Racial disparaties in Chronic Kidney Diseases

Racial Disparities in CKD/ESRD

Kellie Calderon, MD

Hofstra North Shore-LIJ Nephrology, USA

Racial Disparity in CKD/ESRD

“It is much more important to know what sort of a patient has a disease, than what sort of disease a patient has.”

William Osler (1849-1919)

Racial Disparity in ESRD

ESRD Incidence by race

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1980 2002

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Series1

Series24.8

3.8

Prevalent patients surviving cohort year, without CKD in prior year & without ESRD, age 65 & older (Medicare) & 20–64 (MarketScan & Ingenix i3).

Stages of incident CKD as defined by the new diagnosis codes:

Medicare patients age 65 & older, by race

2008

Data

Trends in CKD incidence: Medicare patients age 65 & older

Prevalent patients surviving cohort year, without CKD in prior year & without ESRD, age 65 & older (Medicare) & 20–64 (MarketScan & Ingenix i3).

Cumulative Incidence of CKD by age and race

AA

White

Median age of incident patients,

by race/ethnicity

Incident ESRD patients. For Hispanic patients we present data beginning in 1996, the first full year after the April 1995 introduction of the revised Medical Evidence form, which contains more specific questions on race & ethnicity.

Racial Differences in Risk of End-Stage Renal Disease and Death

Published American Journal of Medicine

July 2009

Andy I. Choi, et al.

VA Medical Center, San Francisco, CA

Racial Differences in Risk of End-Stage Renal Disease and Death

National Sample: 2,015,891 veterans 2001-2005

Objective: Compare white/black differences in

ESRD and Death to identify at what level of kidney function the racial disparities are the greatest

Racial Differences in Risk of End-Stage Renal Disease and Death

Study Sample: All veterans with outpatient creatinine

measured Excluded:

ESRD Transplant

Follow ups link by USRDS

Age-standardized incidence of death by estimated glomerular filtration rate (GFR) at baseline

White/Black Racial Differences in Risk of End-Stage RenalDisease and DeathAndy I. Choi et al. American Journal of Medicine, 2009

Do differences in mortality rate account for these

differences??

Results:

Rates of ESRD exceeded those among white patients ALL levels of baseline GFR

Similar pattern for mortality Equal or higher rates of death among

black persons Highest risk of mortality in blacks with

eGFR 45-59cc/min

Hsu, C.-y. et al. J Am Soc Nephrol 2003;14:2902-2907

Relative risks for progression from CKD to ESRD casesoverall and by subgroup

Journal of the National Medical AssociationAug 2002

Previously Described Factors:

Environmental Access to Health care Economic status Low Birth Weight Higher incidence of co-morbidities

DM HTN

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

Purpose: Identify factors that contribute to the

excess stroke mortality among black individuals and in the southeastern US

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

Population based Cohort study American 45+ years

½ black, ½ male Targeted Sample size of 30,000

persons

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

Patient population:

20%30%

50%

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

Stroke Risk: Blacks in “stroke belt” were more likely to:

Be aware of HTN Be on treatment for HTN

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

eGFR<60cc/min

43.3%

Blacks: 33.7%

Whites: 49.9%

N = 20,669

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

Average GFR:

Blacks: 65.9

White: 60.1

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

GFR 10-20cc/min:

Black: 0.7%

White: 0.2%

Conclusions: Disparity in ESRD incidence in US black

and white individuals MAY to due to differences in: The Rate of Progression of CKD Overall survival with advanced stages of CKD

REGARDS Study:Reasons for Geographic And Racial Differences in Stroke

Kidney Function, Albuminuria, and All-Cause Mortality in the REGARDS (Reasons for

Geographic and Racial Differences in Stroke) Study

Maybe “environmental”…

Genetic Analysis

Nature Genetics 40, 1175 - 1184 (2008) Published online: 14 September 2008 | doi:10.1038/ng.226

Jeffrey B Kopp1,17, Michael W Smith2,16,17, George W Nelson2,17, Randall C Johnson2, Barry I Freedman3, Donald W Bowden3, Taras

