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  1. 1. Hypertensive Renal Disease in African-Americans Janice P. Lea, MD, MSc Associate Professor of Medicine Clinical Specialist in Hypertension Renal Division, Emory University
  2. 2. Diabetes and Hypertension: The Leading Causes of ESRD Primary Diagnosis For Patients Who Start Dialysis United States Renal Data System. Annual data report. 2000. 0 100 200 300 400 500 600 700 R 2 = 99.8% 243,524 281,355 520,240 Number of Dialysis Patients Diabetes 50.1% Hypertension 27% Glomerulonephritis 13% Other 10% No of Patients Projection 95% CI 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
  3. 3. Stage 5 CKD Incidence Rates per Million Vary by Race/Ethnicity Odds ratios: 1 3.89 2.74 1.56 1 1.45 * P <0.0001 † Reference population. Data adjusted for age and gender from 2001 in United States Renal Data System. 2003 Annual Data Report. Available at: www.usrds.org. Incidence Rate per Million (2001)
  4. 4. NHANES III: Adjusted Odds of Reduced Kidney Function Coresh et al. Am J Kidney Dis. 41:1-12, 2003 0.21 4.8 35.2 59.7 White (%) 0.25 3.1 17.4 79.2 AA (%) 15-29 30-59 60-89 >90 GFR
  5. 5. Increasing Numbers of Patients May Overwhelm Nephrologists (amjkd,coresh 2003,nni 1999) 70 350,000 <15 or dialysis Kidney failure 5 80 400,000 15-29 Severe decrease in GFR 4 1520 7,600,000 30-59 Moderate decrease in GFR 3 1060 5,300,000 60-89 Mild decrease in GFR 2 1180 5,900,000  90 Kidney damage with normal or increased GFR 1 Patients per Nephrologist Prevalence eGFR Description Stage
  6. 6. Five-Year Outcomes of CKD RRT = renal replacement therapy. Keith et al. Arch Intern Med . 2004;164:659-663. 45.5 19.9 4 24.3 1.3 3 19.5 1.1 2 Patient Deaths (%) Patients on RRT (%) Stage of CKD
  7. 7. Cardiovascular Disease (CVD) Is Linked to Chronic Kidney Disease (CKD) <ul><li>Relative Risk of CVD is 1.4 – 2.05 X with </li></ul><ul><li>Creatinine > 1.4 – 1.5 mg/dl </li></ul><ul><li>Relative Risk of CVD is 1.5 – 3.5 X with </li></ul><ul><li>Microalbuminuria </li></ul><ul><li>Annual Mortality from CVD is 10 to 100-Fold Greater </li></ul><ul><li>with Kidney Failure </li></ul>Flack, et al. 1993 Levey, et al. 1998 Jensen, et al. 2000 Ruilope, et al. 2001 Mann, et al. 2001
  8. 8. Rates of Death and Cardiovascular Events in Patients According to GFR N = 1,120,295 adults. *Age-standardized rates per 100 person-years; † Cardiovascular event defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease per 100 person-years. Go et al. N Engl J Med. 2004;351:1296-1305. eGFR (mL/min/1.73 m 2 )
  9. 9. The Dual Significance of Proteinuria <ul><li>Proteinuria (albuminuria) results from injury to glomerular circulation </li></ul><ul><ul><li>Increased proteinuria (albuminuria) is associated with progressive kidney disease </li></ul></ul><ul><li>In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulation </li></ul><ul><ul><li>Proteinuria (albuminuria) is associated with increased cardiovascular risk </li></ul></ul>
  10. 10. Proteinuria Is a Risk Factor for CVD Primary composite end-point: CV death, stroke, MI. Wachtell et al. Ann Intern Med . 2003;139:901-906. Comparison of lowest and highest decile of microalbuminuria in 7143 nondiabetic patients Adjusted Hazard Ratio
