Salim Baghli

The Johns Hopkins Bloomberg School of Public Health

Serum Bicarbonate as a Predictor of Survival in End Stage Renal Disease Patients:

A Prospective Cohort Study

Salim Baghli, MD Capstone for part-time MPH Degree May 2010

MPH Advisor: Joseph Coresh, MD, PhD Capstone Advisor: Bernard Jaar, MD, MPH, FASN

Presentation Outline

• Introduction

• Acid Homeostasis

• Metabolic Acidosis and Outcomes in ESRD Patients

• Research Question

• Study Design

• Summary

Introduction

Metabolic Acidosis (MA)

- Chronic condition in kidney disease and End Stage Renal Disease (ESRD) Patients

- Diagnosed by measured serum bicarbonate (HCO3) level less than 22 mEq/L

- Associated with increased relative risk for death and hospitalization in ESRD patients

National kidney foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35: S1-S140, 2000

Introduction

Metabolic Acidosis

- K/DOQI Guidelines recommend pre-dialysis HCO3 level above 22 mEq/L

- Some studies showed that levels below 22 mEq/L (20 to 22 mEq/L) were associated with better outcomes !

- Controversy to be addressed


Acid HomeostasisAcid Production

Acid Control

G.I. System Muscle

Loss of HCO3

Breakdown Dietary Proteins Oxidation Carbs Oxidation Fats

Kidneys

Reclamation Filtered HCO3

AMONIAGENESISExcretion Net Acids n’ Acid

Buffers

Lactic Acid Keto Acid

Acid Homeostasis – Protein Metabolism

- Increases protein catabolism

- Decreases protein synthesis

- Muscle protein degradation

- Decrease albumin synthesis

Ballmer PE, McNurlan MA, Hulter HN, Anderson SE, Garlick PJ, Krapf R. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest. 1995

Acid Homeostasis - Nutrition

• In ESRD patient on Hemodialysis, negative correlation between serum HCO3 levels and:

- Normalized Protein Catabolic Rate (nPCR)- Dietary Protein Intake (DPI)- Creatinine- Blood Urea Nitrogen (BUN)- Normalized Protein Equivalent to Nitrogen Appearance (NPNA)- Albumin

Wu DY, Shinaberger CS, Regidor DL, McAllister CJ, Kopple JD, Kalantar-Zadeh K. Association between serum bicarbonate and death in hemodialysis patients: Is it better to be acidotic or alkalotic? Clinical journal of the American Society of Nephrology : CJASN. 2006

Acid Homeostasis - Nutrition

Paradox !

Positive Nitrogen balance thought to be related to greater acid load caused by greater protein intake

K/DOQI Guidelines: High protein 1.2 g/Kg/day


Acid Homeostasis - Inflammation

Studies looked at association of MA and

- C Reactive Protein (CRP)

- Interleukin 6 (IL-6)

- Tumor Necrosis Factor Alpha (TNFa)

No strong evidence supporting the association between inflammation and metabolic acidosis

Lin S-, Lin Y-, Chin H-, Wu C-. Must metabolic acidosis be associated with malnutrition in haemodialysed patients? Nephrology Dialysis Transplantation. 2002

End Stage Renal Disease Patients

Metabolic Acidosis and Outcomes in ESRD

Reference and year Study Sample Size Measured factors Outcomes Comments

Lowrie EG. 1990 Cohort - 12023 HCO3, labs, Comorbidities, HD treatment time

Mortality Adjusted serum HCO3 (for case- mix) showed best survival in the range of 20 – 22.5 mEq/L

Trinh B. 2002 Cohort - 7719 HCO3, Nutrition parameters, Inflammation markers

Mortality No association between mortality and HCO3 (baseline/six month change)

Bommer J. 2004 Cohort - 7140 HCO3, nutrition, comorbidities

Nutrition, Mortality, hospitalization

Moderate pre-dialysis MA (20 – 22 mEq/L) associated with better nutritional status and lower mortality and hospitalization

Wu DY. 2006 Cohort - 56385 HCO3, MICS Nutrition, Mortality After adjusting for MICS,

HCO3 > 22 mEq/L had

lower death risk


1990, Lowrie et al.

