Chronic Kidney Disease: Everything that you need to know!

Transcription

1 : Everything that you need to know! Matthew R. Weir, MD Professor and Director Division of Nephrology University of Maryland School of Medicine Baltimore, Maryland Overview CKD and CVD Blood Pressure Lipids Mineral Bone Disease Anemia Summary 2

2 The Nephron Is the Functional Unit of the Kidney Loss of Nephrons Translates to Loss of Function Efferent arteriole Bowman s capsule Glomerulus Afferent arteriole Proximal tubule Peritubular venules Proximal convoluted tubule Peritubular capillaries Distal convoluted tube Thick ascending limb Collecting duct 3 Definition of (CKD) Kidney damage for at least 3 months, as defined by structural or functional abnormalities of the kidney, ± decreased GFR, manifest by: pathologic abnormalities, or markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests GFR <60 ml/min/1.73m 2 for at least 3 months ± kidney damage CKD also classified as 1 Decreased renal reserve Renal insufficiency Renal failure (end-stage renal disease; ESRD) GFR = glomerular filtration rate. National Kidney Foundation, Inc KDOQI Clinical Practice Guidelines for : Evaluation, Classification, and Stratification. Available at: 4

3 Clinical Evaluation of Patients at Increased Risk of CKD All patients Blood pressure Serum creatinine RBC or WBC in urine samples Protein in urine Serum glucose and lipids Serum electrolytes Selected patients, depending on risk factors Ultrasound imaging (polycystic kidney, infection, obstruction of stones) Urine Protein:Creatinine or albumin:creatinine ratio Urinary microalbumin Urinary concentration or dilution Urinary acidification KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes in Chronic Kidney Disease July 2006 National Kidney Foundation. 5 CKD Diagnosis Glomerular Filtration Rate (GFR) GFR can be estimated or measured using serum creatinine values egfr estimated from serum creatinine using estimating equations 2 commonly used equations: MDRD and Cockcroft-Gault equation MDRD best for renally impaired patients GFR (ml/min/1.73m 2 ) = 186 (Pcr) (Age) (0.742 if female) For African Americans, the calculated result must be multiplied by 1.21 GFR has classically been evaluated by measuring a 24 hour creatinine clearance Entails 24 hour urine collection and a before and after blood draw Eliminates variability of serum creatinine levels Certain contrast imaging modalities are the most specific measure but rarely done Inulin clearance KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes in Chronic Kidney Disease July 2006 National Kidney Foundation. 6

4 Traditional and Nontraditional Risk Factors Increase CVD Event Risk in Patients With CKD 1 Traditional Risk Factors Older age Male sex Hypertension High LDL-C Low HDL-C Diabetes Smoking Physical inactivity Menopause Family history of heart disease Left ventricular hypertrophy White race CVD = cardiovascular disease; CKD = chronic kidney disease; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol; Apo = apolipoprotein. 1. Shastri S et al. Am J Kidney Dis. 2010;56: Non-Traditional Risk Factors Anemia Volume overload Abnormal mineral metabolism Electrolyte imbalances Albuminuria Lipoprotein(a) and Apo(A) isoforms and lipoprotein remnants Homocysteine Oxidative stress/inflammation Malnutrition Thrombogenic factors Sleep disturbances High sympathetic tone Altered nitric oxide/endothelin balance Particular to individuals with CKD 7 Estimated Glomerular Filtration and Normal Aging 200 Estimated GFR (ml/min/1.73m 2 ) Inulin (Davies and Shock, 1950) NHANES III Estimated GFR (median, 5th, 95th percentiles) Age (years) Uremia, Ca-PO 4 imbalance, volume overload, oxidative stress, inflammation, anemia incident CVD, CVD death 8

5 Natural History of Renal Measures and Impairment in Diabetic Kidney Disease egfr Albumin egfr (ml/min/1.73 m 2 ) Microalbuminuria Albuminuria Urinary Albumin (mg/24 h) Duration of Diabetes (years) Courtesy of Mark E. Molitch, MD. 0 9 Stages of 1 At Risk Treatment Transplant STAGE 1 STAGE 2 STAGE 3 STAGE 4 STAGE 5 Kidney damage with normal or increased kidney function Kidney damage with mildly impaired kidney function Moderately impaired kidney function Severely impaired kidney function Kidney failure Glomerular filtration rate (ml/min/1.73 m 2 ) 1. KDOQI Clinical Practice Guidelines for : Evaluation, Classification, and Stratification. National Kidney Foundation Web site. Accessed May