  11. 11. Microalbuminuria Predicts CV Risk at Levels Below Current Definition Wachtell K et al. Ann Intern Med. 2003;139:901-906. Microalbuminuria assessment in patients with hypertension and diabetes improves CV risk stratification Quintile of urine A/C ratio (mg/g) among 1,063 hypertension patients with diabetes 10 Microalbuminuria Normoalbuminuria Adjusted Hazard Ratio 0 0.5 1 1.5 2 2.5 <6.9  6.9 – <17.2  149.4 LIFE Study: Composite Endpoint  17.2 – <45.0  45.0 – <149.4
  12. 12. Proteinuria Is Also a Risk Factor for Progression of CKD % With Doubling of SCr or ESRD * P -values are for comparison across the subgroups. Jafar et al. Kidney Int. 2001;60:1131-1140. Urine Protein (g/d) P <.001* 0 10 20 30 40 50 <0.5 0.5-3.0 3.0-6.0 >6.0
  13. 13. Early Treatment Makes a Difference
  14. 14. ACE Inhibitors, ARBs, and Combination Therapy in Nondiabetic Nephropathy Primary end point: doubling of SCr or kidney failure. Nakao et al. Lancet. 2003;361:117-124. P = 0.02 * Combination* (n = 88) Losartan (n = 89) Trandolapril (n = 86)
  15. 15. Features of Hypertensive Nephrosclerosis <ul><li>Long history of HTN, prior to known kidney dz. </li></ul><ul><li>No other etiology for kidney disease. </li></ul><ul><li>Proteinuria < 2.5 g/d. Urinalysis no cells. No Diabetes. </li></ul><ul><li>Evidence of other target organ damage-LVH,eye </li></ul><ul><li>FH of HTN, high risk in African-Americans, age of onset of HTN- 25-45. </li></ul><ul><li>Renal biopsy- hyalinization arterioles, intimal thick. small arteries, glom ischemia, fibrosis tubules </li></ul>
  16. 16. Treatment of Hypertension in Nondiabetic Kidney Disease http://www.kidney.org/professionals/kdoqi/guidelines_bp
  17. 17. African Americans: Addition of a Diuretic to ARB Therapy (N=440) * P  0.01 vs placebo. † P  0.05 vs placebo. Clin. Therapeutics, 2001 Change in systolic BP (mm Hg) † * * * * *
  18. 18. Average Number of Antihypertensive Agents Needed Per Patient to Achieve Diastolic BP Goals Bakris et al. Am J Kidney Dis . 2000;36:646. 1 1.5 2 2.5 3 3.5 4 AASK (<92 mm Hg MAP) HOT (<80 mm Hg Diastolic) MDRD (<92 mm Hg MAP) ABCD (<75 mm Hg Diastolic) UKPDS (<85 mm Hg Diastolic) No. of BP medications
  19. 19. African American Study of Kidney Disease and Hypertension (AASK) <ul><li>1094 patients with HTN and CKD , 4 yr f/u GFR = 20-65 mL/min/1.73 m 2 </li></ul><ul><li>Excluded DBP <95 mm Hg, DM, UP/Cr >2.5 </li></ul>MAP = mean arterial pressure; DBP = diastolic blood pressure; UP/Cr = urinary protein to creatinine ratio. Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431. Aggressive Usual Therapy: Metoprolol Metoprolol N = 441 Ramipril Ramipril N = 436 Amlodipine Amlodipine N = 217  92 mm Hg 102-107 mm Hg Goal MAP:
  20. 20. AASK Study Questions <ul><li>Does very aggressive lowering of blood pressure result in slower decline in renal function in hypertensive renal disease? </li></ul><ul><li>Does the type of antihypertensive agent used to initiate blood pressure lowering matter with regard to renal outcomes? </li></ul>
  21. 21. Baseline Characteristics (2) 0.63  1.11 0.44  0.72 31.8 0.57  0.99 0.38  0.73 32.7 0.61  1.01 0.41  .75 33.0 Urine Protein (g/d) Male Female % with UP/Cr > 0.22 2.14  0.75 1.80  0.55 2.28  0.83 1.74  0.55 2.18  0.74 1.76  0.59 Serum Creatinine (mg/dL) Male Female Metoprolol N=441 Amlodipine N=217 Ramipril N=436 Mean  SD or %. No significant differences among drug groups.
