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Creating Research Infrastructure and Functionality to Address Chronic Kidney Disease: The Kidney Research Institute
Creating Research Infrastructure and Functionality to Address Chronic Kidney Disease: The Kidney Research Institute Jonathan Himmelfarb, MD, and Stuart J. Shankland, MD Summary: An expanding proportion of people in the United States and worldwide are affected by kidney disease, leading to a growing concern over the public health implications. Despite the high prevalence and the considerable associated health risks of kidney disease, major gaps in our knowledge base hinder the delivery of optimal medical care to affected individuals. Moreover, research progress that translates into clinical benefit has been slow. For example, over the past 20 years, there has been no successful implementation of a new therapeutic agent specifically designed for the treatment of glomerular diseases, which in part explains why glomerular diseases remain the leading cause of kidney disease in the United States and worldwide. Similarly, the limitations of current approaches to dialysis as treatment of end-stage kidney disease are becoming more apparent, with marginal improvements in risks for hospitalization or mortality over time. Along with recognition of changes in the public health burden of kidney disease, and perception of limited progress in the clinical treatment of kidney disease, a change in kidney disease research is now underway. We are entering a new era in biomedicine emphasizing interdisciplinary and translational research. We here delineate the purpose, mission, and goals, and describe the evolving vision, infrastructure, and research platform of a new Kidney Research Institute, designed to overcome barriers to researching improvements in effective clinical care. Semin Nephrol 29:457-466 © 2009 Published by Elsevier Inc. Keywords: Chronic kidney disease, translational research, clinical trials, bioinformatics, uremia
his issue of Seminars in Nephrology details growing concerns over the impact of kidney disease on global public health. An expanding proportion of people in the United States and worldwide are affected by kidney disease. In the United States, the most recent data suggest that 27 million individuals have chronic kidney disease (CKD), representing nearly 1 in every 7 adults.1 This represents a 30% increase over the past decade. Population sampling studies from around the globe indicate similar prevalence rates, generally ranging between 10% and 14% of the adult population. CKD has been linked with major adverse health outcomes, with a graded increase in risks as
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Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA. Address reprints requests to Jonathan Himmelfarb, MD, 325 9th Ave, Box 359764, Seattle, WA 98104. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2009.06.002
kidney function is lost.2,3 These risks include premature cardiovascular disease, fractures, infections, and diminished physical and mental functioning. Despite the scope of CKD, and the considerable associated health risks, major gaps in our knowledge base hinder the delivery of optimal medical care to affected individuals. The increasing rate in the number of patients who reach stage 5, or end-stage kidney disease (ESKD) requiring dialysis or kidney transplantation, is of particular concern. The 2008 US Renal Data System Annual Data Report noted that 110,851 new cases of ESKD were diagnosed in 2006, up 3.4% from the previous year. Treatment of ESKD already accounts for a considerable component of health care costs. For example, in the United States, dialysis care accounts for 7% of all Medicare expenditures. It has been estimated that globally more than one trillion dollars has been spent on ESKD care in this decade, even though in many countries
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dialysis and kidney transplantation are not readily available.4 Given that the increase in kidney disease appears to be driven by the increasing prevalence of obesity, diabetes, hypertension, and aging of the population, kidney disease is expected to increase as a public health concern for the foreseeable future. There is significant risk that the growing kidney disease burden will render treatment costs unsustainable even in the US health care delivery system.5 NEED FOR TRANSLATIONAL RESEARCH IN CKD Despite a rich historical tradition of active research investigation into the causes, mechanisms, and consequences of kidney disease, progress that translates into clinical benefit has been slow. Historically, it frequently has been observed that dialysis investigators and scientists researching pathophysiology in the kidney often have remained intellectually separated, often even when working in the same academic department. Salient examples of the lack of clinical progress, despite robust research efforts, include the treatment of glomerular diseases, and understanding and treatment of uremic complications with dialysis. Unfortunately, over the past 20 years, there has been no successful implementation of a new therapeutic agent specifically designed for the treatment of glomerular diseases, which in part explains why glomerular diseases remain the leading cause of CKD and ESKD in the United States. On a molecular level, our understanding of glomerular diseases is limited to a few monogenic disorders in which gene mutations encoding glomerular proteins have been described, whereas sparse data are available regarding gene activation and protein targets in the common glomerular disorders triggered by systemic disease.6-8 Although kidney biopsy is currently the gold standard for establishing diagnosis and prognosis in kidney disease, there are considerable limitations on the information obtained. Kidney biopsies do not provide dynamic information on disease activity, extracellular matrix protein turnover, or active reparative processes. In addition, histopathologic analysis provides limited data on potential therapeutic targets, such as growth factors, cyto-
J. Himmelfarb and S.J. Shankland
kines, or immune responsive cells in the kidney parenchyma. Enormous opportunities currently exist to use molecular technologies to improve the diagnostic and prognostic capability of the kidney biopsy, and to develop more diseasespecific targeted therapies. Similarly, the limitations of current approaches to dialysis as treatment of uremia are becoming more apparent, leading us to suggest that dialysis therapy may be at a developmental cross-road or tipping point.9 In analyses from the United States Renal Data System, there have been marginal improvements in risks for hospitalization or mortality over the past decade, despite steady improvement in achieving many identified dialysis clinical performance measures such as Kt/Vurea. Data from several important randomized clinical trials are particularly challenging. The National Institutes of Health– sponsored HEMO Study used a 2 ⫻ 2 factorial design to examine whether a high dose of dialysis or use of high-flux dialysis membranes could improve hemodialysis outcomes.10 Unfortunately, the results supported the null hypothesis for each treatment intervention. The Adequacy of PD in Mexico (ADEMEX) Trial, another well-conducted clinical trial, similarly did not show a relationship between peritoneal dialysis dose and patient outcomes.11 These studies suggest that there may be a threshold dialysis dose above which there may be minimal if any augmented clinical benefit. Other recent studies supporting the null hypothesis include investigations of the use of statins to lower the rate of cardiovascular complications in diabetic dialysis patients,12 homocysteine lowering therapies,13 use of non– calcium-containing phosphorus binders,14 and targeting higher hemoglobin concentrations with erythropoietin.15,16 Given the lack of recent progress and rash of negative studies, a re-examination of the mechanisms of uremic toxicity and engineering principles at the root of dialysis therapy are timely. EVOLVING RESEARCH STRATEGIES Concomitant with recognition of changes in the public health burden of kidney disease, and perception of limited progress in the clinical treatment of kidney disease, a change in kidney disease research is now underway. We are en-
