baseline minimize the extent of injury. chemokines, activated leukocytes, and ad- has inspired leaders in the field of AKI. As kidney function and the risk of hospital- In the end, one must ask, why do we hesion molecules leading to immune cell a result, major advances have been made not have drugs to treat AKI? Clearly the acquired AKI (15). In this study they infiltration. in classification of AKI, biomarkers, epi- found that in cases of dialysis-requiring Oxidative injury, apoptosis, and cellu- disease is complex, but over the past five demiology, pathophysiology, and drug de- AKI, 74 percent occurred among patients lar necrosis contribute to the final pathway years there has been a reappraisal of the velopment. These new drugs on the hori- with an estimated glomerular filtration of organ dysfunction (17). Thus the abil- field of AKI that has led to intense investi- zon have led to a tremendous effort in the rate (eGFR) less than 60 mL/min/1.73 ity of kidney dysfunction to affect other gation. Significant progress has been made translational research arena in AKI. 2 m . There was a graded association be- organs likely contributes to the high mor- to: i) understand the epidemiology of the tween baseline eGFR and the risk of AKI, tality associated with AKI. This concept disease, ii) understand the pathophysiol- Why we need a definition of AKI ranging from a twofold increase among implies that future drugs for the treatment ogy and multisystemic nature of AKI, iii) The AKIN group sought to change the patients with eGFR 45–59 mL/min/1.73 of AKI should have broad effects that may standardize the definition of AKI, iv) iden- name from ARF to AKI given the fact m2 to a 40-fold increase among patients ameliorate damage to multiple organs. tify new biomarkers to diagnose patients DecemberFebruary 20092010 | ASN Kidney News | 17 with AKI early in the course of the disease, 9. Chertow GM, et al. Acute kidney patients: a cohort analysis. Crit Care 16. Ishani A, et al. Acute kidney injury and v) develop novel compounds through injury, mortality, length of stay, and 2006; 10:R73. increases risk of ESRD among elderly. advanced drug discovery programs and in- costs in hospitalized patients. J Am 13. Ricci Z, Cruz D, Ronco C. The RI- J Am Soc Nephrol 2009; 20:223–8. novative translational sciences. Soc Nephrol 2005; 16:3365–70. FLE criteria and mortality in acute 17. Paladino JD, Hotchkiss JR, Rabb Further initiatives are underway to rap- 10. Mehta RL, et al. Acute Kidney Injury kidney injury: A systematic review. H. Acute kidney injury and lung idly synthesize new knowledge in the field Network: Report of an initiative to Kidney Int 2008; 73:538–46. dysfunction: a paradigm for remote of AKI. In sequential and complementary improve outcomes in acute kidney 14. Lopes JA, et al. Acute kidney injury organ effects of kidney disease? Mi- fashion, the AKIN group is planning a injury. Crit Care 2007; R31. in intensive care unit patients: a com- crovasc Res 2009; 77:8–12. summit focused on defining appropriate 11. Ronco C, Kellum JA, Mehta R. parison between the RIFLE and the 18. Vaidya VS, et al. Urinary Biomarkers clinical endpoints for outcomes in AKI Acute dialysis quality initiative Acute Kidney Injury Network classi- for Sensitive and Specific Detection research in San Diego February 27–28, (ADQI). Nephrol Dial Transplant fications. Crit Care 2008; 12:R110. of Acute Kidney Injury in Humans. 2010, and the National Institute of Dia- 2001;16:1555–8. 15. Hsu CY, et al. The risk of acute re- Clin Transl Sci 2008; 1:200–8. betes and Digestive and Kidney Diseases/ 12. Hoste EA, et al. RIFLE criteria for nal failure in patients with chronic 19. Vaidya VS, et al. A rapid urine test National Institutes of Health is planning acute kidney injury are associated kidney disease. Kidney Int 2008; for early detection of kidney inju- a conference focused on current oppor- with hospital mortality in critically ill 74:101–7. ry. Kidney Int 2009; 76:108–14. tunities of clinical trials in AKI, October 2010, in Bethesda, Md. Leading investigators in the field of AKI from around the world will gather and finalize important guidelines and therapeutic opportunities in AKI. We are now ready to implement newly acquired knowledge and develop well- designed clinical trials of promising new drugs as well as re-evaluation of older drugs that have failed in past studies. We anxiously await clinical trials in AKI in the next five years as the results of these trials should finally lead to new treatments for a devastating disease. The fruits of these studies should justify the time spent in reappraising the field of AKI.

