Salim Baghli


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

    1. 1. The Johns Hopkins Bloomberg School of Public Health <ul><li>Serum Bicarbonate as a Predictor of Survival in End Stage Renal Disease Patients: A Prospective Cohort Study </li></ul><ul><li>Salim Baghli, MD </li></ul><ul><li>Capstone for part-time MPH Degree </li></ul><ul><li>May 2010 </li></ul><ul><li>MPH Advisor: Joseph Coresh, MD, PhD </li></ul><ul><li>Capstone Advisor: Bernard Jaar, MD, MPH, FASN </li></ul>
    2. 2. Presentation Outline <ul><li>Introduction </li></ul><ul><li>Acid Homeostasis </li></ul><ul><li>Metabolic Acidosis and Outcomes in ESRD Patients </li></ul><ul><li>Research Question </li></ul><ul><li>Study Design </li></ul><ul><li>Summary </li></ul>
    3. 3. Introduction <ul><li>Metabolic Acidosis (MA) </li></ul><ul><li>Chronic condition in kidney disease and End Stage Renal Disease (ESRD) Patients </li></ul><ul><li>Diagnosed by measured serum bicarbonate (HCO3) level less than 22 mEq/L </li></ul><ul><li>Associated with increased relative risk for death and hospitalization in ESRD patients </li></ul><ul><li>National kidney foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35: S1-S140, 2000 </li></ul>
    4. 4. Introduction <ul><li>Metabolic Acidosis </li></ul><ul><li>K/DOQI Guidelines recommend pre-dialysis HCO3 level above 22 mEq/L </li></ul><ul><li>Some studies showed that levels below 22 mEq/L (20 to 22 mEq/L) were associated with better outcomes ! </li></ul><ul><li>Controversy to be addressed </li></ul><ul><li>National kidney foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35: S1-S140, 2000 </li></ul>
    5. 5. Acid Homeostasis <ul><li>Acid Production </li></ul><ul><li>Acid Control </li></ul>G.I. System Muscle Loss of HCO3 Breakdown Dietary Proteins Oxidation Carbs Oxidation Fats Kidneys Reclamation Filtered HCO3 AMONIAGENESIS Excretion Net Acids n’ Acid Buffers Lactic Acid Keto Acid
    6. 6. Acid Homeostasis – Protein Metabolism <ul><li>Increases protein catabolism </li></ul><ul><li>Decreases protein synthesis </li></ul><ul><li>Muscle protein degradation </li></ul><ul><li>Decrease albumin synthesis </li></ul><ul><li>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 </li></ul>
    7. 7. Acid Homeostasis - Nutrition <ul><li>In ESRD patient on Hemodialysis, negative correlation between serum HCO3 levels and: </li></ul><ul><li>Normalized Protein Catabolic Rate (nPCR) </li></ul><ul><li>Dietary Protein Intake (DPI) </li></ul><ul><li>Creatinine </li></ul><ul><li>Blood Urea Nitrogen (BUN) </li></ul><ul><li>Normalized Protein Equivalent to Nitrogen Appearance (NPNA) </li></ul><ul><li>Albumin </li></ul><ul><li>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 </li></ul>
    8. 8. Acid Homeostasis - Nutrition <ul><li>Paradox ! </li></ul><ul><li>Positive Nitrogen balance thought to be related to greater acid load caused by greater protein intake </li></ul><ul><li>K/DOQI Guidelines: High protein 1.2 g/Kg/day </li></ul><ul><li>National kidney foundation: K/DOQI clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 35: S1-S140, 2000 </li></ul>
    9. 9. Acid Homeostasis - Inflammation <ul><li>Studies looked at association of MA and </li></ul><ul><li>C Reactive Protein (CRP) </li></ul><ul><li>Interleukin 6 (IL-6) </li></ul><ul><li>Tumor Necrosis Factor Alpha (TNFa) </li></ul><ul><li>No strong evidence supporting the association between inflammation and metabolic acidosis </li></ul><ul><li>Lin S-, Lin Y-, Chin H-, Wu C-. Must metabolic acidosis be associated with malnutrition in haemodialysed patients? Nephrology Dialysis Transplantation. 2002 </li></ul>
    10. 10. End Stage Renal Disease Patients
    11. 11. 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
    12. 12. Metabolic Acidosis and Outcomes in ESRD <ul><li>1990, Lowrie et al. </li></ul><ul><li>12023 ESRD on HD </li></ul><ul><li>Lowest risk of death </li></ul><ul><li>HCO3 of 20 to 22.5 mEq/L </li></ul><ul><li>Adjusted for multivariable case-mix </li></ul><ul><li>Limitation </li></ul><ul><li>No adjustment for </li></ul><ul><li>Comorbidities (besides Diabetes and HTN) </li></ul><ul><li>Nutritional parameters </li></ul><ul><li>HD dose </li></ul><ul><li>Inflammatory markers </li></ul><ul><li>Lowrie EG, Lew NL, et al.American Journal of Kidney Diseases. 1990. </li></ul>
    13. 13. Metabolic Acidosis and Outcomes in ESRD <ul><li>2002 Pifer et al. </li></ul><ul><li>7719 ESRD on HD (DOPPS) </li></ul><ul><li>No association between serum HCO3 (baseline or six-month change) and mortality </li></ul><ul><li>Adjusted for nutrition markers and comorbidities </li></ul><ul><li>Limitation </li></ul><ul><li>With regard to inflammation, they adjusted for Neutrophil count and Lymphocyte count only </li></ul><ul><li>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 </li></ul>