6 CKD Prevalence by Stage Stage 1 2 Description Kidney damage with normal or increased GFR Kidney damage with mildly decreased GFR GFR, U.S. ml/min/1.73 Prevalence, m 2 Thousands U.S. Prevalence, % Moderately decreased GFR Severely decreased GFR Kidney failure <15 or dialysis GFR = glomerular filtration rate. Adapted from Sarnak MJ et al. Hypertension. 2003;42(5): Relationship Between CKD and CVD 1 CKD is a risk factor for CVD, and CVD may be a risk factor for the progression of CKD CKD Traditional CV risk factors Non-traditional CV risk factors CVD CKD = chronic kidney disease; CVD = cardiovascular disease; CV = cardiovascular. 1. Menon V et al. Am J Kidney Dis. 2005;45:

7 Systemic Vasculature Common Pathology: Injured Vascular Endothelium Renal Vasculature Interstitial Albumin Leak Cardiovascular Risk Factors: Age Diabetes Hypertension Smoking Absent nocturnal BP dipping Salt sensitivity Left ventricular hypertrophy Dyslipidemia Central obesity Spot Urine Alb:Cr >30 mg/g Insulin resistance Elevated CRP Sympathetic dysfunction Hyperuricemia Microalbuminuria Figure 2. Microalbuminuria: manifestation of diffuse endothelial cell injury. BP = blood pressure; CRP = C-reactive protein Reproduced with permission from Toto RD. J Clin Hypertens. 2004;6(suppl 3): Percent Chance of Cardiovascular Event in 5 Years: No 5 Diabetes Years: No Diabetes Men Nonsmoker Smoker BP BP Total Chol.:HDL-C Total Chol.:HDL-C (mm Hg) / /95 140/85 120/75 120/75 Age / / /95 160/95 Age 140/85 140/ /75 120/75 Women Nonsmoker Smoker Total Chol.:HDL-C Total Chol.:HDL-C >20% 15-20% 10-15% 5-10% 5-10% 2.5-5% 2.5-5% <2.5% <2.5% 180/ / /95 160/95 140/85 140/85 120/75 120/75 Age Age Adapted with permission from Jackson R. BMJ. 2000;320: Adapted with permission from Jackson R. BMJ. 2000;320:

8 15 Patients Diagnosed with CKD Have a Greater Likelihood of Death than ESRD 5% Medicare sample, cohort, 2 year follow-up N=1,045, ,596 33,586 19,335 Percent of Patients Event Free ESRD Death NDM/Non-CKD DM/Non-CKD NDM/CKD DM/CKD Status in the entry period Collins et al. Kid Int. 64 (Suppl 87)S24-S31,

9 Cardiovascular Mortality Is Higher in Patients With ESRD Cardiovascular mortality in the general population (NCHS) and in kidney failure treated by dialysis or transplant (USRDS) Annual mortality (%) GP Male GP Female GP Black GP White Dialysis Male Dialysis Female Dialysis Black Dialysis White Age (years) Transplant Adapted from Foley RN et al. Am J Kidney Dis. 1998;32(5 Suppl 3):S112 S Graded and Independent Relationship Between Estimated Glomerular Filtration Rate (GFR) and CVD Outcomes* *Adjusted for baseline age, sex, income, education, coronary disease, chronic heart failure, stroke or transient ischemic attack, peripheral artery disease, diabetes, hypertension, dyslipidemia, cancer, hypoalbuminemia, dementia, liver disease, proteinuria, prior hospitalizations, and subsequent dialysis requirement. Shastri S et al. Am J Kidney Dis Jul 2. [Epub ahead of print]. 18

10 The key understanding is that patients with CKD benefit as much as non-ckd patients with appropriate medications and therapies, if not more, because of their increased risk! 19 Decreased GFR has consistently been found to be an independent risk factor for CVD outcomes and all cause mortality! 20