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tering a new era in biomedicine that emphasizes interdisciplinary and translational research.17 Boundaries and barriers that previously separated basic science and clinical investigation are disappearing slowly. The revolution in systems biology and biotechnology makes it possible for the first time to engage the complexity of chronic illness, and to design innovative ways to study the many pathways involved in kidney injury. Advances in microarray technology make it possible to measure the expression of thousands of genes simultaneously in biological systems. A revolution in protein chemistry and metabolite analysis permits the simultaneous measurement of analytes present in fentamole concentrations in biological fluids. The human genome project and online annotated databases provide access to a wealth of new information about human and integrative biology. There is a pressing need to apply these new technologies systematically to test creative new hypotheses about kidney injury in human beings to gain a better understanding of pathogenesis, and to develop better predictors of onset and outcome. At the same time, there is a need to address the complicated needs of people with kidney disease to minimize disability and improve quality of life. The time is right to address complexity in human beings with kidney disease to move the field forward, and reduce the disease burden. Evolving research strategies, although likely having beneficial impact, also will create new challenges within the academic environment, and in public-private research relationships. The growth and complexity of translational research efforts will dictate that research sites be expanded, and must interface with a regulatory environment that has become more complex. Currently, common communication processes concerning novel technologies in the rapidly evolving field of translational health science are underdeveloped, and common bioinformatic and other infrastructure needs across research sites often do not exist. In response to these demands, the University of Washington, in collaboration with the nonprofit Northwest Kidney Centers (the world’s first outpatient dialysis program), recently created the Kidney Research Institute (KRI). The Northwest Kidney
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Centers has a rich history of seminal studies in kidney disease, including research of vascular access, use of erythropoietic agents, studies of metabolic bone disease, and novel dialysis technologies. We here delineate the purpose, mission, and goals, and describe the evolving vision, infrastructure, and research platform of the nascent KRI, as an example of the evolving comprehensive approach to studying kidney disease. MISSION OF THE KRI The overall mission of the KRI is as follows.
Research The KRI will focus on conducting research that has high potential to tangibly improve the lives of those with kidney disease. This includes understanding the pathophysiology of uremia and other complications resulting from loss of kidney function, as well as factors contributing to the progression and severity of underlying kidney disease. A major focus will be on diabetic kidney disease research, the leading cause of kidney disease worldwide.
Training As described by Kohan and Rosenberg (p. 539) in this issue of Seminars in Nephrology, there is currently a desperate shortage of physician-scientists in nephrology and other medical disciplines. This shortage is owing at least in part to a lack of adequate research training resources, including formalized mentoring programs. Because of the depth and diversity of research, the KRI is well positioned to provide a critical role for the training of predoctoral and postdoctoral fellows in research related to kidney disease and its complications. The purpose is to train physician-scientists in a multidisciplinary and multicollaborative approach to answer clinically relevant questions. This also will include formal journal clubs, seminars, and other course work. Training will be conducted in close collaboration with the School of Public Health, with the expectation that trainees will obtain a Master’s level degree.
Collaborations/Interactions The KRI will provide an important mechanism for interactions with investigators beyond the
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Division of Nephrology to enhance and diversify research in kidney disease. The KRI will coordinate kidney research at the University of Washington by facilitating interactions across schools (such as the Schools of Public Health and Community Medicine, Education, Business, Engineering, Information Technology, and Public Affairs), departments within the School of Medicine (Transplant and Vascular Surgery, Immunology, Pathology, Sports Medicine, Radiology, Genomics, and Pediatrics), and divisions within the Department of Medicine (Endocrinology, Infectious Disease, Cardiology, Geriatrics, and Rheumatology) to supplement the existing strengths in research and clinical care at the University of Washington. VISION FOR THE KRI The purpose of the KRI will be to establish a leading clinical and translational research effort focusing on the early detection, prevention, and treatment of kidney disease and its complications. The KRI will provide a 360° examina-
tion of kidney disease with scientists in clinical medicine, pharmacology, genetics, pathology, psychology, education, and physiology, working closely with basic scientists in bioengineering, biochemistry, immunology, genomics, and other disciplines. The is based on bringing together leading researchers from multiple disciplines to focus on kidney disease, covering the range from detailed mechanistic studies to large-scale clinical and population-based epidemiologic studies. Productivity and scientific interactions are fostered and optimized by having researchers and clinicians with overlapping and common interests in close proximity to one another. The translational research programs within the proposed network give a unique opportunity for young researchers to be trained on the job in various research settings. This program also can be strengthened by a structured educational program offered to young researchers and faculty of the network. Our goal is to create the infrastructure necessary to sustain a collaborative network dedi-
Figure 1. A collaborative network for the study of CKD.
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cated to the study of kidney disease (Fig. 1). We will use a multidisciplinary approach that will target the major areas of unmet needs in the diagnosis and treatment of kidney disease. There will be a parallel focus on translating scientific discovery into improved models of patient care. We will attempt to develop novel tools that are useful for population-based kidney disease screening and novel assessment tools that are useful to test therapeutics, and to improve care delivery. We will attempt to thematically connect basic researchers (cell biology, pathology, bioengineering, biomarker discovery, genetics) with clinical researchers (epidemiology, clinical trials, statistics, chronic care models) to catalyze new avenues of translational research. We propose to develop a broad-based observational cohort study, kidney biopsy registry, and Clinical Trials Incubator, motivating new trials, attracting collaboration with outside institutions, and providing access to an inclusive group of patients with kidney disease (Fig. 2). Our broad research focus will be to derive a contemporary analysis of the physiologic components of kidney function to better understand uremia (Fig. 3). In complex living organisms, the organ system most responsible for finely regulating environmental homeostasis is the kidney. Because kidney function plays a
critical role in maintaining circulatory and organ system functional homeostasis, the loss of kidney function leads to dysregulation of many metabolic pathways, clinically resulting in the uremic syndrome.18 We will focus on specific metabolic pathways by which the milieu interieur is altered, including oxidative stress, inflammation, and insulin resistance–related pathways. Given the metabolic complexities in kidney disease, we will attempt to apply concepts derived from reverse engineering, which increasingly are being applied to biology. The reverse engineering process involves identifying modules and subsystems, defining the interfaces between subsystems, thereby creating an architecture for system structure.19 When successful, reverse engineering can provide a high level blueprint for understanding how a disease system such as kidney disease works, thereby leading to hypotheses for systems level improvements via new therapeutics. KRI INFRASTRUCTURE Initial considerations for structural resources for the KRI include the following.
