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
National kidney foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35: S1-S140, 2000
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
National kidney foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35: S1-S140, 2000
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
Metabolic Acidosis and Outcomes in ESRD
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.
Metabolic Acidosis and Outcomes in ESRD
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
Metabolic Acidosis and Outcomes in ESRD
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
Metabolic Acidosis and Outcomes in ESRD
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
Questions ?
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