11 Renal Dysfunction Predicts Increased Mortality After Acute MI Mortality <40 ml/min > Years Creatinine clearance <70 ml/min predicted significantly worse outcome after adjustment for covariables* N = 6,252 *Adjusted for age, high BP, diabetes, history of angina, previous MI, current smoker, anterior acute MI, ventricular fibrillation, CHF, wall motion index, and thrombolytic therapy. Sorensen CR et al. Eur Heart J. 2002;23: Renal Dysfunction Predicts Increased Mortality After Acute Stroke 1.0 Cumulative survival Time to death (yrs) >66 ml/min ml/min ml/min <39 ml/min N=2,042 CrCl <51 ml/min predicted significantly worse outcome, even after adjustment for confounders* *Adjusted for age, neurologic score, high BP, ischemic heart disease, smoking, and diuretic use; Kaplan-Meier survival analysis (log-rank test, P<.0001) MacWalter et al. Stroke. 2002;33:

12 With all this bad news, what do we need to do differently? 23 * Estimate GFR * Quantitate albuminuria/proteinuria 24

13 Serum creatinine is not a good measure of estimated GFR! 25 Serum Creatinine Is a Misleading Guide to GFR N=117 Serum Creatinine, mg/dl C inulin ml/min/1.73 m 2 Shemesh et al. Kidney Int. 1985;28:

14 Equations to Predict GFR Based on Serum Creatinine Cockcroft-Gault equation (140 Age) x Weight C Cr (ml/min) = 72 x S Cr x (0.85 if female) Abbreviated MDRD Study equation GFR (ml/min -1 per 1.73 m 2 ) = 186 x (S Cr ) x (Age) x (0.742 if female) x (1.210 if black) Age is given in years and weight in kilograms. GFR = glomerular filtration rate; C Cr = creatinine clearance; MDRD = Modification of Diet in Renal Disease; S cr = serum creatinine in mg/dl. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Guideline 4. Estimation of GFR. Available at: 27 Definitions of Proteinuria Urine Collection Method Normal Total protein 24-Hour excretion (varies with method) < 300 mg/d Spot urine dipstick < 30 mg/dl Spot urine protein-to-creatinine < 200 mg/g (varies with method) Albumin 24-Hour excretion < 30 mg/d Spot urine albumin-specific < 3 mg/dl dipstick Spot urine albumin-to-creatinine < 17 mg/g ratio (men) (varies by sex) < 25 mg/g (women) Microalbuminuria mg/d > 3 mg/dl mg/g (men) mg/g (women) 300 mg/d 30 mg/dl 200 mg/g > 300 mg/d NA > 250 mg/g (men) > 355 mg/g (women) NA indicates not applicable. * Sex-specific cutoff values are from a single study. Use of the same cutoff value for men and women leads to higher values of prevalence for women than men. Current recommendations from the American Diabetes Association define cutoff values for spot urine albumin-tocreatinine ratio for microalbuminuria and albuminuria as 30 and 300 mg/g, respectively, without regard to sex. Reproduced and modified with permission from the National Kidney Foundation. 28 NA NA NA Albuminuria or Clinical Proteinuria

15 CV Mortality According to egfr and Albuminuria Hazard ratios (95% confidence intervals) for CV mortality CV = cardiovascular; GFR = glomerular filtration rate; ACR = albumin-to-creatinine ratio; BP = blood pressure. Shaded areas represent 95% CIs. Models included spline egfr, categorical albuminuria, and their interaction terms as well as adjustment for age, sex, ethnic origin, history of CV disease, systolic BP, diabetes, smoking, and total cholesterol. The reference (diamond) was egfr 95 ml/min/1.73m² plus ACR less than 3 4 mg/mmol (30 mg/g) or dipstick test result negative or trace. Circles represent statistically significant and triangles represent not significant. The estimated HR and 95% CI at egfr 120 ml/min/1.73m² with dipstick 2+ or more for CV mortality were omitted, since only two studies contributed to reliable estimation. To convert ACR in mg/g to mg/mmol, multiply by Prognosis Consortium. Lancet. 2010;375: Percentage of US Population by Estimated Glomerular Filtration Rate (egfr) and Albuminuria Category Levey, AS Kidney Int Jul;80(1):

16 Cardiovascular Death in Relationship to egfr and ACR Cubic Spline Models adjusted for age, sex, egfr, and ACR egfr Estimated Glomerular Filtration Rate ACR Albumin Creatinine Ratio IRR Incidence Ratio Rate (Reference Rate IIR= 1) Arch Intern Med 207;167(22) 31 Overview CKD and CVD Blood Pressure Lipids Mineral Bone Disease Anemia Summary 32

17 Learning Objectives To consider how low to reduce blood pressure to slow progression of CKD To consider how low to reduce blood pressure to reduce the risk of CV events in patients with CKD To appreciate the advantage of RAAS blockade and BP reduction as key aspects of preventing disease progression 33 Three studies in patients with non-diabetic kidney disease which evaluated 2 levels of BP on renal outcomes. MDRD REIN-2 AASK 34

