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Reverse Epidemiology Reverse Epidemiology of Obesity in Kidney of Obesity in Kidney Disease Disease Arun Chawla, MD Arun Chawla, MD Hofstra NSLIJ School of Hofstra NSLIJ School of Medicine Medicine

Obesity paradox

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Page 1: Obesity paradox

Reverse Epidemiology Reverse Epidemiology of Obesity in Kidney of Obesity in Kidney

DiseaseDisease

Arun Chawla, MDArun Chawla, MDHofstra NSLIJ School of MedicineHofstra NSLIJ School of Medicine

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OverviewOverview Conventional epidemiology Conventional epidemiology

ParadoxParadox

Studies…Studies…

Hypothesis to explain what we seeHypothesis to explain what we see

Paradox within paradoxParadox within paradox

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What we all know… for What we all know… for Now!Now! In US, obesity is the second leading

cause of preventable disease and death.

Associated with ESRD - type 2 DM and hypertension.

Epidemic growing and life expectancy being shortened.

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Prevalence of overweight, obesity and extreme obesity among adults: United States, trends

1976-80 through 2005-2006

NHANES December 2008

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Associated co Associated co morbiditiesmorbidities Type 2 DMType 2 DM HypertensionHypertension CADCAD GDMGDM OSAOSA HyperlipidemiaHyperlipidemia OAOA GERDGERD GoutGout

ESRDESRD NASHNASH VTEVTE CholelithiasisCholelithiasis DepressionDepression Pulmonary Pulmonary

HypertensionHypertension CTSCTS InfertilityInfertility Breast/Colon cancerBreast/Colon cancer

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Multivariate Relative Risk of Death from CVD, Cancer, and All Other Causes among Men and Women Who Had Never

Smoked and Who Had No History of Disease at Enrollment, According to BMI

Calle E et al. Nejm 1999

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Multivariate Relative Risk of Death from All Causes among Men and Women According to BMI, Smoking, and

Disease Status

Calle E et al. N Engl J Med 1999

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So…So…

Given the magnitude of the risks of obesity in the general population, it is important to clarify whether these risks apply to patients on dialysis, who have an overall cardiovascular risk at least 10 times greater than the general population.

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First thoughts….First thoughts….

In 1982, Degoulet et al looked into In 1982, Degoulet et al looked into 1453 subjects treated in 33 French 1453 subjects treated in 33 French dialysis centers over 5 years and dialysis centers over 5 years and noticed no increase in mortality with noticed no increase in mortality with higher BMI. higher BMI.

After 17 years came the first trial …After 17 years came the first trial …

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Influence of Excess Weight Influence of Excess Weight on Mortality and Hospital on Mortality and Hospital

Stay in 1346 Dialysis Stay in 1346 Dialysis PatientsPatients

Fleishmann and SalahudeenFleishmann and Salahudeen

Kidney International 1999Kidney International 1999

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MethodsMethods

Cohort of 1346 HD patients in Cohort of 1346 HD patients in MississippiMississippi

Followed prospectively for 1 year for Followed prospectively for 1 year for hospitalization and mortality.hospitalization and mortality.

On dialysis for more than 90 days On dialysis for more than 90 days (avg. 4.3 yrs) (avg. 4.3 yrs)

38% had BMI >27.538% had BMI >27.5 13% had BMI <2013% had BMI <20 Normal considered BMI of 20-27.5Normal considered BMI of 20-27.5

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De

ath

Ha

zard

Kaplan-Meier Death Kaplan-Meier Death HazardHazard

Fleishmann et al. Kidney Fleishmann et al. Kidney International 1999International 1999

Survival in days

400

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ResultsResults Causes of death similar amongst three Causes of death similar amongst three

groups.groups.

For a unit increase in BMI>27.5 risk of For a unit increase in BMI>27.5 risk of dying showed RR reduction of 6% in the dying showed RR reduction of 6% in the univariate model and 4% in the univariate model and 4% in the multivariate model. multivariate model.

With 1 unit decrease of BMI below 20 the With 1 unit decrease of BMI below 20 the risk of death increased by 1.6 fold.risk of death increased by 1.6 fold.

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Hospital admission rate per Hospital admission rate per year and Length of stay (LOS)year and Length of stay (LOS)

……

0

2

4

6

8

10

12

14

16

underweight Normalweight

Overweight

LOS

00.20.40.60.8

11.21.41.61.8

Underweight OverweightAd Rate

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ConclusionConclusion

Special attention to nutrition to Special attention to nutrition to achieve high end of normal BMI achieve high end of normal BMI maymay help to reduce morbidity and help to reduce morbidity and mortality in hemodialysis patients. mortality in hemodialysis patients.

Results were significant even after adjustment for markers of nutrition like albumin, transferrin and creatinine.

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LimitationsLimitations

Smaller sample sizeSmaller sample size Mainly AA (88%) so no diversityMainly AA (88%) so no diversity Survival advantage not shown in Survival advantage not shown in

CaucasiansCaucasians Short follow upShort follow up BMI not the most accurate tool to BMI not the most accurate tool to

comment on body composition.comment on body composition.