Space The KRI occupies more than 5,000 square feet of newly built contiguous space to house re-
Figure 2. The KRI infrastructure and platform.
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Figure 3. Physiologic approach to uremia.
search faculty, trainees, statistical support staff, administration, and clinical/translational research coordinators. The space also includes conference rooms for research meetings, and videoconferencing capability. This infrastructure will enable scheduled meetings of all key personnel, and facilitate recurrent updating of all investigators and staff on key aspects of planning, problem solving, assay development, and data review and analysis. Investigators will work in multigenerational, multidisciplinary small teams based on shared interests within kidney disease.
Repository and Laboratory The KRI will house an expansive tissue repository suitable for the blood, urine, and kidney biopsy tissue specimens contained in this research proposal. The KRI additionally houses 3,000 square feet of dedicated wet laboratory space as part of a shared laboratory research space at Harborview Medical Center. The KRI will work collaboratively with several University of Washington Core facilities to apply genetic, functional genomic, epigenetic, proteomic, and metabolomic technologies to the study of kidney disease, and to enhance understanding of biological pathways and networks relevant to uremic complications.
Clinical Research Base The KRI has extensive dedicated clinical research space available at several sites including Harborview Medical Center and the Haviland Center of the Northwest Kidney Centers. Clinical research space includes multiple examination rooms with state-of-the-art equipment for cardiovascular physiologic testing, body composition analyses, and supervised exercise programs.
Bioinformatics Support The KRI will use a Microsoft Access (Redmond, WA)– based relational database, allowing webbased entry with a high level of functionality and data confidentiality. This database is scalable, adaptable, and suitable for the proposed studies. However, each project in this tiered research program requires a different scientific foundation, different methods of analysis, and different sources of data. To support a comprehensive kidney disease research program, development of a robust bioinformatics platform is required. To accomplish this, we plan to partner with efforts already underway through the Institute for Translational Health Sciences, funded through the National Institutes of Health Clinical and Translational Science Award process at the University of Washington. The
Research infrastructure for CKD
integrated approach will be the Virtual Data Warehouse model. In partnership with the Institute for Translational Health Sciences, we will develop and maintain a confidential secure database to capture, inventory, and analyze the accumulated query experience to identify recurring query patterns. KRI RESEARCH PROGRAM
Biomarker Discovery Platform Although a plethora of studies have provided detailed evaluations of circulating biomarkers of cardiovascular risk in CKD, currently available biomarkers add only marginal predictive power over clinical demographics, comorbidities, and the level of the glomerular filtration rate.20 Similarly, few studies comprehensively have evaluated the utility of biomarkers for predicting kidney disease development and progression, beyond measures estimating the glomerular filtration rate. Thus, there is a need for novel strategies to increase biomarker utility in kidney disease. We will focus these studies on understanding the relationship of novel biomarkers derived from proteomic, metabolomic, genetic, and epigenetic studies to phenotypes associated with kidney disease. This overall study approach is divided into biomarker profile discovery, selection, and validation phases. We will take a pathway approach to select candidate genes, proteins, and metabolites that might provide links with the development of kidney disease, influence kidney disease progression, and/or influence specific complications such as cardiovascular disease. The discovery process requires a systematic exploration of all available avenues for important biomarker identification. For this phase, when intensive and largely qualitative biomarker profiling is required, it is important to have access to samples from well-characterized patient populations that differ markedly in the severity of the disease process from matched healthy subjects. During the biomarker profile selection phase, it is additionally important to have access to samples from well-screened patient populations that are somewhat more heterogeneous in their disease characteristics, but in whom associations with the important end
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point (cardiovascular risk) have been well defined and documented. It also is useful to be able to assess how therapies designed to alleviate risk (such as kidney transplantation, dialysis, or novel pharmacologic and lifestyle-altering therapies) alter biomarker profiles. During the selection phase, a goal is to identify a smaller set of biomarker profiles that give maximum classification performance with respect to assessment. Here, models will be built to assess the performance of biomarker profiles in capturing and classifying risk by carefully assessing accuracy, sensitivity, specificity, and cross-validation. During the validation phase, it is critical to assess whether models of biomarker profiles are reproducible in heterogeneous clinical populations of varying disease severity. PROGRAMMATIC DEVELOPMENT OF A KIDNEY BIOPSY REGISTRY We plan a new programmatic development of a kidney biopsy registry and kidney tissue bank suitable for immunohistochemistry, in situ hybridization, laser microdissection, and molecular analyses. We will use research protocols that obtain an extra core of kidney tissue (with informed consent) to be processed for microarray analysis of the glomerular transcriptome. We will coordinate clinical data with biopsy data, modifying the approach pioneered by the North Carolina Glomerulonephritis Collaborative Network. This includes the use of userfriendly care report forms that make it possible for busy clinicians to provide key clinical information for correlation with biopsy specimens. To date, few efforts to map human glomerular transcriptional profiles have been reported. The few studies to date, although successful at identifying limited subsets of glomerular markers, suffer from limitations in scale and technology.21-24 A recent meta-analysis of studies examining the glomerular transcriptome and development of a predicted protein–protein interaction network in the glomerulus was limited greatly by the lack of available data and by a complete lack of accompanying clinical outcome data.25 Our overall strategic approach will be to target specific pathways for analysis in the majority of biopsies, while applying more unbiased, global analyses of the transcriptome to a
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limited number of biopsies that are disease and stage-of-disease focused. A particularly powerful approach will be to assess changes in the glomerular transcriptome in serial kidney biopsies obtained in experimental protocols evaluating novel therapies for glomerular diseases. The opportunities afforded will enable the following: (1) comprehensive links to clinical outcome studies, thereby better identifying clinical and prognostic variables in tissues important for optimal care for patients and to support prognostic and outcome measures for clinical trials, and (2) enhanced ability to harness emerging technologies to discover new prognostic markers and treatable targets in renal disease.
