First International Summit on Kidney Disease Prevention, 25–27 July 2002: Consensus Document
Sylvia Paz B. Ramirez* on behalf of the Summit on Kidney Disease Prevention Participants*
*The Center for Prevention and Research, National Kidney Foundation Singapore, Singapore; and Faculty of Medicine, National University of Singapore, Singapore.
Correspondence to Dr. Sylvia Ramirez, Chief, Prevention, NKF Singapore, 81 Kim Keat Road, Singapore 328836. Phone: 65-6351-5279; Fax: 65-6354-9410; E-mail: paesr{at}nus.edu.sg
This Summit on the Prevention of Kidney and Related Diseaseswas held at the NKF Singapore to identify approaches to preventingthe global epidemic of end-stage renal disease. During the meeting,a list of discussion points was generated and areas for focusedfuture research were identified. Through a series of presentationsand discussions during the summit, specific recommendationsfor the prevention of chronic kidney disease were generatedand categorized as: (1) Interventions or Clinical Action Plansthat merit immediate implementation; (2) Randomized ClinicalTrials that should be prioritized; and (3) Observational Studiesthat deserve consideration.
A. Population-based surveys, prospective observational studies,and clinical trials related to chronic kidney disease shoulduse common terminology and methods to characterize their populations.
1. The global burden ofchronic kidney diseaseis unclear and likely underestimatedin part because of inconsistentresearch methods.
2.To better define the prevalence of chronickidney disease, thefollowing are needed:
a.A standard nosology fordefining chronic kidney disease.
b.The linking of population-basedsurvey information to end-stagerenal disease registries.
B. Clinical studies are neededto further demonstrate that proteinuriaor albuminuria are bothrisk factors for chronic kidney diseaseand therapeutic targetsfor prevention.
1. Thedistribution of proteinuriain differentpopulations needs tobe determined.
2.Albuminuria should bevalidated as a markerof clinical outcome,as well as a measureof therapeutic benefitin different populations.
3.In this regard, secondary analysis ofexistingrandomized trials,which primarily targeted BP reductionratherthan proteinuriareduction, should be considered.
C. There continues tobe a need to evaluate various clinicaland demographic characteristicsas well as risk factors or riskmarkers for the occurrence andprogression of chronic kidneydisease. Some markers for considerationinclude:
2.TGF-1, interleukins, and other markersof inflammation.
3.Markers of oxidative stress (e.g., reactiveoxygen species)and nitric oxide status (e.g., nitric oxideconcentration, nitricoxide synthase activity).
4. Homocysteine,lipoprotein (a), apoprotein(a), and other markers of dyslipidemia.
5. Obesity or body mass index.
6.Low birth weight.
7. Family history of renaldisease.
8. Cystatin C.
9.Genetic markers.
D. To identify individuals with chronickidney disease at theearliest possible stage, there is a needto develop predictionequations for the occurrence and progressionof chronic kidneydisease.
1.There is a need to developestimating equationsfor GFR thathave been validated acrosspopulations.
2.Methodology for the measurementof serumcreatinine and GFRshould be universally standardized.
E. Both population-basedprimary prevention strategies and high-riskindividualized interventioninitiatives need to be implementedto reduce the burden of chronickidney disease on a population-widescale.
1.Prevention strategiesneed to incorporatenot only renal diseaseprevention but generalchronic diseaseprevention (obesity,cardiovascular disease,diabetes, and hypertension),as theseconditions and diseasesare themselves risk factorsfor chronickidney disease.
2.In designing strategiesto implement population-widechangesin systems of health care,discussions on public healthpolicy,legislation, and healthcare reimbursement should beincluded.
3.Novel primary care models for the deliveryof primary and secondaryprevention programs should be studiedand considered for implementation.
4. Primarycare physicians should be targetedto increase their awarenessof the problem, and to aid in developmentand implementationof prevention strategies:
a.Education of the patientpopulation is a potentially effectivevehicle to positivelyinfluence physician behavior.
b.Improvement is neededin the dissemination to and implementationby primary care physiciansof clinical practice guidelines forthe prevention of chronickidney disease. General approachesto accomplish this task shouldbe identified and implemented.
c. Global guidelines forchronic kidney disease prevention may need to be developed.
5. Simultaneously, priority should begivento educating the general population and to implementingpreventionprograms. Such prevention and education programsneed to takeinto account sociocultural factors in their design.