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Questions Fat mass or muscle mass?

Mild versus severe obesity?

Is high BMI only a short term advantage?

Interactions of race or ethnicity?

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Association of Body Size with Outcomes Among Patients

Beginning Dialysis

Johansen Et alAm J Clinical Nutrition 2004

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HypothesisHypothesis

Extremely high BMI would not be associated with increased survival time.

If there were a survival advantage at

higher BMI, it would be explained in part by the increased lean body mass (LBM) that usually accompanies high BMI.

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MethodsMethods

Data obtained from the USRDS and CMS.

Mortality, hospitalisation and dialysis modality (i.e. HD or PD), for adult patients beginning dialysis between April 1, 1995, and November 30, 2000.

Follow-up extended through November 30, 2001 with median follow up of 2 years.

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Johansen, K. L et al. Am J Clin Nutr 2004

FIGURE 1. Hazard ratios for death among men ({blacksquare}) and women ({square}) by category of BMI (A), Benn index (B), and estimated fat mass (C)

Copyright ©2004 The American Society for Nutrition BMI

De

ath

Ha

zard

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Effects of adjustment for serum creatinine and creatinine index on the relation

between BMI and survival

Curve more steep!!!

Copyright ©2004 The American Society for Nutrition Johansen, K. L et al. Am J Clin Nutr 2004

BMI

De

ath

Ha

zard

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ConclusionsConclusions BOTH THEIR HYPOTHESIS PROVED

WRONG!!!

Higher adiposity was associated with increased survival, even after adjustment for demographics, laboratory values, comorbidities, dialysis modality and even when adiposity was assessed by different methods.

Pattern observed even for cardiovascular death

Less evident with PD and Asians

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StrengthsStrengths

Large sample sizeLarge sample size Complete dataComplete data All racial and ethnic groupsAll racial and ethnic groups Longer follow upLonger follow up

LimitationsLimitations Observational designObservational design

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Does weight gain Does weight gain help????help????

Association of Morbid Obesity and Weight Change Over Time with Cardiovascular Survival in

Hemodialysis PopulationK.Kalantar-Zadeh et al

Am J Kidney Diseases 2005

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MethodsMethods

Patients enrolled with DA Vita IncPatients enrolled with DA Vita Inc Cohort on July 1, 2001 and subsequently Cohort on July 1, 2001 and subsequently

patients were enrolled through June 30, patients were enrolled through June 30, 2003- Non-concurrent cohort.2003- Non-concurrent cohort.

Data organized to form “8 quarterly mean Data organized to form “8 quarterly mean values” to include 2 year observation values” to include 2 year observation period.period.

11 categories <18, >45 and then 9 in 11 categories <18, >45 and then 9 in between 18 and 44.9between 18 and 44.9

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Data collectedData collected CBC, BUN, Hemoglobin, albumin,

creatinine (muscle mass), dialysis dose and ferritin and TIBC (marker of nutrition).

For each analysis, 3 models were examined based on the level of multivariate adjustment:

(1) the unadjusted model (2) case-mix– adjusted models (3) case-mix and laboratory

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K.Kalantar-Zadeh et al Am J Kidney Dis 2005

39.3

15.9

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Fig 1. Time-dependent association between BMI and 2-year all-cause mortality in 54,535

MHD patients

K.Kalantar-Zadeh et al Am J Kidney Dis 2005

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Fig 2. Time-dependent association between BMI and 2-year cardiovascular mortality in

54,535 MHD patients

K.Kalantar-Zadeh et al Am J Kidney Dis 2005

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Fig 4. Association between the rate of weight change over time and subsequent all-cause

mortality in 46,629 HD patients

K.Kalantar-Zadeh et al Am J Kidney Dis 2005

P<.0001

p.068

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Fig 5. Association between the rate of weight change over time and cardiovascular mortality

in 46,629 HD patients

K.Kalantar-Zadeh et al Am J Kidney Dis 2005

P .101

P<.001

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ConclusionsConclusions Even after exhaustive adjustment for time

varying laboratory markers, both all-cause and cardiovascular mortality showed decreasing rates across increasing BMI categories, even morbid obesity.

Lower BMI at baseline consistently is found to be a strong predictor of elevated mortality.

Weight loss was associated with increased CV and all-cause death, whereas weight gain showed a trend toward improved survival and reduced cardiovascular mortality.

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Association Of Low Body Mass Index Association Of Low Body Mass Index And Weight Loss With Increased And Weight Loss With Increased

Mortality In 14,065 Transplant-wait-Mortality In 14,065 Transplant-wait-listed Hemodialysis Patients listed Hemodialysis Patients

K.Kalantar-Zadeh et al Circulation 2008

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What we Now know…!What we Now know…!

Leavey SF, et al. Body mass index and mortality in ‘healthier’ as compared with' sicker’ hemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrology Dial Transplant 2001

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??????????

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Hypothesis Hypothesis

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TNF- alpha receptors in obesity

TNF-alpha is elevated in CHF and in dialysis patients and may contribute to cardiac injury through its pro-apoptotic and negative inotropic effects (2).

Adipose tissue produces soluble TNF-alpha receptors, which may play a cardio-protective role.