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ical efficacy. The incubator concept provides a mechanism to bridge the clinical laboratory and large-scale clinical trials. The failure of some prior large clinical trials in kidney disease may be explained in part by the relative lack of biological data in human beings showing efficacy with intermediate end points, such as reduction of inflammatory responses in the kidney or in the systemic circulation. Although animal models have been very useful in studying pathogenetic mechanisms, it remains difficult to predict the efficacy of new treatments in human beings using animal data. A clinical trials incubator may provide a novel bridge between preclinical studies and major clinical trials, and help address the current dearth of clinical trials data that has been noted in kidney disease.
CLINICAL TRIALS INCUBATOR The current evidence base from randomized clinical trials to support interventions in the CKD population is recognized as being woefully inadequate, and clinical studies evaluating novel therapies desperately are needed.26 The Cochrane Renal Group recently reported that the number of randomized clinical trials published in kidney disease from 1966 to 2002 is fewer than for all other specialties of internal medicine. Other than the use of inhibitors of the renin-angiotensin system, no therapeutic agents have been shown definitely to slow the progression of CKD to end-stage renal disease (ESRD). In addition to the lack of interventional trials directed specifically at kidney disease, patients with kidney disease have been underrepresented in major trials in cardiovascular disease and hypertension.27 Indeed, many trials have explicit exclusion criteria based on level of kidney function. Thus, even though patients with CKD experience an extraordinarily high rate of cardiovascular complications, clinical practice recommendations must be extrapolated from studies in other patient populations. We plan to establish the infrastructure for pilot clinical projects that are powered to determine whether novel new therapies modify critical aspects of kidney disease–associated complications. The goal is to identify new therapies with biological signals that are strong enough to warrant sending these new treatments to larger clinical trials for studies of clin-
APPLICATION OF THE CHRONIC CARE MODEL TO KIDNEY DISEASE The Chronic Care Model, developed at Group Health Cooperative’s Center for Health Studies, facilitates integrated care of complex patients with chronic disease. As a chronic, costly disease that requires early detection and aggressive management of risk factors at early stages to decrease complications, CKD is ideal for application of the Chronic Care model. A kidney disease prevention plan could be based on the 10 Essential Services of Public Health, developed by the Center for Disease Control’s Public Health Practice Program Office and the Office of Disease Prevention and Health Promotion in the early 1990s. Within this framework, the plan outlines goals and activities that are specific to the prevention and control of CKD and includes public education, screening of highrisk individuals, classes for individuals with midto late-state CKD, and outreach to primary care physicians. By using a structure and framework designed and created to allow ongoing measurement of results, this approach is highly suitable as a scalable model for applying the Chronic Care Model to CKD. We plan on adapting the Chronic Care Model to test the hypothesis that measurable improvements in CKD health care delivery can be achieved through the use of tools supporting a patient-centered medical decision-making approach.
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IMPORTANCE OF LIFESTYLE FACTORS Lifestyle factors are root causes of CKD development and progression, yet have received scant attention in translational research. We plan to develop studies of healthy lifestyle interventions to mitigate the effects of overfeeding, obesity, and tobacco use on the development and progression of kidney disease. As described by Ritz and Koleganova (p. 504) in this issue of Seminars in Nephrology, the obesity epidemic has occurred concurrently with the dramatic increase in the prevalence of CKD and ESKD. Recent epidemiologic studies indicate a significant relationship between the degree of adiposity and the incidence of CKD.28 Furthermore, the presence of an increased body mass index has been shown independently to predict progression to ESRD even after adjustments for baseline blood pressure and the presence or absence of diabetes mellitus.29 A recent meta-analysis suggested that 24.2% and 33.9% of CKD cases among US men and women, respectively, could be related to overweight and obesity.30 We recently showed that adiposity amplifies the oxidative stress and inflammation that accompany moderate to severe CKD and contribute to cardiovascular risk. These data suggest that interventions targeting pathways that are known to be associated with adiposity, including caloric excess and reduced physical activity, may decrease the incidence of CKD, progression to ESRD, and may ameliorate cardiovascular risk. However, the concept that dietary interventions, coupled with exercise, can reduce metabolic complications in the CKD population must be tested rigorously through carefully designed, randomized clinical trials. REFERENCES 1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038-47. 2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. 3. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285-95. 4. Lysaght MJ. Maintenance dialysis population dynam-
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ics: current trends and long-term implications. J Am Soc Nephrol. 2002;13 Suppl 1:S37-40. Schoolwerth AC, Engelgau MM, Hostetter TH, Rufo KH, Chianchiano D, McClellan WM, et al. Chronic kidney disease: a public health problem that needs a public health action plan. Prev Chronic Dis. 2006;3: A57. Somlo S, Mundel P. Getting a foothold in nephrotic syndrome. Nat Genet. 2000;24:333-5. Hudson BG, Tryggvason K, Sundaramoorthy M, Neilson EG. Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med. 2003;348:2543-56. Ly J, Alexander M, Quaggin SE. A podocentric view of nephrology. Curr Opin Nephrol Hypertens. 2004;13: 299-305. Himmelfarb J. Dialysis at a crossroads: reverse engineering renal replacement therapy. Clin J Soc Nephrol. 1-896-902, 2006. Eknoyan G, Beck GJ, Cheung AK, Daugirdas JT, Greene T, Kusek JW, et al, Hemo Study Group. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med. 2002;347:2010-9. Paniagua R, Amato D, Vonesh E, Correa-Rotter R, Ramos A, Moran J, et al. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol. 2002;13:1307-20. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-48. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007; 298:1163-70. Suki WN, Zabaneh R, Cangiano JL, Reed J, Fischer D, Garrett L, et al. Effects of sevelamer and calciumbased phosphate binders on mortality in hemodialysis patients. Kidney Int. 2007;72:1130-7. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and erythropoietin. N Engl J Med. 1998;339:584-90. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006; 355:2085-98. NIH Roadmap. web. 11-30-0005. [cited 2009 June 7]. Available from: www.nihroadmap.nihgov. Meyer TW, Hostetter TH. Uremia. N Engl J Med. 2007;357:1316-25. Chikofsky EJ, Cross JH. Reverse engineering and design recovery: a taxonomy. IEEE Software. 1990;7:66-71. Rubin C, Nolin TD, Himmelfarb J. Are biomarkers useful for assessing cardiovascular risk in patients