  22. 22. Clinical Evidence for Risk Reduction With ACE Inhibitor or  Blockade: AASK Patients with existing kidney damage (baseline UP/Cr >0.22). Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431. Ramipril vs Amlodipine P = 0.004 Ramipril vs Metoprolol P = 0.04 Metoprolol vs Amlodipine P = 0.17 -38 -22 -20 Composite risk of rapid GFR decline-decrease from baseline of 50% or 25 mL/min/1.73 m 2 , kidney failure, or death
  23. 23. Percent Change in Proteinuria from Baseline Geometric mean urine protein/creatinine ratio declined faster in ramipril and metoprolol groups than amlodipine group (p < 0.001) % Change (SE) -33 -18 0 22 49 82 122 172 Follow-up Month 0 6 12 18 24 30 36 42 48 Metoprolol Ramipril Amlodipine
  24. 24. % of Patients Reached Urine Protein/Creatinine Ratio>0.22 During Follow-up by Drug Group Ramipril vs. Metoprolol: p=0.014 Amlodipine vs. Metoprolol: p=0.009 Ramipril vs. Amlodipine: p<0.001 % w i t h E v e n t s 0 10 20 30 40 50 60 Follow-up Month 0 6 12 18 24 30 36 42 48 54 60 Analysis of patients with UP/Cr < 0.22 at baseline Metoprolol Ramipril Amlodipine
  25. 25. African American Study of Kidney Disease and Hypertension (AASK) Trial Wright et al. JAMA. 2002;288:2421-2431. Amlodipine Treatment Arm Proteinuric patients progressed more rapidly to a renal event In patients with baseline urinary protein/creatinine ratio >0.22 (≈ baseline protein >300 mg/d) Ramipril Treatment Arm Metoprolol Treatment Arm The AASK trial, like other studies, confirms that amlodipine is associated with increases in proteinuria
  26. 26. Role of Angiotensin II in Renal Disease Pathways Ang II Efferent constriction PG, NO Afferent dilation Glomerular hypertension Proteinuria Hypertension TGF-  Extracellular matrix Interstitial fibrosis PG = prostaglandin; NO = nitric oxide. Focal segmental glomerulosclerosis
  27. 28. METHODS <ul><li>Post hoc analysis of a randomized 3X2 factorial trial (AASK). </li></ul><ul><li>Outcomes: 1) GFR slope – analyzed by single-slope mixed effects model 2) ESRD - Cox proportional hazards regression analysis </li></ul><ul><li>Predictor variables: 1) baseline proteinuria 2) baseline GFR 3) initial change in proteinuria at 6 months </li></ul>
  28. 32. Lea J et.al. Arch Intern Med. 2005;165:947 Six Month Change in Proteinuria from Baseline Predicts Outcome of Kidney Disease: Results from the AASK trial 4.0 2.0 1.0 0.5 0.25 >-50% 0.125 >-50% to 20% - 20% to +25% +25% to 100% >+100% Relative Risk of ESRD
  29. 33. Conclusions <ul><li>Changes in low levels of proteinuria ( microalbuminuria ) are predictive of ESRD in nondiabetic kidney disease. </li></ul><ul><li>The association of early changes in proteinuria with subsequent renal outcomes suggests that effects of antihypertensive agents on proteinuria should be considered when selecting agents for their potential to slow renal disease progression. </li></ul>
  30. 34. Metabolic Syndrome and CKD <ul><li>The metabolic syndrome is independently associated with an increased risk for incident CKD in nondiabetic adults in a prospective study – ARIC (Chertow et al, JASN 2005). </li></ul><ul><li>Metabolic syndrome is a strong and independent risk factor for chronic kidney disease in a cross-sectional analyses of 6217 subjects from NHANES. The multivariate adjusted OR of CKD in subjects with MS was 2.6 compared to those without MS (Chen et al, Ann. Intern. Med. 2004) . </li></ul>