Mark Okusa, MD, is the John C. Buchanan Distinguished Professor of Medicine, Divi- sion of Nephrology and Center for Immunity, Inflammation and Regenerative Medicine at the University of Virginia Health System in Charlottesville, Va.

References 1. Xue JL, et al. Incidence and mortality of acute renal failure in Medicare beneficiaries, 1992 to 2001.J Am Soc Nephrol 2006;17:1135–42. 2. Waikar SS, et al. Declining mortality in patients with acute renal fail- Renal WeekEnds ure, 1988 to 2002. J Am Soc Nephrol 2006; 17:1143–50. 3. Uchino S, et al. Acute renal failure in The perfect complement to Renal Week critically ill patients: a multinational, - For the Renal Week sessions you missed multicenter study. J Am Med Assoc 2005; 294:813–8. - For a synopsis of key topics in nephrology 4. Bellomo R, et al. Acute renal fail- - For critiques and perspectives by leaders in the ﬁ eld ure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Sec- ond International Consensus Con- ference of the Acute Dialysis Quality ASN Renal WeekEnds 2010 at a city near you: Initiative (ADQI) Group. Crit Care Dallas, TX, February 6 - 7 2004; 8:R204–12. 2010 5. Liano F, Pascual J. Outcomes in acute Washington, DC, February 13 - 14 renal failure. Semin Nephrol 1998; Atlanta, GA, February 27 - 28 18:541–50. 6. Hoste EA, Schurgers M. Epidemiol- Chicago, IL, March 6 - 7 ogy of acute kidney injury: how big New York, NY, March 13 - 14 is the problem? Crit Care Med 2008; Los Angeles, CA, March 20 - 21 36:S146–51. 7. Chertow GM, et al. Independent association between acute renal failure Expert faculty summarize, critique, and integrate all key lectures, and mortality following cardiac sur- symposia, and abstract presentations from Renal Week 2009. gery. Am J Med 1998; 104:343–8. 8. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on Program information is available online at www.asn-online.org mortality. A cohort analysis. J Am Med Assoc 1996; 275:1489–94.

RenalWeekends2010 Ad.indd 1 1/15/10 2:59:20 PM 18 | ASN Kidney News | February 2010