12023 ESRD on HD

Lowest risk of death

HCO3 of 20 to 22.5 mEq/L

Adjusted for multivariable case-mix

Limitation

No adjustment for- Comorbidities (besides Diabetes and

HTN)- Nutritional parameters- HD dose- Inflammatory markers

Lowrie EG, Lew NL, et al.American Journal of Kidney Diseases. 1990.


2002 Pifer et al.

7719 ESRD on HD (DOPPS)

No association between serum HCO3 (baseline or six-month change) and mortality

Adjusted for nutrition markers and comorbidities

Limitation

With regard to inflammation, they adjusted for Neutrophil count and Lymphocyte count only

Pifer TB, McCullough KP, Port FK, Goodkin DA, Maroni BJ, Held PJ, Young EW. Mortality risk in hemodialysis patients and changes in nutritional indicators: DOPPS. Kidney Int. 2002 Dec


2004 Bommer et al.

7140 ESRD on HD (DOPPS)

Lowest risk of death HCO3 of 20.1 to 21 mEq/L

Adjusted for comorbidities, nutrition and HD dose

Limitation

No adjustment for inflammation markers

Bommer J, Locatelli F, American Journal of Kidney Diseases 2004


2006 Wu et al.

56385 ESRD on HD

Lowest unadjusted mortality HCO3 of 17 to 23 mEq/L

Association reversed after adjustment for MICS and lowest risk HCO3 over 22 mEq/L

Limitation

No use of explicit inflammation markers (CRP, IL-6). Used surrogate markers (WBC, Lymphocytes, TIBC)

Short follow up (24 months)

Wu DY, Clinical journal of the American Society of Nephrology : CJASN. 2006

Research Question

Relation between serum HCO3 and mortality in MHD patients

prospective cohort study of incident dialysis patients

will adjust for the important confounders

- Co-morbidities- Nutritional parameters - Inflammation markers - Dialysis dose

Study Design - CHOICE

Choices for Healthy Outcomes in Caring for ESRD

National prospective cohort study

Analyzed the association between patients and provider’s choices, costs, and patients’ outcomes

Started in October 1995 with 1041 incident dialysis patients

1995 to 1998 with 81 dialysis centers in 19 states in the US

Powe NR, Fink NE. the CHOICE study: A national study of dialysis outcomes in the United States. Nefrologia 19:S68-S72, 1999 (suppl 1).

Study Design - CHOICE

• Independent predictorSerum HCO3 level: 767 HD patients mean serum bicarbonate for baseline 3-

months period after enrollment in the study

• Outcomes of interest- All-cause mortality. Active follow up through clinics records and from

centers for Medicare and Medicaid services (CMS)- CV mortality. Death from heart disease, stroke, peripheral vascular disease

• Confounders- Demographic: Age, sex, race, facility clustering, smoking status- Clinical: Comorbid conditions addressed as Index of Co-Existent Disease

(ICED) - Laboratory: inflammatory markers (CRP and IL-6) and nutritional

parameters (albumin, PO4, creatinine, BMI, cholesterol) - Mean dialysis dose

Statistical method

• STATA software (Statacorp Release 11, TX – 77845)

• Simple logistic regression for association between HCO3

level and nutritional parameters, inflammatory markers, and HD dose

• Multivariable Cox proportional hazard regression models

for association between serum HCO3 levels and outcomes. (all cause mortality and CV Mortality)

• Serum HCO3 continuous variable and also categorized

into multiple levels of 10 mEq/L difference

Statistical method

Model 1 Unadjusted Model

Model 2 Adjustment for demographic parameters

Model 3 Adjustment for Model 2 plus comorbidities using ICED. We will also adjust for the mean hemodialysis dose for the first three months

Model 4 Previous models plus inflammatory markers

Model 5 Previous models plus nutritional parameters

Summary

Mild MA in ESRD population is a subject of controversy

Optimal level of predialysis serum HCO3 level for a better outcome is still a subject of debate

Mild MA in ESRD could be related to higher protein diet which increases acid load and improves nutritional parameters like albumin

We are hoping to better understand the relation between predialysis serum HCO3 and outcomes through our cohort analysis

Thank you

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Salim Baghli