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with chronic kidney disease? Curr Opin Nephrol Hypertens. 2007;16:506-11. Takemoto M, He L, Norlin J, Patrakka J, Xiao Z, Petrova T, et al. Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J. 2006;25:1160-74. Higgins JP, Wang L, Kambham N, Montgomery K, Mason V, Vogelmann SU, et al. Gene expression in the normal adult human kidney assessed by complementary DNA microarray. Mol Biol Cell. 2004;15:649-56. He L, Sun Y, Patrakka J, Mostad P, Norlin J, Xiao Z, et al. Glomerulus-specific mRNA transcripts and proteins identified through kidney expressed sequence tag database analysis. Kidney Int. 2007;71:889-900. Chabardes-Garonne D, Mejean A, Aude JC, Cheval L, Di SA, Gaillard MC, et al. A panoramic view of gene expression in the human kidney. Proc Natl Acad Sci U S A. 2003;100:13710-5. He L, Sun Y, Takemoto M, Norlin J, Tryggvason K, Samuelsson T, et al. The glomerular transcriptome
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and a predicted protein-protein interaction network. J Am Soc Nephrol. 2008;19:260-8. Himmelfarb J. Chronic kidney disease and the public health: gaps in evidence from interventional trials. JAMA. 2007;297:2630-3. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA. 2006; 296:1377-84. Ejerblad E, Fored CM, Lindblad P, Fryzek J, McLaughlin JK, Nyren O. Obesity and risk for chronic renal failure. J Am Soc Nephrol. 2006;17:1695-702. Hsu CY, McCulloch CE, Iribarren C, Darbinian J, Go AS. Body mass index and risk for end-stage renal disease. Ann Intern Med. 2006;144:21-8. Wang Y, Chen X, Song Y, Caballero B, Cheskin LJ. Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int. 2008; 73:19-33.
his issue of Seminars in Nephrology details growing concerns over the impact of kidney disease on global public health. An expanding proportion of people in the United States and worldwide are affected by kidney disease. In the United States, the most recent data suggest that 27 million individuals have chronic kidney disease (CKD), representing nearly 1 in every 7 adults.1 This represents a 30% increase over the past decade. Population sampling studies from around the globe indicate similar prevalence rates, generally ranging between 10% and 14% of the adult population. CKD has been linked with major adverse health outcomes, with a graded increase in risks as
T
Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, WA. Address reprints requests to Jonathan Himmelfarb, MD, 325 9th Ave, Box 359764, Seattle, WA 98104. E-mail: [email protected] 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2009.06.002
kidney function is lost.2,3 These risks include premature cardiovascular disease, fractures, infections, and diminished physical and mental functioning. Despite the scope of CKD, and the considerable associated health risks, major gaps in our knowledge base hinder the delivery of optimal medical care to affected individuals. The increasing rate in the number of patients who reach stage 5, or end-stage kidney disease (ESKD) requiring dialysis or kidney transplantation, is of particular concern. The 2008 US Renal Data System Annual Data Report noted that 110,851 new cases of ESKD were diagnosed in 2006, up 3.4% from the previous year. Treatment of ESKD already accounts for a considerable component of health care costs. For example, in the United States, dialysis care accounts for 7% of all Medicare expenditures. It has been estimated that globally more than one trillion dollars has been spent on ESKD care in this decade, even though in many countries
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dialysis and kidney transplantation are not readily available.4 Given that the increase in kidney disease appears to be driven by the increasing prevalence of obesity, diabetes, hypertension, and aging of the population, kidney disease is expected to increase as a public health concern for the foreseeable future. There is significant risk that the growing kidney disease burden will render treatment costs unsustainable even in the US health care delivery system.5 NEED FOR TRANSLATIONAL RESEARCH IN CKD Despite a rich historical tradition of active research investigation into the causes, mechanisms, and consequences of kidney disease, progress that translates into clinical benefit has been slow. Historically, it frequently has been observed that dialysis investigators and scientists researching pathophysiology in the kidney often have remained intellectually separated, often even when working in the same academic department. Salient examples of the lack of clinical progress, despite robust research efforts, include the treatment of glomerular diseases, and understanding and treatment of uremic complications with dialysis. Unfortunately, over the past 20 years, there has been no successful implementation of a new therapeutic agent specifically designed for the treatment of glomerular diseases, which in part explains why glomerular diseases remain the leading cause of CKD and ESKD in the United States. On a molecular level, our understanding of glomerular diseases is limited to a few monogenic disorders in which gene mutations encoding glomerular proteins have been described, whereas sparse data are available regarding gene activation and protein targets in the common glomerular disorders triggered by systemic disease.6-8 Although kidney biopsy is currently the gold standard for establishing diagnosis and prognosis in kidney disease, there are considerable limitations on the information obtained. Kidney biopsies do not provide dynamic information on disease activity, extracellular matrix protein turnover, or active reparative processes. In addition, histopathologic analysis provides limited data on potential therapeutic targets, such as growth factors, cyto-
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kines, or immune responsive cells in the kidney parenchyma. Enormous opportunities currently exist to use molecular technologies to improve the diagnostic and prognostic capability of the kidney biopsy, and to develop more diseasespecific targeted therapies. Similarly, the limitations of current approaches to dialysis as treatment of uremia are becoming more apparent, leading us to suggest that dialysis therapy may be at a developmental cross-road or tipping point.9 In analyses from the United States Renal Data System, there have been marginal improvements in risks for hospitalization or mortality over the past decade, despite steady improvement in achieving many identified dialysis clinical performance measures such as Kt/Vurea. Data from several important randomized clinical trials are particularly challenging. The National Institutes of Health– sponsored HEMO Study used a 2 ⫻ 2 factorial design to examine whether a high dose of dialysis or use of high-flux dialysis membranes could improve hemodialysis outcomes.10 Unfortunately, the results supported the null hypothesis for each treatment intervention. The Adequacy of PD in Mexico (ADEMEX) Trial, another well-conducted clinical trial, similarly did not show a relationship between peritoneal dialysis dose and patient outcomes.11 These studies suggest that there may be a threshold dialysis dose above which there may be minimal if any augmented clinical benefit. Other recent studies supporting the null hypothesis include investigations of the use of statins to lower the rate of cardiovascular complications in diabetic dialysis patients,12 homocysteine lowering therapies,13 use of non– calcium-containing phosphorus binders,14 and targeting higher hemoglobin concentrations with erythropoietin.15,16 Given the lack of recent progress and rash of negative studies, a re-examination of the mechanisms of uremic toxicity and engineering principles at the root of dialysis therapy are timely. EVOLVING RESEARCH STRATEGIES Concomitant with recognition of changes in the public health burden of kidney disease, and perception of limited progress in the clinical treatment of kidney disease, a change in kidney disease research is now underway. We are en-