ASN Prepares for World Kidney Industry Spotlight Day 2010 nearly 44 percent of new cases. As a result, approximately 180,000 people FDA to Review ESAs in the United States “are living with In the latest word on the safety of erythropoiesis-stimulating agents (ESAs), the kidney failure as a result of diabetes.” FDA plans a public meeting this year to reevaluate the use of the agents in the Building on traditions estab- treatment of anemia in patients with chronic kidney disease. The recent findings lished during previous World Kid- of the TREAT trial (Trial to Reduce Cardiovascular Events with Aranesp Therapy) ney Day events, ASN will hold of the Amgen ESA Aranesp, in combination with earlier findings about ESAs, has a reception on Capitol Hill with prompted the reevaluation. The news appeared in a Jan. 7 New England Journal of other organizations (such as the Medicine (NEJM) article written by four physician-authors from the FDA’s Center To increase public awareness about National Kidney Foundation), and for Drug Evaluation and Research. kidney disease, the American Society ASN leaders will visit nearly 100 The TREAT trial found a significant, substantial increase in the incidence of Nephrology (ASN) is participat- congressional offices to inform law- of fatal or nonfatal stroke in the ESA group compared with a placebo group (5 ing in the fifth annual World Kidney makers about the most pressing is- percent of patients vs. 2.6 percent) and also a significantly higher rate of throm- Day on Thursday, March 11, 2010. sues facing patients with kidney dis- boembolic events among patients taking ESAs. The International Society of Nephrol- ease and those who care for them. The NEJM authors noted that three trials showed that hemoglobin concentra- ogy and the International Federation In addition, ASN will coordinate a tion targets of 14.0, 13.5, and 13.0 g/dL—and the ESA regimens used to achieve of Kidney Foundations established media campaign to help inform the them—are harmful. According to their commentary, a future, controlled trial World Kidney Day in 2006 to raise public about kidney disease. needs to show that assignment to any higher hemoglobin target, compared with awareness of kidney disease, highlight The ongoing debate about health any lower target, or to ESA dosing regimens necessary to attain these targets, risk factors, and encourage behaviors reform and the proposed rule for prevents cardiovascular events or does not increase their likelihood. that reduce the incidence of kidney implementing the end stage renal disease. The theme for this year’s disease provisions of the Medicare World Kidney Day is “Protect Your Improvements for Patients and Kidneys: Control Diabetes.” Providers Act highlight the critical Is Salt the New Trans Fat? According to the National Institute need to improve care for patients of Diabetes and Digestive and Kidney with kidney disease. To learn more Salt in food, like sugar and fat before it, appears to be the latest target of ingredi- Diseases, diabetes is the most common about World Kidney Day, please ent awareness. cause of kidney failure, accounting for visit www.asn-online.org In January, New York City Mayor Mike Bloomberg announced a health initiative that encourages food manufacturers and restaurant chains across the country to reduce the amount of salt in their products by 25 percent over the next five years. In December 2009, Sara Lee announced its commitment to reducing salt an average of 20 percent over that time period. Sara Lee announced it would ASN Responds to Disaster in Haiti concentrate its efforts to reduce salt in fresh bread, hot dogs, lunchmeat, breakfast By Rachel Shaffer foods, and cooked sausage. Earlier, the company launched a line of lower-sodium lunchmeats and sodium-reduced breads. The massive earthquake of 7.0 magnitude in the region. Salt has long been on the health consciousness radar screen for its role in high that hit Haiti Tuesday, January 12, result- • establish daily conference calls for the blood pressure and links to cardiovascular disease. Now salt’s role in kidney health ed in an estimated 75,000 dead, 200,000 nephrology community to coordinate is coming into consciousness too. injured, and 1 million displaced people. relief efforts. World Action on Salt and Health (WASH) is a global group seeking to To help respond to this crisis, the Amer- “Nearly 30 members of the nephrol- improve the health of populations throughout the world by achieving a gradual ican Society of Nephrology (ASN) im- ogy community met daily by conference reduction in salt intake. Of the 80 nations—including the United States—that mediately contacted other kidney-related call during the crisis,” said Didier Portilla, organizations, including the International MD, chair of the ASN Disaster Relief make up WASH members, Australia is working very hard to impress citizens Society of Nephrology, the Kidney Care Task Force. “KCER organized these calls, about kidney danger. The Australian arm of WASH, AWASH, notes that 14 Emergency Response (KCER) Coalition which provided updates from nephrolo- percent of Australians have some form of kidney damage. The AWASH website and the Florida ESRD Network, the Na- gists in Haiti and the Dominican Repub- notes that high blood pressure, caused by salt, contributes to kidney damage tional Kidney Foundation, the Sociedad lic, assessed the health care infrastructure because of the harm it does to blood vessels. For the same reason, once kidney Latino-Americana de Nefrologia e Hi- in these countries, and identified needs for damage has occurred, high blood pressure accelerates the progression toward pertension (SLANH), and the Society of physicians and nurses.” kidney failure. Nephrology of the Dominican Republic “Dialysis providers and other organiza- (SNDR) as well as dialysis providers and tions worked to target supplies to reach the industry organizations. ASN also worked areas where they were most needed,” said with the U.S. government, Doctors With- Mark Okusa, MD, FASN, chair of the out Borders, the USNS Comfort, and ASN Acute Kidney Injury Advisory Group. Partners in Health. “Due to logistical problems in transport to Led by its Disaster Relief Task Force, Port au Prince, Haiti, we focused on three ASN helped: cities in the Dominican Republic to rap- ASN • develop a protocol for crush injury cur- idly transport supplies into Haiti.” rently employed in Haiti to reduce the According to Portilla, “SLANH Presi- incidence of AKI from rhabdomyolysis. dent Ricardo Correa-Rotter, MD, and Student • identify over 60 members who volun- SNDR President Sandra Rodriguez, MD, teered to travel to the region and pro- deserve tremendous credit for establish- vide care. ing this connection and saving lives, as do Scholar • coordinate supplies generously donat- Dr. Okusa and Rajnish Mehrotra, MD, ed by dialysis providers and industry to FASN.” Mehrotra chairs the ASN Dialy- Grant ensure medical providers had the items sis Advisory Group. they needed to treat patients in crisis ASN encourages its members and the ASN supports medical including dialyzers, dialysis machines, rest of the community to contribute di- students with an interest in dialysis fluids, sodium polysytrene sul- rectly to entities specifically dedicated to fonate for treatment of hyperkalemia, providing disaster relief to Haiti, such as either basic or clinical research to spend 10-52 weeks handheld portable systems for meas- the American Red Cross or the William engaged in continuous full-time research. urement of renal function, and serum J. Clinton Foundation. A list of organi- Learn more at www.asn-online.org electrolytes and dialysis catheters. zations collecting funds for the disaster is • create a supply chain to rapidly deliver provided by InterAction through its web- the items of greatest need. site at http://www.interaction.org/crisis- Application Deadline: Friday, March 5, 2010 • support the health care infrastructure list/earthquake-haiti. ASN Membership Member Beneﬁ ts Education "4/QSPWJEFTNFNCFSEJTDPVOUTGPSBWBSJFUZPGFYDFQUJPOBMFEVDBUJPOBMBDUJWJUJFT