  31. 35. OBJECTIVE <ul><li>Does Metabolic Syndrome predict the rate of CKD progression to ESRD in African-Americans with Hypertensive Renal Disease?? </li></ul>
  32. 36. African American Study of Kidney Disease and Hypertension (AASK) <ul><li>1094 patients with HTN and CKD , 4 yr f/u GFR = 20-65 mL/min/1.73 m 2 </li></ul><ul><li>Excluded DBP <95 mm Hg, DM or FBS>140 , UP/Cr >2.5 </li></ul>MAP = mean arterial pressure; DBP = diastolic blood pressure; UP/Cr = urinary protein to creatinine ratio. Wright et al for the AASK Study Group. JAMA. 2002;288:2421-2431. Aggressive Usual Therapy: Metoprolol Metoprolol N = 441 Ramipril Ramipril N = 436 Amlodipine Amlodipine N = 217  92 mm Hg 102-107 mm Hg Goal MAP:
  33. 37. METHODS <ul><li>Predictor variables: individual and composite components of the metabolic syndrome at baseline defined by the presence of any two of the following in addition to hypertension (NCEP): </li></ul><ul><ul><li>fasting plasma glucose > 110 mg/dl </li></ul></ul><ul><ul><li>triglycerides > 150 mg/dl </li></ul></ul><ul><ul><li>HDL chol <40 mg/dl in men, < 50 mg/dl in women </li></ul></ul><ul><ul><li>BMI>30. </li></ul></ul><ul><ul><li>Note: BP > 130/85 or on meds was present in all. </li></ul></ul>
  34. 38. ATP III: The Metabolic Syndrome* * Diagnosis is established when  3 of these risk factors are present Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. < 40 mg/dL < 50 mg/dL Men Women > 102 cm (> 40 in) > 88 cm (> 35 in) Men Women  110 mg/dL Fasting glucose  130/  85 mm Hg Blood pressure HDL-C  150 mg/dL TG Abdominal obesity† (Waist circumference‡) Defining Level Risk Factor
  35. 39. METHODS <ul><li>Outcome : Time until the clinical composite outcome including: 50% or 25 ml/min/1.73m 2 GFR decline (GFR event)-iothalamate, ESRD, or Death. </li></ul><ul><li>Statistical Analyses: Multivariable Cox Proportional Hazards Models run for the metabolic syndrome composite and for each covariate with the composite renal outcome with and without adjustments for covariates. </li></ul>
  36. 40. RESULTS <ul><li>41% met criteria for metabolic syndrome using modified NCEP. </li></ul><ul><li>40.6% had BMI > 30 kg/m 2 . </li></ul><ul><li>None of the individual components of the MS predicted CKD progression in multivariate tests. </li></ul>
  37. 41. Baseline Characteristics .65 95(24) 95.6(14.3) 95.5(14) DBP .15 151(24) 148(23.3) 150(23.8) SBP <.0001 107(48.4) 186(95.6) 140.5(81) TRIG (n=842) <.0001 54(15.6) 40(12.2) 48.3(16.1) HDL <.0001 91.4(15.7) 105.2(21.5) 94.9(18.5) gluc <.0001 28.6(6.1) 33.5(6.2) 30.6(6.5) BMI P value MS – (n=634) MS + (n=208) Total (n=1094) (SD) Variable
  38. 42. Cox Regression Analyses with Renal Outcomes 1.2(.87-1.62) 1.1(.83-1.5) 1.25(.96-1.62) .95(.73-1.23) 1.14(.77-1.7) 1.0(.78-1.3) Multivariate HR(CI) .28 .48 .09 .67 .51 .95 P value DBP>90 SBP>140 TRIG>150 HDL<40 Glucose>110 BMI>30 Met. Syndrome components
  39. 43. Modified NCEP with BMI <ul><li>41% subjects meet criteria for metabolic syndrome. </li></ul><ul><li>Cox model – unadjusted HR- 1.31 (1.02-1.67), p=.03 for MS with composite outcomes. </li></ul><ul><li>Adjusted for all covariates except proteinuria- HR-1.37(1.06-1.77), p=.013. With proteinuria- 1.23 (.95-1.58), p=.11. </li></ul>