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tering a new era in biomedicine that emphasizes interdisciplinary and translational research.17 Boundaries and barriers that previously separated basic science and clinical investigation are disappearing slowly. The revolution in systems biology and biotechnology makes it possible for the first time to engage the complexity of chronic illness, and to design innovative ways to study the many pathways involved in kidney injury. Advances in microarray technology make it possible to measure the expression of thousands of genes simultaneously in biological systems. A revolution in protein chemistry and metabolite analysis permits the simultaneous measurement of analytes present in fentamole concentrations in biological fluids. The human genome project and online annotated databases provide access to a wealth of new information about human and integrative biology. There is a pressing need to apply these new technologies systematically to test creative new hypotheses about kidney injury in human beings to gain a better understanding of pathogenesis, and to develop better predictors of onset and outcome. At the same time, there is a need to address the complicated needs of people with kidney disease to minimize disability and improve quality of life. The time is right to address complexity in human beings with kidney disease to move the field forward, and reduce the disease burden. Evolving research strategies, although likely having beneficial impact, also will create new challenges within the academic environment, and in public-private research relationships. The growth and complexity of translational research efforts will dictate that research sites be expanded, and must interface with a regulatory environment that has become more complex. Currently, common communication processes concerning novel technologies in the rapidly evolving field of translational health science are underdeveloped, and common bioinformatic and other infrastructure needs across research sites often do not exist. In response to these demands, the University of Washington, in collaboration with the nonprofit Northwest Kidney Centers (the world’s first outpatient dialysis program), recently created the Kidney Research Institute (KRI). The Northwest Kidney
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Centers has a rich history of seminal studies in kidney disease, including research of vascular access, use of erythropoietic agents, studies of metabolic bone disease, and novel dialysis technologies. We here delineate the purpose, mission, and goals, and describe the evolving vision, infrastructure, and research platform of the nascent KRI, as an example of the evolving comprehensive approach to studying kidney disease. MISSION OF THE KRI The overall mission of the KRI is as follows.
Research The KRI will focus on conducting research that has high potential to tangibly improve the lives of those with kidney disease. This includes understanding the pathophysiology of uremia and other complications resulting from loss of kidney function, as well as factors contributing to the progression and severity of underlying kidney disease. A major focus will be on diabetic kidney disease research, the leading cause of kidney disease worldwide.
Training As described by Kohan and Rosenberg (p. 539) in this issue of Seminars in Nephrology, there is currently a desperate shortage of physician-scientists in nephrology and other medical disciplines. This shortage is owing at least in part to a lack of adequate research training resources, including formalized mentoring programs. Because of the depth and diversity of research, the KRI is well positioned to provide a critical role for the training of predoctoral and postdoctoral fellows in research related to kidney disease and its complications. The purpose is to train physician-scientists in a multidisciplinary and multicollaborative approach to answer clinically relevant questions. This also will include formal journal clubs, seminars, and other course work. Training will be conducted in close collaboration with the School of Public Health, with the expectation that trainees will obtain a Master’s level degree.
Collaborations/Interactions The KRI will provide an important mechanism for interactions with investigators beyond the
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Division of Nephrology to enhance and diversify research in kidney disease. The KRI will coordinate kidney research at the University of Washington by facilitating interactions across schools (such as the Schools of Public Health and Community Medicine, Education, Business, Engineering, Information Technology, and Public Affairs), departments within the School of Medicine (Transplant and Vascular Surgery, Immunology, Pathology, Sports Medicine, Radiology, Genomics, and Pediatrics), and divisions within the Department of Medicine (Endocrinology, Infectious Disease, Cardiology, Geriatrics, and Rheumatology) to supplement the existing strengths in research and clinical care at the University of Washington. VISION FOR THE KRI The purpose of the KRI will be to establish a leading clinical and translational research effort focusing on the early detection, prevention, and treatment of kidney disease and its complications. The KRI will provide a 360° examina-
tion of kidney disease with scientists in clinical medicine, pharmacology, genetics, pathology, psychology, education, and physiology, working closely with basic scientists in bioengineering, biochemistry, immunology, genomics, and other disciplines. The is based on bringing together leading researchers from multiple disciplines to focus on kidney disease, covering the range from detailed mechanistic studies to large-scale clinical and population-based epidemiologic studies. Productivity and scientific interactions are fostered and optimized by having researchers and clinicians with overlapping and common interests in close proximity to one another. The translational research programs within the proposed network give a unique opportunity for young researchers to be trained on the job in various research settings. This program also can be strengthened by a structured educational program offered to young researchers and faculty of the network. Our goal is to create the infrastructure necessary to sustain a collaborative network dedi-
Figure 1. A collaborative network for the study of CKD.