t 3FOBM8FFL&OETTVNNBSJ[F DSJUJRVF BOEJOUFHSBUFLFZ3FOBM8FFL QSFTFOUBUJPOTJOQPXFSGVMUXPEBZDPVSTFT QSFTFOUFEJOTJYMPDBUJPOT Member BDSPTTUIF6OJUFE4UBUFT Categories t UI"OOVBM#PBSE3FWJFX$PVSTFBOE6QEBUFQSFQBSFTOFQISPMPHJTUTGPS UIF"#*.JOJUJBMDFSUJàDBUJPOBOENBJOUFOBODFPGDFSUJàDBUJPOFYBNJOBUJPOT Active Member ($275) BOEQSPWJEFTBDPNQSFIFOTJWFVQEBUFGPSUIFQSBDUJDJOHOFQISPMPHJTU An individual who holds an MD, a PhD, or the equivalent, resides in North or Central America, and ful lls at least one of the following criteria: t "4/3FOBM8FFLSFNBJOTUIFXPSMETQSFNJFSHBUIFSJOHPGLJEOFZ QSPGFTTJPOBMTQSFTFOUJOHBEWBODFTJOUSFBUNFOU SFTFBSDI BOEFEVDBUJPO r $PNQMFUJPOPGSFTFBSDIPSDMJOJDBMUSBJOJOHJOOFQISPMPHZ

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Journal of the American Society of Nephrology (JASN) Join or Renew 5IFMFBEJOHLJEOFZKPVSOBMJOUIFXPSME Clinical Journal of the American Society of Nephrology (CJASN) 5IFQSJNBSZSFTPVSDFGPSDVUUJOHFEHFDMJOJDBMSFTFBSDIJOOFQISPMPHZ ASN membership Nephrology Self-Assesment Program (NephSAP) An essential tool for earning continuing medical education credits and NBJOUFOBODFPGDFSUJàDBUJPOQPJOUT online at ASN Kidney News "OFXTNBHB[JOFPGGFSJOHFYDFQUJPOBMDPWFSBHFPGDVSSFOUJTTVFTPGJOUFSFTU UPLJEOFZQSPGFTTJPOBMT www.asn-online.org/membership/ ASN Kidney News Podcasts "CJNPOUIMZBVEJPQSPHSBNQSPWJEJOHJOEFQUIEJTDVTTJPOTPGUPQJDTUIBU JOUFSFTUBOEDIBMMFOHFUIFHMPCBMLJEOFZDPNNVOJUZ ASN Kidney Daily "EBJMZFNBJMDPMMBUJOHLJEOFZSFMBUFEOFXTGSPNNFEJDBMKPVSOBMT OFXTQBQFST BOEPUIFSNFEJB Renal Express 5IF"4/OFXTMFUUFSLFFQJOHNFNCFSTDVSSFOUPOTPDJFUZQSPHSBNTBOEOFXT