2) Feldman et al. The role of tumor necrosis factor in the pathophysiology of heart failure. J Am Coll Cardiol 2000; 35:537– 44.

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Neurohormonal Neurohormonal alterationsalterations

The lean subjects had significantly higher increases in plasma adrenaline and renin concentrations during treadmill testing, despite similar baseline values and a history of hypertension (3).

Heightened sympathetic and renin-angiotensin activities are associated with a poor prognosis in heart failure and fluid overload states (such as those seen in dialysis patients).

3) Weber MA et al. Contrasting clinical properties and exercise responses in obese and lean hypertensive patients. J Am Coll Cardiol 2001;37:169 –74

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Selection BiasSelection Bias

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More stable More stable hemodynamic status hemodynamic status

Despite having similar PCWP and cardiac indexes, overweight and obese patients with fluid overload tend to have higher systemic blood pressure values (1).

Due to better tolerance larger proportion of obese and overweight patients take ACE inhibitors.

1) Horwich et al . The relationship between obesity and mortality in patientswith heartfailure. J Am Coll Cardiol 2001;38:789 –9

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Endotoxin-lipoprotein hypothesis

Lower serum total cholesterol and lipoprotein concentrations are strongly and independently associated with impaired survival in dialysis (4).

It reflects a richer pool of internal lipoproteins that can actively bind to and remove circulating endotoxins, which effectively retards inflammation and subsequent atherosclerosis (5).4) Nishizawa et al. Paradox of risk factors for cardiovascular mortality in uremia: is a higher cholesterol level better for atherosclerosis in uremia? Am J Kidney Dis 2001;38 S4–7.5) Niebauer J, et al. Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999;353: 1838–42.

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Malnutrition-inflammation complex syndrome – “Cachexia in slow motion” Undernourished people more likely to develop PEM Undernourished people more likely to develop PEM

and slow to recover form illnesses and its and slow to recover form illnesses and its complications.complications.

Increased release of IL-6 and TNF may suppress appetite (6), may cause muscle proteolysis and hypoalbuminemia, and may be involved in the processes that lead to atherosclerosis.

Patients with lower albumin, low cholesterol, creatinine and homocysteine concentration might represent MICS making them prone to infection and inflammation and slower recovery.

Nutritional Inflammatory hypothesis (6) Kalantar-Zadeh K. Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients. Am J Clin Nutr 2004.

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Time discrepancies among competitive risk factors

US population US population versus developing versus developing countriescountries

Survival advantages that exist in obese dialysis patients may, in the short term, outweigh the harmful effects of these risk factors on CVD in the long term.

Dialysis patients, ironically, do not live long enough to die of the consequences of overnutrition!

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Dialysis modality????Dialysis modality????

Body mass index, Dialysis Modality, and Survival: Analysis of the United States Renal Data System Dialysis Morbidity and

Mortality Wave II Study

ABBOTT et alKIDNEY INT. 2004

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Methods

Retrospective cohort study of the USRDS DMMS Wave II database.

Patients who started dialysis in 1996 and were followed until October 2001 (5yrs)

Outcome: Mortality Divided into 4 groups 1 (<21.9), 2

(21.9-24.9), 3 (25-29.9) and 4(>29.9)

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PD patients-PD patients-Less AA, younger, more renal transplant.Less AA, younger, more renal transplant.

Decreased prevalence of CAD, CHF, CVA, Decreased prevalence of CAD, CHF, CVA, LVH on EKG, PVD, and cancer.LVH on EKG, PVD, and cancer.

Decreased Erythropoietin useDecreased Erythropoietin use

Higher ACE, statins and beta blockers.Higher ACE, statins and beta blockers.

No significant difference of BMINo significant difference of BMI

Demographic and clinical Demographic and clinical variablesvariables

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PD patientsPD patients

In the lowest group were at an increased risk of mortality

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Kaplan-Meier plot of patient survival by BMI

HD survival 39.8% vs. 32.3% PD survival 38.7% vs. 40.4%

ABBOTT et al KIDNEY INT. 65

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ConclusionsConclusions

Low BMI was independently associated with higher mortality regardless of dialysis modality.

HR for death in patients with BMI >30 was 0.89 for HD and significant while no such correlation in PD patients.

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““Paradox within Paradox within paradox”paradox” Adequacy of dialysis not known.Adequacy of dialysis not known.

Whether “uremic” and “inflammatory” Whether “uremic” and “inflammatory” malnutrition differ by dialysis modality has malnutrition differ by dialysis modality has not been established.not been established.

Changes in B.P, med use, lab values etc. Changes in B.P, med use, lab values etc. wasn’t followed.wasn’t followed.

1.5–4.25% of dextrose in their peritoneal dialysate (often around the clock), which is estimated to be absorbed at 45%.

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CKD patients??CKD patients??

(1) Evans et al; Natural history of chronic reanl failure; Results from an unselected population cohort in Sweden. AJKD 2005

(2) BMI and mortality in CKD. Madero et al Abstract JASN 2006

(3) Reverse epidemiology in patients with CKD. Kovesdy etal. Seminars in Dialysis 2007