Assistant Professor In Residence Division of Nephrology University of California San Francisco Evolving Paradigms in Chronic Kidney Disease Epidemiology Findings from MESA Kidney Disease is an Epidemic in the United States ID: 1033993
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1. Carmen A. Peralta, MD, MASAssistant Professor In ResidenceDivision of NephrologyUniversity of California, San FranciscoEvolving Paradigms in Chronic Kidney Disease Epidemiology: Findings from MESA
2. Kidney Disease is an Epidemic in the United StatesThe ESRD population has grown to >650,000 in the U.S.This reflects Medicare expenditures of over $30 billion, more than 7% of total Medicare expendituresFoley and Collins, J Am Soc Nephrol 2007CKD defined as:kidney damage (albumin-to-creatinine ratio ≥30 mg/g) oreGFR <60mL/min/1.73m2Chronic kidney disease affects 13% of the U.S. population
3. Blacks and Hispanics are Disproportionally Affected by ESRDIncident ESRD patients. Rates adjusted for age & gender.Data from USRDS, 2007Reasons for race/ethnic differences in kidney disease are not well understood.
4. Paradigm #3: CKD can only be detected once disease is establishedParadigm #1: Hispanics have been considered one groupOutlineNormalCKDeGFRESRDCardiovascular DiseaseDeathDamageRace/EthnicityParadigm #2: Race/Ethnic Differences only observed once CKD is established
5. Paradigm #1 OutlineHispanics have been considered one group in studies of CKDThis is probably incorrectGenetic admixture as a tool to understand race/ethnicity Race/Ethnicity is more likely a multi-dimensional construct
6. Genetic Admixture AnalysisProvides a method to investigate potential genetic factors that contribute to racial differences in complex phenotypesMay also provide a more sensitive method than categorical racial groupings to study ancestry
7. AdmixtureTwo or more populations mix (individuals of mixed ancestry)Population 1Population 2
8. West AfricansEuropeansModern HispanicsAdapted courtesy of Dr. Linda KaoNative Americans
9. Genetic Ancestry and Country of Origin Determine Kidney Disease Risk among Hispanic-AmericansResearch Questions: Does genetically determined individual African, Native American or European ancestry differ by country of origin among Hispanics? Is country of origin associated with differences in albuminuria when compared to whites? Peralta CA et al., Circ CVD Gen 2010
10. MethodsSubjects: 705 Hispanics and 712 whites from the Multi-Ethnic Study of Atherosclerosis (MESA)Predictors: Self-identified ethnicity, self-identified country of origin and % ancestryOutcome: Albumin/Creatinine RatioCovariates: income, education, body mass index (BMI), high density lipids (HDL), total cholesterol, triglycerides, hypertension, diabetes, smoking, and fasting glucose Peralta CA et al., Circ CVD Gen 2010
11. ResultsPeralta CA et al., Circ CVD Gen 2010
12. CVD Risk Factors Differ Among Hispanics by Country of OriginCharacteristicsMexican & Central AmericanN=418Puerto RicanN=92DominicanN=90LDL, HDL, SBP, DM not statistically significantBMI303028*Waist Circumference102 10096†Waist-to-hip ratio0.96 0.94† 0.93*Total Cholesterol200 195† 195†Triglycerides176 134† 123*Fasting Glucose10510796 †Peralta CA et al., Circ CVD Gen 2010
13. Country of Origin in the Association of Hispanic Ethnicity and Albuminuria Peralta CA et al., Circ CVD Gen 2010*P value 0.05-0.001***
14. Paradigm #1 ConclusionsHispanics differ by country of origin geneticallyHispanics differ by country of origin in risk factor profileThe risk of albuminuria for Hispanics compared to whites varies by country of originPeralta CA et al., Circ CVD Gen 2010“Future studies should not consider Hispanics to be a homogenous group but should collect data on country of origin and even AIMs, if possible.” Drawz et al in Circ CVD Genetics editorialParadigm #1 Dogma Disputed
15. Race/Ethnicity is a Multi-Dimensional ConstructAccessibility to recreationalresources, sidewalksAdequate food shoppingBiological FactorsBlood pressureDiabetesObesityHyperlipidemia Kidney DiseaseGenetic FactorsNeighborhood & EnvironmentGene-Environment InteractionsPhysical activityDietIndividual socioeconomicsIncomeEducationAcculturationEnvironmental FactorsBiologicalFactorsEndothelial functionsalt sensitivityInflammationNephron mass