ASN_Membership Ad.indd 1 12/21/09 5:20:57 PM 20 | ASN Kidney News | February 2010 Fellows Corner What I Wish I’d Known Before I Started Fellowship

e have all experienced those the right answer, you go with what the ant was to provide the best, most focused of these family- moments when we wonder nurse says. Most of the time, the nurse is input in my area of expertise, primary related variables what we have gotten ourselves experienced and helps you make the right services were much more appreciative.” at the time of Winto. Nephrology fellowship is one of these decision.” Any of the basic building blocks Finally, Nathan Hellman of Mas- my fellowship life-altering events, so we asked a sampling of inpatient nephrology would have been sachusetts General Hospital focused on interviews, it of current fellows the one thing they wish helpful, she added. more personal aspects. Hellman is a new now seems silly they had known before starting training. Rajiv Vij of the North Shore Univer- member of the ASN Kidney News edito- to have not tak- Some answers focused on the practi- sity Hospital did not realize how many rial board. en these factors cal. Deepti Torri, of North Shore Long Is- choices there were within nephrology. “Try and think beyond the two to into account at land Jewish Medical Center in New Hyde These include private practice, clinical three years of fellowship to what you will the time of my Park, N.Y., said better understanding investigation, and basic science research. be doing in your post-educational life.” decision,” Hell- of renal physiology would have helped. “For candidates who are uncertain, I Changes in personal status, like marriage man said. “I do “Taking Texbook of Medical Physiology by support application to either clinical fel- and children, alter one’s perspective. “I not think that Arthur Guyton out of the dusty bookshelf lowship programs with an option to do a find myself having to incorporate into my my situation is and reading the renal physiology chapters third year of research, or to programs that professional desires a whole new series of that unique, as the fellowship period is from beginning to end would have been have an open-mindedness with respect to variables: affordability of day care options, very often a time of rapid change: new time well spent,” Torri said. the new niches in nephrology,” he said. employability options for my wife, and relationships, marriage, children; even the Ruba Nijmeh, fellow at Ohio State One interesting answer focused on the proximity to relatives are just a few exam- transition from everyday clinical work to University Medical Center in Columbus, transition from resident to specialty fel- ples,” Hellman said. “I am not suggesting the different pace of a research project can remembers the first overwhelming days low. As a resident, “your goal was more of that the academic aspects of a nephrol- be profound. It may be impossible to pre- of fellowship when the pager went off for a facilitator and making sure all of your ogy program be overlooked—they are dict exactly how things will change, but the acute dialysis room. “You answer your patients’ bases were covered,” according to still probably the most important factor keep in mind that they certainly will.” page, and the nurse on the other end of Josh Bitter of the Ohio State University to consider—but rather that the decision- Change is almost universal, but one the phone is asking you for orders: what Medical Center. Transitioning from the making process becomes more complex thing will remain constant: new fellows type of bath you want, how many hours, big-picture, coordination of care view to with increasing life responsibilities. will always find something they wish they what anticoagulation, etc.,” Nijmeh said. an organ system view presented challeng- “Even though things have generally had known before their journey to become “Of course, as you don’t happen to know es. “Once I realized my role as a consult- worked out for me despite my ignorance nephrologists.