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cated to the study of kidney disease (Fig. 1). We will use a multidisciplinary approach that will target the major areas of unmet needs in the diagnosis and treatment of kidney disease. There will be a parallel focus on translating scientific discovery into improved models of patient care. We will attempt to develop novel tools that are useful for population-based kidney disease screening and novel assessment tools that are useful to test therapeutics, and to improve care delivery. We will attempt to thematically connect basic researchers (cell biology, pathology, bioengineering, biomarker discovery, genetics) with clinical researchers (epidemiology, clinical trials, statistics, chronic care models) to catalyze new avenues of translational research. We propose to develop a broad-based observational cohort study, kidney biopsy registry, and Clinical Trials Incubator, motivating new trials, attracting collaboration with outside institutions, and providing access to an inclusive group of patients with kidney disease (Fig. 2). Our broad research focus will be to derive a contemporary analysis of the physiologic components of kidney function to better understand uremia (Fig. 3). In complex living organisms, the organ system most responsible for finely regulating environmental homeostasis is the kidney. Because kidney function plays a
critical role in maintaining circulatory and organ system functional homeostasis, the loss of kidney function leads to dysregulation of many metabolic pathways, clinically resulting in the uremic syndrome.18 We will focus on specific metabolic pathways by which the milieu interieur is altered, including oxidative stress, inflammation, and insulin resistance–related pathways. Given the metabolic complexities in kidney disease, we will attempt to apply concepts derived from reverse engineering, which increasingly are being applied to biology. The reverse engineering process involves identifying modules and subsystems, defining the interfaces between subsystems, thereby creating an architecture for system structure.19 When successful, reverse engineering can provide a high level blueprint for understanding how a disease system such as kidney disease works, thereby leading to hypotheses for systems level improvements via new therapeutics. KRI INFRASTRUCTURE Initial considerations for structural resources for the KRI include the following.
Space The KRI occupies more than 5,000 square feet of newly built contiguous space to house re-
Figure 2. The KRI infrastructure and platform.
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Figure 3. Physiologic approach to uremia.
search faculty, trainees, statistical support staff, administration, and clinical/translational research coordinators. The space also includes conference rooms for research meetings, and videoconferencing capability. This infrastructure will enable scheduled meetings of all key personnel, and facilitate recurrent updating of all investigators and staff on key aspects of planning, problem solving, assay development, and data review and analysis. Investigators will work in multigenerational, multidisciplinary small teams based on shared interests within kidney disease.
Repository and Laboratory The KRI will house an expansive tissue repository suitable for the blood, urine, and kidney biopsy tissue specimens contained in this research proposal. The KRI additionally houses 3,000 square feet of dedicated wet laboratory space as part of a shared laboratory research space at Harborview Medical Center. The KRI will work collaboratively with several University of Washington Core facilities to apply genetic, functional genomic, epigenetic, proteomic, and metabolomic technologies to the study of kidney disease, and to enhance understanding of biological pathways and networks relevant to uremic complications.
Clinical Research Base The KRI has extensive dedicated clinical research space available at several sites including Harborview Medical Center and the Haviland Center of the Northwest Kidney Centers. Clinical research space includes multiple examination rooms with state-of-the-art equipment for cardiovascular physiologic testing, body composition analyses, and supervised exercise programs.
Bioinformatics Support The KRI will use a Microsoft Access (Redmond, WA)– based relational database, allowing webbased entry with a high level of functionality and data confidentiality. This database is scalable, adaptable, and suitable for the proposed studies. However, each project in this tiered research program requires a different scientific foundation, different methods of analysis, and different sources of data. To support a comprehensive kidney disease research program, development of a robust bioinformatics platform is required. To accomplish this, we plan to partner with efforts already underway through the Institute for Translational Health Sciences, funded through the National Institutes of Health Clinical and Translational Science Award process at the University of Washington. The
Research infrastructure for CKD
integrated approach will be the Virtual Data Warehouse model. In partnership with the Institute for Translational Health Sciences, we will develop and maintain a confidential secure database to capture, inventory, and analyze the accumulated query experience to identify recurring query patterns. KRI RESEARCH PROGRAM
Biomarker Discovery Platform Although a plethora of studies have provided detailed evaluations of circulating biomarkers of cardiovascular risk in CKD, currently available biomarkers add only marginal predictive power over clinical demographics, comorbidities, and the level of the glomerular filtration rate.20 Similarly, few studies comprehensively have evaluated the utility of biomarkers for predicting kidney disease development and progression, beyond measures estimating the glomerular filtration rate. Thus, there is a need for novel strategies to increase biomarker utility in kidney disease. We will focus these studies on understanding the relationship of novel biomarkers derived from proteomic, metabolomic, genetic, and epigenetic studies to phenotypes associated with kidney disease. This overall study approach is divided into biomarker profile discovery, selection, and validation phases. We will take a pathway approach to select candidate genes, proteins, and metabolites that might provide links with the development of kidney disease, influence kidney disease progression, and/or influence specific complications such as cardiovascular disease. The discovery process requires a systematic exploration of all available avenues for important biomarker identification. For this phase, when intensive and largely qualitative biomarker profiling is required, it is important to have access to samples from well-characterized patient populations that differ markedly in the severity of the disease process from matched healthy subjects. During the biomarker profile selection phase, it is additionally important to have access to samples from well-screened patient populations that are somewhat more heterogeneous in their disease characteristics, but in whom associations with the important end
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point (cardiovascular risk) have been well defined and documented. It also is useful to be able to assess how therapies designed to alleviate risk (such as kidney transplantation, dialysis, or novel pharmacologic and lifestyle-altering therapies) alter biomarker profiles. During the selection phase, a goal is to identify a smaller set of biomarker profiles that give maximum classification performance with respect to assessment. Here, models will be built to assess the performance of biomarker profiles in capturing and classifying risk by carefully assessing accuracy, sensitivity, specificity, and cross-validation. During the validation phase, it is critical to assess whether models of biomarker profiles are reproducible in heterogeneous clinical populations of varying disease severity. PROGRAMMATIC DEVELOPMENT OF A KIDNEY BIOPSY REGISTRY We plan a new programmatic development of a kidney biopsy registry and kidney tissue bank suitable for immunohistochemistry, in situ hybridization, laser microdissection, and molecular analyses. We will use research protocols that obtain an extra core of kidney tissue (with informed consent) to be processed for microarray analysis of the glomerular transcriptome. We will coordinate clinical data with biopsy data, modifying the approach pioneered by the North Carolina Glomerulonephritis Collaborative Network. This includes the use of userfriendly care report forms that make it possible for busy clinicians to provide key clinical information for correlation with biopsy specimens. To date, few efforts to map human glomerular transcriptional profiles have been reported. The few studies to date, although successful at identifying limited subsets of glomerular markers, suffer from limitations in scale and technology.21-24 A recent meta-analysis of studies examining the glomerular transcriptome and development of a predicted protein–protein interaction network in the glomerulus was limited greatly by the lack of available data and by a complete lack of accompanying clinical outcome data.25 Our overall strategic approach will be to target specific pathways for analysis in the majority of biopsies, while applying more unbiased, global analyses of the transcriptome to a
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limited number of biopsies that are disease and stage-of-disease focused. A particularly powerful approach will be to assess changes in the glomerular transcriptome in serial kidney biopsies obtained in experimental protocols evaluating novel therapies for glomerular diseases. The opportunities afforded will enable the following: (1) comprehensive links to clinical outcome studies, thereby better identifying clinical and prognostic variables in tissues important for optimal care for patients and to support prognostic and outcome measures for clinical trials, and (2) enhanced ability to harness emerging technologies to discover new prognostic markers and treatable targets in renal disease.