  40. 44. TABLE 3: Hazard ratio of metabolic syndrome with Time to Event analyses with and without adjustments for significant covariates and BMI and adjusted for BP goal group and Antihypertensive Drug group.       Hazard Ratio Confidence Interval P value MS unadjusted   1.31 1.03-1.68 .03 MS adjusted for other covariates, + uprot/cr 1.37 1.23 1.07-1.77 .95-1.58 .01 .11 By BP goal 1.37 1.05-1.8 .02 By Drug group 1.35 1.03-1.78 .03
  41. 45. Cox regression analyses for ESRD alone, ESRD + death <ul><li>MS and ESRD alone, HR- 1.73( 1.2-2.5). </li></ul><ul><li>MS and ESRD+death, HR- 1.62 (1.2-2.2). </li></ul>
  42. 46. Cox Model for Metabolic Syndrome and Renal Outcomes .95-1.58 1.23 MS 2.1-3.6 2.76 UProt/Cr .68-1.17 .89 Uric acid .98-1.65 1.24 Phos .37-.67 .61 GFR 1.3-2.8 1.78 Cr .72-1.39 1.0 BUN .84-1.46 1.11 alcohol 1.15-1.95 1.49 smoker .72-1.2 .89 Males .78-1.31 1.01 Age CI HR Variable
  43. 47. Cox Model for Metabolic Syndrome and Renal Outcomes 1.07-1.77 1.37 MS .68-1.17 .89 Uric acid .98-1.65 1.27 Phos .37-.67 .51 GFR 1.3-2.8 1.96 Cr .72-1.39 1.0 BUN .84-1.46 1.11 alcohol 1.15-1.95 1.49 smoker .72-1.2 .94 Males .78-1.31 1.01 Age CI HR Variable
  44. 48. Kaplan Meier Survival Curve – Metabolic Syndrome status
  45. 49. Strengths and Limitations <ul><li>Well-characterized population of African-Americans with CKD. </li></ul><ul><li>Iothalamate GFR’s to assess renal function. </li></ul><ul><li>No waist circumferences, but BMI used to assess obesity. </li></ul><ul><li>242 missing values- lack of triglycerides. </li></ul>
  46. 50. SUMMARY <ul><ul><li>African-Americans with CKD in the AASK Study have a prevalence of metabolic syndrome (NCEP) of 41%. </li></ul></ul><ul><ul><li>African-Americans with hypertensive CKD and metabolic syndrome have a 37% higher risk of reaching the composite clinical endpoints of GFR decline, ESRD, or death. </li></ul></ul><ul><ul><li>These findings persisted after adjusting for other factors known to influence renal outcomes except for proteinuria and did include adjustments for BP goal group and antihypertensive therapy. </li></ul></ul>
  47. 51. Conclusions <ul><ul><li>This is the first prospective study reporting that metabolic syndrome predicts the rate of CKD progression. </li></ul></ul><ul><ul><li>Further studies are needed to confirm this association and should include more specific measures of insulin resistance. </li></ul></ul><ul><ul><li>Our findings may explain some of the variability observed in the progression to ESRD and may provide a new target for treating CKD in a high risk group. </li></ul></ul>
  48. 52. You Have The Power To Prevent Kidney Disease
  49. 53. Perception of increased risk of CKD by patient characteristic as reported by primary care physicians
  50. 54. Reducing Risks of Kidney Disease in African-Americans <ul><li>Education </li></ul><ul><li>Early detection of kidney disease </li></ul><ul><li>Adequate treatment of hypertension and diabetes </li></ul><ul><li>Adequate access to healthcare </li></ul><ul><li>Proper dietary habits </li></ul><ul><li>More clinical research in African-Americans to better understand the increased risks </li></ul>

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