18 Perspective All 3 RCT examining 2 levels of BP goals do not appear to convincingly show the benefit of a lower BP goal. The only exception might be in patients with more proteinuria (more than 1 g/day) Even a meta-analysis of 11 RCT of ACE inhibitor therapy is 1860 patients with non-diabetic kidney disease that BP levels below 120 mmhg did not offer additional renal protection compared to mmhg Jafar TH, et al. Ann Intern Med 139; , Diabetic Kidney Disease No RCT examining different BP goals on renal outcomes No RCT examining the impact of reducing proteinuria, independent of BP, and renal disease progression We do have secondary analyses from trials in people with Type 2 DM and CKD 36

19 IDNT and RENAAL Trial Comparison of Major Endpoints RRR (%) RENAAL IDNT Losartan vs control Irbesartan vs control Irbesartan vs amlodipine Amlodipine vs control Doubling of Creat, 16 (P=0.02) 20 (P=0.02) 23 (P=0.006) -4 (P=0.69) ESRD, or death Doubling of Creat 25 (P=0.006) 33 (P=0.003) 37 (P<0.001) -6 (P=0.60) ESRD 28 (P=0.002) 23 (P=0.07) 23 (P=0.07) 0 (P=0.99) Death -2 (P=0.88) 8 (P=0.57) -4 (P=0.8) 12 (P=0.4) CV Morbidity 10 (P=0.26) 9 (P=0.4) -3 (P=0.79) 12 (P=0.29) & Mortality Lewis EJ et al. N Engl J Med 2001 Brenner B et al. N Engl J Med IDNT: Impact of Quartile of Achieved Mean Systolic Blood Pressure on Time to Renal Endpoint % of Patients with Doubling of Serum Cr or ESRD Follow-up SBP (mm Hg) > < Follow-up Time (mo) Pohl MA, et. al. J Am Soc Nephrol 16: ,

20 RAAS Blockade and Lower BP Prevents incident microalbuminuria, but does not change mesangial matrix volume in patients with BP at 120 mmhg (perhaps >135 mmhg?) Prevents progression from micro to macro albuminuria transition (especially in those with BP >140mmHg, and older) Prevents progression from macroalbuminuria to doubling of creatinine, ESRD, or death 39 Out-of-office BP and CV outcomes more strongly related than office BP and CV outcomes among patients with CKD

21 RAAS Blockade: Provides on average a 20% relative risk reduction! 41 Perspectives on RAAS Blockade Likely more evident at higher levels of BP (over 140 mmhg) May be less evident at lower levels of achieved BP (<130mmHg) RAAS blockade is not a substitute for poor BP control 42

22 What is Your Definition of Hypertension? We must delete the word hypertension ; it has no meaning The blood pressure goal should be established for each patient, based on the benefit: risk ratio for the therapeutic intervention 43 Overview CKD and CVD Blood Pressure Lipids Mineral Bone Disease Anemia Summary 44

23 Rationale for Lipid Lowering Clinical Trials in the CKD Population CKD and ESRD patients are at increased risk of cardiovascular complications CKD and ESRD patients have abnormal lipid profiles Secondary analyses of lipid lowering studies indicated statin treatment improved CV outcomes in CKD patients Secondary analyses of these studies also demonstrated slowing of CKD progression Need for randomized placebo-controlled statin trials in CKD and ESRD patients 1. Scandinavian Simvastatin Survival Study (4S). Lancet.1994;344(8934): Shepherd J et al. N Engl J Med. 1995;333(20): Heart Protection Study Collaborative Group. Lancet. 2002;360(9326): Seliger SL et al. Kidney Int. 2002;61(1): Liao JK. Am J Cardiol. 2005;96(5A):24F 33F. 6. Fellström BC et al. Kidney Int. 2003;63(Suppl 84):S204 S Mechanism of CVD Development in Patients With Uremia Uremia Immuno-deficiency (T- & B- cell, phagocytosis, Ig-formation Ab B T Dyslipidemia (TG, ApoB, ApoA1, HDL ) Atherogenic lipid fractions (ox_ldl, small dense LDL) Oxidative stress (ROS, AGE, AOPP) Inflammatory activity Endothelial dysfunction Malnutrition ADMA Accelerated Atherosclerosis TG, triglycerides; HDL, high density lipoprotein; LDL, low density lipoprotein; ROS, reactive oxygen species; AGEs, advanced glycation end products; AOPP, advanced oxidation of plasma proteins; ADMA, asymmetric dimethylarginine Fellström BC et al. Kidney Int. 2003;63(Suppl 84):S204 S