6. Differences in resource availabilityinvarious target populations should be taken into account inthedesign of education and prevention programs. Indeed, thereneedsto be a specific emphasis on the creation of programsfor economicallydisadvantaged populations and less-developedcountries.
F. Consideration should be given to potentialethnic differences,which may occur in response to preventionand intervention strategies.
1.In general, the resultsof clinical trialsmay be extrapolatedacross ethnic groups.
2. Whereas ethnic-specificresponses tointerventionsshould be evaluated, standards ofcare shouldbe implementedregardless of ethnic group.
3.Although policies and clinical standardsmay be universal, methodsfor translating these policies intoclinical practice need tobe population- and culture-specific.
4.In the process of evaluating the generalizabilityof interventionstrategies across populations, variations inthe relative riskassociated with various risk factors for chronickidney diseaseshould be measured and taken into considerationin developingprevention programs. In particular, age-, gender-,and ethnic-specificabsolute risks for chronic kidney diseaseshould be evaluated.
G. Molecular genetics and epidemiology will serve as thebasisupon which prevention interventions will be designed inthefuture. The following issues related to molecular geneticsasapplied to prevention should be considered:
1.Genetic markers for riskprediction.
a.As more information becomesavailable, genetic markers shownto be associated with increasedsusceptibility to the developmentof renal disease, diabetes,or hypertension, should be evaluatedin research studies designedto define population-based riskprediction, as well as individualrisk prediction.
b.Although specific screeningstrategies have not been identified,it is possible that thereis a role for genetic screening ofpopulations at high-riskfor chronic kidney disease.
c.In the study and implementationof genetic screening and riskprediction, ethnic differencesin susceptibility genes mustbe taken into consideration. Thus,broader representation ofspecific ethnic groups should be ensuredin large genetic studies.
2. In performing genetic studies, thefollowingshould be considered:
a.In addition to well-establishedanalytic methods such as sib-pairanalysis, linkage analysis,linkage dysequilibrium mapping,and quantitative trait locianalysis, novel methodologies shouldbe developed and applied.
b.Environmental effectsshould be taken into consideration ingenetic studies. Noveltechniques to evaluate the effect ofgene–environmentinteractions should be utilized.
c.The existence and degreeof population strata ("admixture")should be taken into accountand adjusted for in genetic case-controlassociation studies,using established molecular epidemiologicmethodologies thathave been specifically developed for thispurpose.
3. Numerous clinical studiesdemonstrate theincreased likelihood of renal disease in familymembers of patientswith end-stage renal disease. Before theidentification of specificgenetic susceptibility genes, thepresence of family historyof end-stage renal disease shouldalready be incorporated inrisk prediction equations, as wellas in the development ofscreening guidelines.
4.Other issues to be considered include:
a.The need to establishprotocols and policies to provide accessibilityof population-basedmaterials/tissue to investigators in orderto facilitate geneticstudies.
b.The recognition of theneed to implement appropriate legal andethical safeguards topreserve patients’ rights.
H. Economic issues should be considered in the design of preventionand education programs.
1.In addition to determiningthe incidenceand prevalence of chronicdisease, its economicburden shouldbe an additional considerationin estimating populationdiseaseburden.
2.Studies on the cost-effectivenessof variousprevention approaches,including population-basedscreeningas opposed to high-riskintervention strategies, shouldbe performed.
3.The creation of economicallyfavorablereimbursement modelsfor health care systems may bean effectiveapproach to themodification and improvement ofchronic kidneydisease caredelivered by the medical community.
The following are interventions considered to have undergonesufficient evaluation to demonstrate their efficacy in preventionof chronic kidney disease and related diseases, such as diabetesmellitus and hypertension. As such, the following should beimplemented urgently:
A. Population-based intervention strategies:
1.Develop effective obesityprevention initiativesthat providespecific emphasis on physicalactivity.
2.Develop population-wide educationalprogramsto promote a healthylifestyle for the entire population.
3.Initiate a review of health resourceallocationand a greaterallocation of funds to education andprevention.
B. Highrisk intervention strategies:
1.Develop a chronic kidneydisease surveillancemodel for nationalend-stage renal diseaseregistries, includingroutine collection,screening, analysis,and reporting of patternsand outcomesof care for chronic kidneydisease.
2. Implementdisease managementmodels forthe approach to diabetes, hypertension,and chronickidney disease.
3. Implementproven primarycare models tooptimize standards of care forchronic kidneydisease and otherassociated chronic diseases.