ASN Provides Key Information to U.S. Senate Finance Committee

n December 2009, Sen. Because ASN is an accredited conflicts. The ASN Committee on Renal WeekEnds, and the Annual Charles E. Grassley (R-IA), rank- provider of continuing medical Corporate Relations presented its Board Review Course and Update. Iing minority member of the U.S. education, the society adheres final report to the ASN Council in Speakers at ASN meetings follow Senate Finance Committee, wrote to the six “Standards for Com- early 2009, and the committee’s all ACCME standards regarding 33 nonprofit medical groups— mercial Support” recommended recommendations were endorsed disclosure, and the society makes among them the American Socie- by the Accreditation Council for unanimously. every effort to see that present- ty of Nephrology (ASN), the Ameri- Continuing Medical Education This effort resulted in a ers disclose all potential conflicts can Medical Association, and the (ACCME). These standards (www. number of advances such as of interest, and that sessions are American College of Physicians— accme.org) ensure independence developing a new section on the moderated to meet these stand- to request information on indus- and objectivity of the programs ASN website: the ASN Conflict of ards of disclosure. try funding awarded to those presented to physicians and oth- Interest Initiative: Transparency Having successfully partnered societies. As part of his ongoing er learners. Commercial interests in Relationships with Commercial in the past to advance patient review of medical education pro- do not plan, deliver, or evaluate Interests (http://www.asn-online. care, clinical research, and medi- grams in the United States, Sen. educational content provided by org/coi/). This section, open to cal education, societies and com- Grassley asked each organization ASN, and ASN has established the public, provides a wealth of mercial interests can continue to to supply details about commer- numerous means of separation information about ASN as well as do so in the future provided they cial support received in the years between fundraising and plan- general resources on managing follow strict standards of disclo- 2006 through 2009, as well as ning, executing, and evaluating potential conflicts. In a further sure, evaluation, and documenta- information about internal poli- educational programs. effort to provide vital information tion. ASN recognizes the value of cies on managing and disclosing Any professional society should and resources to ASN members inquiries such as those conduct- potential conflicts of interest. actively and regularly assess po- and others in the kidney commu- ed by Sen. Grassley and supports ASN leaders were pleased to tential conflicts of interest related nity, ASN published the commit- all efforts that promote effective be able to send to Sen. Grassley to executing its mission, goals, tee’s final report and an editorial policies such as those outlined the information requested and and agendas. Thus, in addition outlining ASN policies and plans by the society at http://www.asn- share with the Senate Finance to supporting ACCME guidelines, for implementing the recommen- online.org/coi/.ASN members, Committee the society’s long- ASN regularly examines and up- dations (J Am Soc Nephrol 2009; other kidney professionals, and standing commitment to educa- dates its own policies on man- 20:1853–59 and 1860–62). patients benefit from the society’s tional and scientific objectivity. aging potential conflicts. Most ASN also provided Sen. Grass- ongoing review of its policies to ASN maintains a strong founda- recently, ASN in 2008 convened ley information on advertising ensure they appropriately support tion of institutional integrity, integ- the Committee on Corporate Re- in ASN journals and ASN Kidney ASN’s mission of promoting the rity in its interactions with other lations, and this group conducted News, meeting exhibits at ASN Re- highest quality care for patients, organizations, and serves as a a comprehensive assessment of nal Week and other ASN venues, supporting cutting-edge research, model for self-governance and the society’s mechanisms for ad- as well as unrestricted educa- and educating the next genera- transparency. dressing and managing potential tional grants for ASN Renal Week, tion of kidney professionals. How do you navigate unprecedented change? As a team.

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09SPE_Corporate_Ad_ASN.indd 1 1/4/10 3:24 PM 22 | ASN Kidney News | February 2010 Policy Update

Medicare Moves Forward with Elimination of ASN Leaders Advance Consultation Codes Partnership with National As of Jan. 1, the Centers for Medicare and Medicaid Services (CMS) Institutes of Health changed physician coding to eliminate inpatient and outpatient consulta- Also this January, ASN representatives in- tion codes. CMS published a “Medicare Matters” article guiding physi- cluding Sharon Anderson, MD; Thomas Coff- cians on coding under the new policy. Readers may review the changes man, MD; Jonathan Himmelfarb, MD; Thomas on ASN’s Policy and Public Affairs—Patient Care website at http://asn- Hostetter, MD; and John Sedor, MD; met with online.org/policy_and_public_affairs/patient-care.aspx. the National Institute for Diabetes and Digestive and Kidney Diseases Sen. Arlen Specter (D-PA) contemplated offering an (NIDDK) Division of Kidney, Urologic, and Hematologic Diseases Director amendment that would delay the elimination of consul- Robert A. Star, MD, and other NIDDK leadership. The group discussed tation codes for one year in the Senate version of issues including areas where ASN could strengthen their relationship with the health reform bill, but it was not ultimately NIDDK, community involvement with the institute, research infrastructure included. Such an amendment may be intro- concerns, and interdisciplinary research. duced as the bills are merged, though none To help publicize kidney disease as a public health issue and advo- had been at presstime. ASN will alert mem- cate for a kidney disease research agenda, ASN plans to meet with other bers of any changes regarding the use of con- NIH institutes and government agencies including, but not limited to, the sultation codes. National Heart, Lung, and Blood Institute, the National Institute on Ag- ing, the National Institute of Environmental Health Sciences, the National Center on Minority Health and Health Disparities, the Center for Scientific Review, the Agency for Healthcare Research and Quality, the Department of Veteran Affairs (VA), the Centers for Disease Control and Prevention, and CMS. Health Reform Legislation ASN Meets with Key Legislators MD, FASN, met with Sen. Richard Durbin’s (D-IL) staff on Capitol Hill to discuss Lawmakers began reconcil- and advocate for inclusion of lifetime immunosuppressive drug coverage in the ing the House and Senate final health reform bill. ASN representatives reiterated the society’s support versions of health reform of lifting the current 36-month Medicare limit on immunosuppressive cover- legislation (H.R. 3692 and age and collaborated on strategies to shepherd the measure into final health H.R. 3590, respectively) in reform legislation. In addition, ASN staff promoted the immunosuppressive is- closed-door negotiations on their return to Capitol Hill in early January. Were a sue to other key members of Congress independently and in partnership with single version developed through this process, the bill would go back to each organizations such as the American Society of Transplantation and the Renal body for a final vote before being sent to the President for his signature. Physicians Association (RPA)—including publishing an open letter to members Yet after the Jan. 19 Republican victory in the Massachusetts special Sen- of Congress in the Washington, DC, newspaper Roll Call. ate election eliminated Democrats’ 60-seat Senate majority, lawmakers halted Although at press time it remained unclear exactly what path the health negotiations and signaled they would suspend health reform progress until the reform bills would take, ASN will continue to closely monitor the legislation and new Massachusetts Senator takes his seat. advocate for appropriate policies over the coming month. Key provisions of Earlier in January, an ASN delegation including President Sharon Anderson, each bill relevant to the nephrology community are included in the chart.