16. Paradigm #2- Race/Ethnic Differences only observed once CKD is establishedBackgroundNational estimates have shown lower CKD prevalence in Hispanics compared with whitesYet Hispanics have higher ESRD incidenceDue to this paradox, investigators suggest ethnic differences are most likely explained by more rapid progression of established disease
17. Race/Ethnic Differences Before the Onset of CKDResearch Question: Is race/ethnicity associated with kidney function decline among persons without established CKD?Setting: MESA White, Black, Hispanic, ChineseeGFRcreat >60ml/min/1.73m2 at baselineN=5,179 adults ages 45-84 from MESAPredictor: Race/EthnicityOutcome: Kidney Function Decline over 5 years using creatinine and cystatin CPeralta CA et al., JASN 2011
18. Kidney Function Decline in Hispanics and Whites: MESA*adjusted for age, gender, income, education, baseline eGFR-cysC, hdl, ldl, CRP, BMI, DM, HTN -1.2-1-0.8-0.6-0.4-0.200.2WhitesAll HispanicsDominicansPuerto RicansMexicansFully Adj*Peralta CA et al., JASN 2011eGFRcys in mil/min/1.73m2 per year
19. Paradigm #2 ConclusionsDogma Disputed:Hispanics have higher rates of kidney function decline compared with whites prior to the onset of CKDFindings significantly differ by country of origin among HispanicsDifferences are not fully explained by traditional risk factorsPeralta CA et al., JASN 2011
20. Paradigm #3 CKD only detected when disease is establishedAvailable filtration markers (creatinine, cystatin C) detect CKD once disease is already establishedAlbuminuria proposed as earlier marker of kidney damageOnly 25% of persons with eGFR <60 have albuminuriaTo date, CKD mostly detected when disease is established, thus closing the window for primary prevention
21. Early Detection: A Leap for CKD Novel urinary biomarkers discovered in setting of acute kidney injuryNGAL KIM-1Both biomarkers made by tubules in response to damageRise rapidly in response to injury and before levels of serum creatinineUnclear whether biomarkers are elevated with early, chronic kidney damage
22. Urinary Biomarkers of Kidney Injury and Kidney Function DeclineResearch Question:To study associations of urinary KIM-1 and NGAL levels with rapid kidney function decline and incident chronic kidney disease in large, ethnically diverse cohortPeralta CA et al., AJKD 2012
23. MethodsSubjects: 686 MESA participants without CKD at baselineDesign: Case-controlFollow-up: 5 yearsPredictors: NGAL and KIM-1, and standardized for creatininePartnership with Bonventre lab at BWHMeasured at baselineContinuous and in decilesPeralta CA et al., AJKD 2012
24. Methods1:1 ratio case-control studyCases: persons who developed kidney function decline by MESA year 5 visit:Incident CKD: eGFR <60 + eGFR decline >1ml/min/year), and/orRapid kidney function decline: ≥3ml/min/1.73m2/yearControls: matched for age, gender, race, diabetes, baseline eGFR Covariates: age, hypertension, ACR ≥30 mg/gPeralta CA et al., AJKD 2012
25. Association of Urinary KIM-1 and NGAL Levels with Kidney Function DeclineMarkerModelOdds Ratio (95% CI)KIM-1Age-Adjusted1.15 (1.02, 1.29)HTN+ACR-Adjusted1.15 (1.02, 1.29)NGALAge-Adjusted1.04 (0.99, 1.10)HTN+ACR-Adjusted1.04 (0.99, 1.10)Peralta CA et al., AJKD 2012KIM-1 and NGAL are per doubling of log transformed biomarker.
26. Association of KIM-1 and NGAL with Kidney Function Decline: Top DecileMarkerModelOdds Ratio (95% CI)KIM-1Age-Adjusted2.09 (1.21, 3.62)HTN+ACR-Adjusted2.02 (1.15, 3.56)NGALAge-Adjusted1.63 (0.96, 2.78)HTN+ACR-Adjusted1.55 (0.89, 2.70)Peralta CA et al., AJKD 2012
27. ResultsHigher levels of KIM-1 were significantly associated with kidney function declinePresence of albuminuria only minimally attenuated findings NGAL levels not significantly associated with kidney function decline Peralta CA et al., AJKD 2012
28. Paradigm #3 ConclusionsDogma DisputedNovel urinary biomarkers of tubular injury may be promising tool for identifying persons at risk for CKDMESA RWG is at the forefront of research in this areaIdentifying early kidney damage may allow study of targeted prevention strategies
29. Future DirectionsNormalCKDeGFRESRDCardiovascular DiseaseDeathDamageRace/EthnicityOur multi-disciplinary approach in MESA has opened the window for studying primary prevention of CKD
30. Acknowledgements MESA Renal Working GroupStudy Participants and InvestigatorsPrimary Mentor:Michael Shlipak, MD MPHCurrent Funding: K23 – The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program