24 Cochrane Renal Group - Effects of Statins in Patients with : Meta-analysis and Metaregression of Randomized Controlled Trials Objective - To analyze the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations). Design - Meta-analysis. Data sources - Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006). Study selection - Randomized and quasi-randomized controlled trials of statins compared with placebo or other statins in chronic kidney disease. Data extraction and analysis - Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarized as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model. Strippoli GF et al. BMJ Cochrane Metanalysis - Cardiovascular Events: Effect of Statins Compared with Placebo or No Treatment in Pre-dialysis, Dialysis, and Transplant Patients* Patients with Earlier Stages of CKD May Realize Greater Benefit Study or subcategory Pre-dialysis patients Statin n Placeb o n Relative risk (random) (95% CI) Weight (%) Relative risk (random) (95% CI) Subtotal (95% CI) (0.66 to 0.85) Dialysis patients Subtotal (95% CI) (0.74 to 0.99) Transplant patients Subtotal (95% CI) (0.48 to 1.01) Mixed population (pre-dialysis and dialysis patients) Subtotal (95% CI) (0.24 to 1.63) Total (95% CI) 11,361 11,502 Favors Favors (0.73 to 0.84) statin placebo *Only studies with at least one event are included in the plot. Strippoli GF et al. BMJ. 2008;336:

25 NKF KDOQI Guidelines and the 2010 CVD and CKD Core Curriculum: Management of Dyslipidemia All patients with CKD, even in the absence of known CVD, should be considered at high risk of CVD outcomes 1 Goal lipid levels (LDL-C and non-hdl-c) LDL cholesterol <100 mg/dl (<2.59 mmol/l) (level B evidence) 1,2 LDL cholesterol <70 mg/dl is a therapeutic option in patients with CKD and diabetes (level B evidence) 1,2 non-hdl cholesterol <130 mg/dl (<3.36 mmol/l) (level B evidence) 1,2\ Special attention should made to CKD patients with diabetes Patients with Stages 1-4 should be treated with a statin (level B evidence) 1,2 Patients with Stage 5 on hemodialysis should not be initiated on a statin unless there is a specific cardiovascular indication (level A evidence) 1,2 1. Shastri S et al. Am J Kidney Dis Jul 2. [Epub ahead of print]; 2. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and. Am J Kidney Dis. 2007; 49(2 suppl 2):S KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes in July 2006 National Kidney Foundation SHARP: Major Atherosclerotic Events 25 Proportion suffering event (%) Risk ratio 0.83 ( ) Logrank 2P= Placebo Simv/Eze Years of follow-up 50

26 Summary Nevertheless, given the data from the HPS and the SHARP study, we feel that there is a strong argument to abandon a threshold-based algorithm for treating hyperlipidemia. Rather it may be advisable to treat those with high risk for atherosclerotic cardiac events regardless of initial LDL level, and to treat with a potent dose of a statin alone or in combination with a second line drug to achieve a marked (at least 40%) reduction in LDL, at least to ATP-III LDL goal levels. 51 Summary Whether a lower goal LDL of <70 mg/dl may be indicated in CKD patients, as suggested in the 2004 follow-up NCEP guidelines for the general population, is not clear, but we feel that it is a reasonable therapeutic option in patients with CKD. The data from the SHARP study suggests that this may be the case. 52

27 Summary Acknowledging the high risk of CVD in CKD while understanding that only a fraction of this is CHD, we feel that it is reasonable, but not mandatory, to consider reduced GFR or proteinuria (and perhaps albuminuria) to be a CHD risk equivalent. 53 Overview CKD and CVD Blood Pressure Lipids Mineral Bone Disease Anemia Summary 54