H.R. 3962 (House version) H.R. 3590 (Senate version)

• Sec. 1232: Provides extended lifetime coverage of immunosuppressive • Sec. 10336: Requires GAO to conduct a study on the impact on drugs for kidney transplant patients. Includes all oral drugs in the Medicare beneficiary access to dialysis services, including oral drugs, bundled prospective payment system including oral drugs that are not that are furnished under the bundled prospective payment system. the oral equivalent of an intravenous drug (such as oral phosphate binders and calcimimetics) • Sec. 7002: Establishes a pathway for the licensure of biosimilar biological products, and for other purposes. This would provide up to • Sec. 2575-2577: Establishes a pathway for the licensure of biosimilar 12 years of data exclusivity to manufacturers of a new biologic product, biological products, and for other purposes. This would provide up to and provides an additional 6-month exclusivity extension for pediatric 12 years of data exclusivity to manufacturers of a new biologic product, applications. and provides an additional 6-month exclusivity extension for pediatric applications. • Sec. 6301: Establishes a Patient-Centered Outcomes Research Institute aimed at assisting “patients, clinicians, purchasers, and • Sec. 1401: Establishes within the Agency for Healthcare Research policy-makers in making informed health decisions by advancing the and Quality (AHRQ) a Center for Comparative Effectiveness Research to quality and relevance of evidence concerning the manner in which conduct, support, and synthesize research relevant to the comparative diseases, disorders, and other health conditions can effectively and effectiveness of the full spectrum of health care items, services and appropriately be prevented, diagnosed, treated, monitored, and systems, including pharmaceuticals, medical devices, medical and managed through research and evidence synthesis.” surgical procedures, and other medical interventions. • Sec. 3022: Establishes a “Medicare Shared Savings Program” under • Sec. 1730A: Establishes an Accountable Care Organization (ACO) which physicians may work together to manage and coordinate care pilot program. for Medicare fee-for-service beneficiaries through an accountable care organization” (ACO). • Sec. 1191: Adds renal dialysis facilities as an additional telehealth- eligible site. February 2010 | ASN Kidney News | 23 Journal View

Medicare Data Show Rising Rate of Atherosclerotic Increased Physical Activity May Protect Against Renovascular Disease Rapid Drops in Kidney Function