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ical efficacy. The incubator concept provides a mechanism to bridge the clinical laboratory and large-scale clinical trials. The failure of some prior large clinical trials in kidney disease may be explained in part by the relative lack of biological data in human beings showing efficacy with intermediate end points, such as reduction of inflammatory responses in the kidney or in the systemic circulation. Although animal models have been very useful in studying pathogenetic mechanisms, it remains difficult to predict the efficacy of new treatments in human beings using animal data. A clinical trials incubator may provide a novel bridge between preclinical studies and major clinical trials, and help address the current dearth of clinical trials data that has been noted in kidney disease.
CLINICAL TRIALS INCUBATOR The current evidence base from randomized clinical trials to support interventions in the CKD population is recognized as being woefully inadequate, and clinical studies evaluating novel therapies desperately are needed.26 The Cochrane Renal Group recently reported that the number of randomized clinical trials published in kidney disease from 1966 to 2002 is fewer than for all other specialties of internal medicine. Other than the use of inhibitors of the renin-angiotensin system, no therapeutic agents have been shown definitely to slow the progression of CKD to end-stage renal disease (ESRD). In addition to the lack of interventional trials directed specifically at kidney disease, patients with kidney disease have been underrepresented in major trials in cardiovascular disease and hypertension.27 Indeed, many trials have explicit exclusion criteria based on level of kidney function. Thus, even though patients with CKD experience an extraordinarily high rate of cardiovascular complications, clinical practice recommendations must be extrapolated from studies in other patient populations. We plan to establish the infrastructure for pilot clinical projects that are powered to determine whether novel new therapies modify critical aspects of kidney disease–associated complications. The goal is to identify new therapies with biological signals that are strong enough to warrant sending these new treatments to larger clinical trials for studies of clin-
APPLICATION OF THE CHRONIC CARE MODEL TO KIDNEY DISEASE The Chronic Care Model, developed at Group Health Cooperative’s Center for Health Studies, facilitates integrated care of complex patients with chronic disease. As a chronic, costly disease that requires early detection and aggressive management of risk factors at early stages to decrease complications, CKD is ideal for application of the Chronic Care model. A kidney disease prevention plan could be based on the 10 Essential Services of Public Health, developed by the Center for Disease Control’s Public Health Practice Program Office and the Office of Disease Prevention and Health Promotion in the early 1990s. Within this framework, the plan outlines goals and activities that are specific to the prevention and control of CKD and includes public education, screening of highrisk individuals, classes for individuals with midto late-state CKD, and outreach to primary care physicians. By using a structure and framework designed and created to allow ongoing measurement of results, this approach is highly suitable as a scalable model for applying the Chronic Care Model to CKD. We plan on adapting the Chronic Care Model to test the hypothesis that measurable improvements in CKD health care delivery can be achieved through the use of tools supporting a patient-centered medical decision-making approach.
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IMPORTANCE OF LIFESTYLE FACTORS Lifestyle factors are root causes of CKD development and progression, yet have received scant attention in translational research. We plan to develop studies of healthy lifestyle interventions to mitigate the effects of overfeeding, obesity, and tobacco use on the development and progression of kidney disease. As described by Ritz and Koleganova (p. 504) in this issue of Seminars in Nephrology, the obesity epidemic has occurred concurrently with the dramatic increase in the prevalence of CKD and ESKD. Recent epidemiologic studies indicate a significant relationship between the degree of adiposity and the incidence of CKD.28 Furthermore, the presence of an increased body mass index has been shown independently to predict progression to ESRD even after adjustments for baseline blood pressure and the presence or absence of diabetes mellitus.29 A recent meta-analysis suggested that 24.2% and 33.9% of CKD cases among US men and women, respectively, could be related to overweight and obesity.30 We recently showed that adiposity amplifies the oxidative stress and inflammation that accompany moderate to severe CKD and contribute to cardiovascular risk. These data suggest that interventions targeting pathways that are known to be associated with adiposity, including caloric excess and reduced physical activity, may decrease the incidence of CKD, progression to ESRD, and may ameliorate cardiovascular risk. However, the concept that dietary interventions, coupled with exercise, can reduce metabolic complications in the CKD population must be tested rigorously through carefully designed, randomized clinical trials. REFERENCES 1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038-47. 2. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. 3. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285-95. 4. Lysaght MJ. Maintenance dialysis population dynam-
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with chronic kidney disease? Curr Opin Nephrol Hypertens. 2007;16:506-11. Takemoto M, He L, Norlin J, Patrakka J, Xiao Z, Petrova T, et al. Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J. 2006;25:1160-74. Higgins JP, Wang L, Kambham N, Montgomery K, Mason V, Vogelmann SU, et al. Gene expression in the normal adult human kidney assessed by complementary DNA microarray. Mol Biol Cell. 2004;15:649-56. He L, Sun Y, Patrakka J, Mostad P, Norlin J, Xiao Z, et al. Glomerulus-specific mRNA transcripts and proteins identified through kidney expressed sequence tag database analysis. Kidney Int. 2007;71:889-900. Chabardes-Garonne D, Mejean A, Aude JC, Cheval L, Di SA, Gaillard MC, et al. A panoramic view of gene expression in the human kidney. Proc Natl Acad Sci U S A. 2003;100:13710-5. He L, Sun Y, Takemoto M, Norlin J, Tryggvason K, Samuelsson T, et al. The glomerular transcriptome
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