Oleksyk2, Louise M McKenzie2, Hiroshi Kajiyama1, Tejinder S Ahuja4, Jeffrey S Berns5, William Briggs6, Monique E Cho1, Richard A Dart7, Paul L Kimmel8, Stephen M Korbet9, Donna M Michel10, Michele H

Mokrzycki11, Jeffrey R Schelling12, Eric Simon13, Howard Trachtman14, David Vlahov15 & Cheryl A Winkler2

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

MALD Mapping Admixture Linkage

Disequilibrium Strategy for identifying genes underlying

ancestry-driven health disparities

Nonmuscle myosin heavy chain 9

MYH9

Chromosome 22q12

1960 Amino Acids

227kDa

Expressed in:

Platelets

Thymus

Spleen

Kidney

MYH9

Function: Binds actin Protein of the cytoskeleton Role in cell shape and motility Role in cell division

MYH9

AD Giant Platelet Disorders Triad:

Thrombocytopenia Large Platelets Leukocyte Inclusions

MYH9

2000: Described in a set of overlapping syndromes: macrothrombocytopenia, Inclusion bodies in neutrophils sensorineural deafness cataracts glomerular injury

Linked to MYH9 coding region mutations Missense nonsense deletions

The May-Hegglin AnomalyFechtner Syndrome Sebastian syndromes

Sensorineural Hearing Loss

Cataracts

Nephritis

Mutations in MYH9:

In the kidney… Encodes for Podocyte nonmuscle myosin

IIa

Copyright ©2010 American Society of Nephrology

Bostrom, M. A. et al. Clin J Am Soc Nephrol 2010;5:1107-1113

Figure 2. Proposed pathogenesis of MYH9-associated nephropathy

Re-visiting the AASK Cohort…

Association Analysis of the Non-Muscle Myosin Heavy Chain 9 Gene in

Hypertensive Nephropathy: Results from the African American Study of Kidney

Disease and Hypertension

AASK Re-visited… Tested for 4 polymorphisms in MYH9

497 Participants with Hypertensive nephropathy

946 AA Controls from

Preliminary analysis indicates that tendency to lose kidney function over time

Is associated with MYH9 variants!!

Wake Forest

A risk allele for focal segmental glomerulosclerosis in African Americans is

located within a region containing APOL1 and MYH9

2010 International Society of Nephrology

Found that APOL1 variants associated with non-diabetic glomerular disease in AA populations Stronger association than with European

Americans Higher prevalence of this gene than

anticipated in population Suggests a recent natural selection

Apolipoprotein L1

Located on Chromosome 22q12 Protein component in HDL

Apolipoprotein L1

Innate Immunity Trypanosomas brucei brucei

Trypanosoma brucei rhodesiense Resistant Trypanosoma brucei gambiense Resistant

HDL particles taken up by the parasite Generates ionic pores in the lysosomal

membrane

The trypanolytic factor of human serumEtienne Pays, Benoit Vanhollebeke, Luc Vanhamme,Françoise Paturiaux-Hanocq, Derek P. Nolan and David Pérez-MorgaNature, 2006

Human Sera

Recombinant ApoL1

Association of Trypanolytic ApoL1 Variants with Kidney Disease in

African Americans

Giulio Genovese et al. Originally published in Science Express on 15 July 2010

Science 13 August 2010:Vol. 329. no. 5993, pp. 841 - 845

205 AA “idiopathic” FSGS 180 AA Controls

Strongest genetic association found was APOL1

Two Locus allele “G1”

FSGS 52% Controls 18%

Larger Cohort:

Frequency of G1 and G2

Odds Ratio

1.26 for one-risk allele

7.3 for two-risk alleles

1030 AA H-ESRD

1025 AA matched controls

L. Lecordier et al.

PLoS Pathogens 2009

C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei

rhodesiense

Trypanosoma brucei rhodesienseAfrican Sleeping Sickness.

Serum Resistance Associated Protein

C Terminal Helix of APOL1

Resistant to ApoL1 destruction

G1 and G2 located there!!

Nephron Power, 2010

IN THE NEWS-

" Its not me, its the guy next to me,"

says MYH9