The diagnosis of atherosclerotic reno- treated by endovascular intervention. Older adults with higher levels of for participants with a physical activity vascular disease (ARVD) among older Atherosclerotic renovascular disease habitual physical activity are less likely score of 7 or 8, compared to those with Americans has tripled in recent years, was associated with excess mortality in to experience rapid declines in kidney a score of 2 or 3. Leisure-time energy while the percentage of patients under- each year studied, although the esti- function, reports a study in the Archives expenditure and walking pace were both going revascularization appears to be mated hazard ratios were lower in more of Internal Medicine. associated with reduced risk of decreased decreasing, reports a study in Kidney recent years. Overall, 15.51 percent of The study included 4011 ambulatory kidney function. International. patients died, with a mortality rate of older adults (mean age 72 years) from Information on identifiable risk Based on U.S. Medicare 5% De- 57.87 per 1000 patient years. the Cardiovascular Health Study. All factors affecting the age-related decline nominator Files from 1992 to 2004, the Atherosclerotic renovascular disease underwent kidney function measurement in renal function could have important study included more than 16 million is increasingly being diagnosed, mainly at least twice over a seven-year follow-up implications for public health. Increased patients 66 years or older. Trends in in elderly patients. Studies have shown period. Information on weekly energy physical activity is associated with a the diagnosis, rates, associated factors, a rising prevalence of ARVD among expenditure and walking speed was used decreased risk of cardiovascular disease treatment, and outcomes of ARVD were patients starting renal replacement to calculate a physical activity score (with and mortality. The metabolic benefits analyzed. therapy, but there are few data on a possible score of 2 to 8). Rapid decline of exercise might also influence the The overall incidence of ARVD di- the burden of ARVD in the general in kidney function was defined as a re- long-term risks of glomerulosclerosis and agnosis during the 13-year study period population. duction of greater than 3.0 mL/min/1.73 progressive kidney dysfunction. m2 per year in estimated glomerular Older adults with higher levels of was 3.09 per 1000 patient years. The The new analysis shows that the rate filtration rate, based on cystatin C meas- physical activity appear to be at lower rate of ARVD increased progressively of ARVD among U.S. older adults has urements. risk of rapid declines in kidney function. over the years, increasing more than increased substantially since the early Rapid decline in kidney function The protective effect increases along with threefold between 1992 and 2004. 1990s. The use of revascularization occurred in 23.9 percent of study par- the intensity and amount of physical Revascularization was performed likewise increased during the 1990s, but ticipants, with a rate of 4.1 events per activity, and remains significant after within six months of diagnosis in 13.4 appears to be decreasing in more recent 100 person-years. Such a rapid drop in adjustment for other disease risk factors. percent of patients. The rate of revascu- years. The trend toward decreased mor- kidney function occurred in 16 percent Further studies are needed to determine larization increased progressively from tality suggests that earlier recognition of participants in the most active group whether exercise can protect against 1992 to 1999, but then declined from may permit more timely and effective (physical activity score of 8), compared age-related declines in kidney function 1999 to 2004. There was a trend away management of renovascular disease to 20 percent in the least active group [Robinson-Cohen C, et al. Physical from direct surgical revascularization and [Kalra PA, et al. Atherosclerotic reno- (physical activity score of 2). On multi- activity and rapid decline in kidney func- toward endovascular revascularization— vascular disease in the United States. variate analysis, the risk of rapid decline tion among older adults. Arch Intern Med by 2004, 98.5 percent of patients were Kidney Int 2010; 77:37–43]. in kidney function was 28 percent lower 2009; 169:2116–2123].

Network of Minority Research Investigators to Meet in April The Network of Minority Research Investigators (NMRI) will hold its 8th An- and outcomes across racial and socioeconomic lines, CKD is a global public nual Workshop April 22−23, 2010, at the Bethesda Marriot Hotel in Bethesda, health problem that cannot be overlooked. The NMRI Workshop will draw Md. NMRI, a collaboration of current and potential biomedical research attention to these issues and highlight possible avenues for future research. investigators and technical personnel from traditionally underserved commu- Designed for NMRI members as well as minority investigators from the nities, was established by the Office of Minority Health Research Coordination training level to senior faculty, the workshop aims to provide mentorship, within the National Institute of Diabetes and Digestive and Kidney Diseases poster presentations, and scholarly exchange among leaders in the field. (NIDDK), to facilitate participation in medical research in fields relevant to Participation in the workshop is by invitation only, and invited attendees NIDDK. are reimbursed for travel expenses. Participants are strongly encouraged to Chronic kidney disease (CKD) has increased 30 percent during the past submit an abstract for poster presentation. To determine your eligibility to decade. Today, approximately 26 million Americans suffer from the disease. participate, or for more information on the workshop, please contact Winnie Characterized by substantial differences in incidence, progression, treatment, Martinez at [email protected].

Key to Guess the Index to Advertisers Nephrologist from page 5 Amgen ...... Back Cover A. C. Craig Tisher, MD; John Stokes, MD, Fresenius Medical Care ...... 6 FASN; and Robert Alpern, MD

Spectra Laboratories ...... 21 B. Heini Murer, PhD, and Gerhard Giebisch, MD Genzyme ...... 2–3 C. Founding Fathers of the US with Richard Glassock, MD, in Philly Yale-New Haven Hospital ...... 11 D. Patricia Preisig, PhD, FASN