4.Promote the screening for chronic kidneydisease in family membersof patients with end-stage renal disease.
b.Engage industry to provideresources (marketing, education,and others) to promote theimplementation of chronic kidneydisease prevention guidelines.
c.Initiate the systematicreporting of GFR using estimating equationsthat rely on serumcreatinine. Simultaneously, a standardizedcreatinine measurementwith validation in a range of populationsshould be developedand promoted.
The discussants identified several clinically relevant researchquestions that could be addressed in the setting of randomizedclinical trials. Prioritization would be useful because it islikely that only a few trials could be conducted.
1. Does aggressive BP reduction to a lower BP goal (<120/75mmHg), compared with the usual goal, retard kidney disease progressionin diabetic patients with or without microalbuminuria?
2.What is the appropriate BP goal in other populations of chronickidney disease patients with chronic kidney disease unrelatedto diabetes or polycystic kidney disease?
3. Is comprehensiveteam-based care to reduce chronic kidneydisease risk factorssuperior to standard care in retardingthe progression of chronickidney disease?
4. Do the effects of aggressive therapiesthat reduce proteinuriaretard progression of kidney diseaseindependent of their blood-pressurelowering effects?
5. Whatis the appropriate target for anti-proteinuric therapyusingangiotensin converting enzyme inhibitors (ACEI) or angiotensinreceptor blockers (ARB)?
6. In the setting of ACEI, is thereadded benefit from ARB indelaying chronic kidney disease progression?
7. Are HMG-CoA inhibitors effective in the reduction of proteinuria?
8. Do appetite suppressive drugs have a role in the managementof diabetes mellitus?
9. Do ACEI and/or ARB therapy preventincident diabetes mellitusamong individuals with impaired glucosetolerance?
In addition to trials that address the above research questions,there was a consensus that additional research that focuseson developing and evaluating strategies to implement lifestylechanges for obesity, diabetes, or hypertension, particularlyin the clinic setting should be conducted.
IV. Suggestions for Observational and Laboratory-Based Studies
1. Validation of the MDRD equation for estimation of creatinineclearance in other ethnic populations.
2. Appropriately designedgenetic association study of angiotensinconverting enzyme (ACE)gene and angiotensin II (AGII) receptorgene haplotypes withresponse to ACEI/ARB therapy, to determineif at-risk haplotypescan identify patients who are most likelyto benefit from ACEI/ARBtherapy.
3. Longitudinal cohort study of diabetic patientswith microalbuminuriafrom different ethnic groups to estimatethe true frequencyof progression to overt diabetic nephropathyand end-stage renaldisease in specific ethnic groups.
4.Screening:
a. Longitudinalcohort studyevaluating theefficacy of screening in the detectionand interventionof thedevelopment or progression of chronickidney diseasein thegeneral population.
b.Determinecost-effectiveness of population-basedversus high-riskscreeningstrategies in the detection and interventionof chronickidneydisease.
5. Laboratory-based studies:
a.Study the regulationof glomerular matrixsynthesis and degradation.
b.Study the regulation of growth factors/cytokinesin the kidney.
c. Identify urinary proteinexpression patternsusing proteomic approaches to predict ordetect chronic kidneydisease progression or regression.
6. Comorbidities in the setting of chronic kidney disease:
a. Study the progressionof cardiovascularrisk factors as a function of change in GFR
b. Study the prevalence and incidence ofnoncardiovascularconditions, including anemia, metabolic bonedisease, depression,and others, as a function of change inGFR.
Participants in the Summit on Kidney Disease Prevention, 25 to 27 July 2002
Lawrence J. Appel, Robert C. Atkins, Maximillian de Courten,Michael M. Engelgau, John M. Flack, Barry I. Freedman, ThomasH. Hostetter, Wendy E. Hoy, Stephen I-Hong Hsu, Kunitoshi Iseki,Sudha K. Iyengar, Camille A. Jones, William M. McClellan, MarkE. Molitch, William F. Owen Jr, Sylvia Paz B. Ramirez, JeromeRossert, F. Paolo Schena, Jaakko Tuomilehto, and Philip G Zager.
Footnotes
See complete list of Summit Participants at the end of thispaper.
This article has been cited by other articles:
S. P. B. Ramirez Chronic Kidney Disease Prevention in Singapore
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March 1, 2008;
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Introduction
I. Priority Areas That...
1, interleukins, and other markers of inflammation. 