28 CKD-MBD: A Complex Multisystem Disorder Laboratory Abnormalities Elevated FGF-23 PTH Phosphorus Decreased 1,25(OH) 2 D 3 Calcium Vascular and soft tissue calcification Calcification CKD-MBD Bone Disease Abnormal bone Turnover Mineralization Volume Linear growth Strength CKD-MBD = chronic kidney disease-mineral bone disorder; PTH = parathyroid hormone. Kidney Int. 2009;76(suppl 113). 55 Phosphorus and Calcium Concentrations Remain in the Normal Range Until Late in CKD Serum Phosphorus (mg/dl) Phosphorus Calcium <20 egfr Interval (ml/min/1.73 m 2 ) Serum Calcium (mg/dl) Data presented are median values. SEEK Study; N = egfr = estimated glomerular filtration rate. Adapted from Levin A et al. Kidney Int. 2007;71:

29 Summary Disordered mineral and bone disease occurs very early in CKD The earliest changes may be unrelated to mineral disorder These early hormonal abnormalities set into play a complex disruption of the normal mineral regulatory system Disruptions in phosphorus and calcium balance appear as CKD progresses and further disrupts the normal physiology of vascular and bone health As these disturbances progress, serum levels of phosphorus and calcium may become evident and further worsen cardiovascular and bone disease The disordered phosphorus, calcium, and ipth seen in most ESRD patients are the result of this progressive disease process 57 Treatment In CKD predialysis: observational studies suggest that: Phosphate binders may be beneficial Vitamin D replacement may be beneficial Active vitamin D analogues may be beneficial None of these therapies have been adequately tested 58

30 Overview CKD and CVD Blood Pressure Lipids Mineral Bone Disease Anemia Summary 59 The Prevalence of Anemia in CKD Is High Prevalence of Anemia by GFR, Hb level 12 g/dl Patients (%) CKD Stage Hb=hemoglobin. McClellan et al. Curr Med Res Opin. 2004;20(9): Stage 1-2 Stage 3 Stage 4 Stage 5 60

31 Anemia Significantly Impacts Mortality in CKD Patients Medicare sample (5%), follow-up from 1996 to 1997 of enrollees aged 65 years of, adjusted for age, sex, and race Relative Risk of Death None 2.0 Anemia only 2.4 DM/CKD 3.6 DM/CKD/ Anemia 4.6 DM/CHF/ Anemia DM/CHF/ CKD/Anemia DM=diabetes mellitus; CHF=congestive heart failure. Collins et al. Adv Stud Med. 2003;3(3C):S14-S Hb Levels Should Be Evaluated in ALL CKD Patients, Regardless of Stage a No workup No CKD, any stage Check Hb Hb 13.5 g/dl ( ) Hb 12.0 g/dl ( ) DON T FORGET ABOUT GI SOURCE!!!!! Yes Workup a Note that these are screening recommendations, not treatment recommendations. Modified from National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146 (A). 62

32 Published Randomized Controlled Trials in CKD: The Bottom Line Study N Study Population Hb (g/dl) or Hct(%) Target CV Outcome Quality of Life Besarab. N Engl J Med Foley. Kidney Int Roger. J Am Soc Nephrol Parfrey. J Am Soc Nephrol Levin. Am J Kidney Dis Singh. N Engl J Med Drüeke. N Engl J Med HD + CHF/CAD 146 HD - CHF/CAD 155 Stage HD - CHF/CAD 172 Stage Stage Stage No benefit No benefit No benefit No benefit No benefit No benefit No benefit Improved? Improved No difference Improved Improved No difference Improved 63 Risk of Poorly Controlled Blood Pressure; Higher Hb vs Lower Hb (Fixed Effects Analysis) Risk ratio (95% CI) Weight (%) Roger et al 0.53 ( ) 2.2 Parfrey et al Drueke et al Rossert et al 1.11 ( ) ( ) ( ) 4.4 Overall 1.27 ( ) Risk ratio Increased risk in lower target Increased risk in higher target Phrommintikul et al. Lancet. 2007;369;

33 Risk of All-Cause Mortality; Higher Hb vs Lower Hb (Fixed Effects Analysis) Risk ratio (95% CI) Weight (%) Besarab et al Foley et al Furuland et al Levin et al Parfrey et al Drueke et al Rosset et al Singh et al Overall 1.21 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Risk ratio Increased risk in lower target Phrommintikul et al. Lancet. 2007;369; Increased risk in higher target 65 Overall Goal: Keep Hgb in the range! 66

34 CKD Resets the Focus on CV Risk Reduction Strategies BP <130/80 mmhg? Evaluate and treat lipids Extinguish microalbuminuria/proteinuria? Reduction in dietary salt/saturated fat Intensify glycemic control Control anemia Control calcium / phosphorus balance Anti-platelet therapy 67