    14. 14. Metabolic Acidosis and Outcomes in ESRD <ul><li>2004 Bommer et al. </li></ul><ul><li>7140 ESRD on HD (DOPPS) </li></ul><ul><li>Lowest risk of death HCO3 of 20.1 to 21 mEq/L </li></ul><ul><li>Adjusted for comorbidities, nutrition and HD dose </li></ul><ul><li>Limitation </li></ul><ul><li>No adjustment for inflammation markers </li></ul><ul><li>Bommer J, Locatelli F, American Journal of Kidney Diseases 2004 </li></ul>
    15. 15. Metabolic Acidosis and Outcomes in ESRD <ul><li>2006 Wu et al. </li></ul><ul><li>56385 ESRD on HD </li></ul><ul><li>Lowest unadjusted mortality HCO3 of 17 to 23 mEq/L </li></ul><ul><li>Association reversed after adjustment for MICS and lowest risk HCO3 over 22 mEq/L </li></ul><ul><li>Limitation </li></ul><ul><li>No use of explicit inflammation markers (CRP, IL-6). Used surrogate markers (WBC, Lymphocytes, TIBC) </li></ul><ul><li>Short follow up (24 months) </li></ul><ul><li>Wu DY, Clinical journal of the American Society of Nephrology : CJASN. 2006 </li></ul>
    16. 16. Research Question <ul><li>Relation between serum HCO3 and mortality in MHD patients </li></ul><ul><li>prospective cohort study of incident dialysis patients </li></ul><ul><li>will adjust for the important confounders </li></ul><ul><li>- Co-morbidities </li></ul><ul><li>Nutritional parameters </li></ul><ul><li>Inflammation markers </li></ul><ul><li>Dialysis dose </li></ul>
    17. 17. Study Design - CHOICE <ul><li>Choices for Healthy Outcomes in Caring for ESRD </li></ul><ul><li>National prospective cohort study </li></ul><ul><li>Analyzed the association between patients and provider’s choices, costs, and patients’ outcomes </li></ul><ul><li>Started in October 1995 with 1041 incident dialysis patients </li></ul><ul><li>1995 to 1998 with 81 dialysis centers in 19 states in the US </li></ul><ul><li>Powe NR, Fink NE. the CHOICE study: A national study of dialysis outcomes in the United States. Nefrologia 19:S68-S72, 1999 (suppl 1). </li></ul>
    18. 18. Study Design - CHOICE <ul><li>Independent predictor </li></ul><ul><li>Serum HCO3 level: 767 HD patients mean serum bicarbonate for baseline 3-months period after enrollment in the study </li></ul><ul><li>Outcomes of interest </li></ul><ul><li>All-cause mortality. Active follow up through clinics records and from centers for Medicare and Medicaid services (CMS) </li></ul><ul><li>CV mortality. Death from heart disease, stroke, peripheral vascular disease </li></ul><ul><li>Confounders </li></ul><ul><li>- Demographic: Age, sex, race, facility clustering, smoking status </li></ul><ul><li>Clinical: Comorbid conditions addressed as Index of Co-Existent Disease (ICED) </li></ul><ul><li>Laboratory: inflammatory markers (CRP and IL-6) and nutritional parameters (albumin, PO4, creatinine, BMI, cholesterol) </li></ul><ul><li>Mean dialysis dose </li></ul>
    19. 19. Statistical method <ul><li>STATA software (Statacorp Release 11, TX – 77845) </li></ul><ul><li>Simple logistic regression for association between HCO3 level and nutritional parameters, inflammatory markers, and HD dose </li></ul><ul><li>Multivariable Cox proportional hazard regression models for association between serum HCO3 levels and outcomes. (all cause mortality and CV Mortality) </li></ul><ul><li>Serum HCO3 continuous variable and also categorized into multiple levels of 10 mEq/L difference </li></ul>
    20. 20. Statistical method <ul><li>Model 1 Unadjusted Model </li></ul><ul><li>Model 2 Adjustment for demographic parameters </li></ul><ul><li>Model 3 Adjustment for Model 2 plus comorbidities using ICED. We will also adjust for the mean hemodialysis dose for the first three months </li></ul><ul><li>Model 4 Previous models plus inflammatory markers </li></ul><ul><li>Model 5 Previous models plus nutritional parameters </li></ul>
    21. 21. Summary <ul><li>Mild MA in ESRD population is a subject of controversy </li></ul><ul><li>Optimal level of predialysis serum HCO3 level for a better outcome is still a subject of debate </li></ul><ul><li>Mild MA in ESRD could be related to higher protein diet which increases acid load and improves nutritional parameters like albumin </li></ul><ul><li>We are hoping to better understand the relation between predialysis serum HCO3 and outcomes through our cohort analysis </li></ul>
    22. 22. <ul><li>Thank you </li></ul><ul><li>Questions ? </li></ul>