1. Mortality in patients with Chronic Kidney Disease Why there are more patients requiring renal replacement therapy renal replacement therapy John R Brouillette MD FASN Nephrology Associates, PC Birmingham, AL CRIOS CKD Participant Council Philadelphia Marriott Downtown Meeting Room 403 November 9, 2005

2. 1)Why are there thirty times more patients with chronic kidney disease (CKD) than there are patients requiring renal replacement therapy? 2) What is the definition of someone with CKD versus someone with end-stage kidney disease (ESRD)? 3) Do the mortality rates in patients with CKD differ from patients who have ESRD and are receiving renal replacement therapy? 4) Is CKD a risk factor for cardiovascular disease (CVD) and why? 5) Do all patients with CKD end up on dialysis?

3. Guidelines and Databases in Kidney Disease 1972 Social Security extended Medicare coverage to patients under the age of 65 with ESRD 1988 United States Renal Data System (USRDS) was established 1993 National Institutes of Health: Consensus Statement on Morbidity and Mortality of Dialysis patients - Guideline: When to refer a patient to a nephrologist Women: Serum creatinine (SCr) ≥ 1.5 mg / dL Men: SCr ≥ 2.0 mg / dL

4. Guidelines and Databases in Kidney Disease (cont’d) 1995 National Kidney Foundation (NKF): guidelines developed for the care of dialysis patients to reduce morbidity and mortality Dialysis Outcomes Quality Initiative (DOQI) 1997 DOQI Guidelines were published - Hemodialysis adequacy - Peritoneal dialysis adequacy - Vascular access - Anemia management 1999 USRDS data demonstrated significant, measurable improvements in care and outcomes of dialysis patients based on implementation of DOQI - Mortality rates remained at 20-25% per year Fall 1999 National Kidney Foundation started Kidney Disease Outcomes Quality Initiative (KDOQI)

5. Guidelines and Databases in Kidney Disease (cont’d) 1999 Kidney Disease Outcomes Quality Initiative (K/DOQI) - Focus: Evaluation, stratification, and classification of chronic kidney disease Chronic Renal Failure CKD - Work groups ( ASSKH, AAKP, ACP-ASIM, ASN, NIDDKD ) - Extensive literature review

6. Guidelines and Databases in Kidney Disease (cont’d) February 2002 Clinical Practice Guidelines for Chronic Kidney Disease Evaluation, Classification and Stratification - Fifteen guidelines - subsequent guidelines released through 2004 January 2003 Renal Physicians Association: Clinical Practice Guidelines - Focus: Appropriate patient preparation for renal replacement therapy - Guidelines for patients with advanced kidney disease (Stage 4 CKD K/DOQI) Glomerular Filtration Rate ≤ 30 mL / min/1.73m 2

7. Stages of Chronic Kidney Disease GFR Stage Description ( mL/min / 1.73 m 2 ) 1 Kidney damage with normal ≥90 or increased GFR 2 Kidney damage with mild 60 – 89 decrease in GFR 3 Moderate decrease in GFR 30 – 59 4 Severe decrease in GFR 15 – 29 5 Kidney failure <15

8. K/DOQI #1 cont’d Definition of Chronic Kidney Disease Criteria for diagnosis 1)Kidney damage for ≥3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either: - Pathological abnormalities from tissue biopsy - Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests 2. GFR < 60 mL / min / 1.73 m 2 for ≥ 3 months, with or without kidney damage

10. Application of Kidney Data to “Now Known” Guidelines Chronic kidney disease: How many patients with CKD are there? - National Health and Nutrition Examination Survey III (NHANES) Epidemiological data collected from 1988–1994 on the health and nutritional status of (a sample) of the 177 million noninstitutionalized people older than 20 years of age in the United States - Application of the NIH guidelines from 1993 the following was determined SCr Men Women > 1.5 mg/dL 4.98 % 1.55% > 2.0 mg/dL 0.64% 0.33%

11. Application of Kidney Data to New Guidelines Extrapolation of data from NHANES data to K/DOQI Guideline 1 Stages and Prevalence of Chronic Kidney Disease Stage Description GFR Prevalence % of population 1 normal or GFR ≥ 90 3,501,000 0.9 2 mild or GFR 60-89 7,780,000 2.0 3 moderate GFR 30-59 16,338,000 4.2 4 severe GFR 15-29 1,167,000 0.3 5 kidney failure < 15 335,000 0.16 * Based on 2003 population data 389,000,000

12. Application of Guidelines to Kidney Data cont’d Extrapolation of NHANES data to estimates of subgroups of the US population at increased risk of having Chronic kidney disease (stages I through V) Subgroup Estimated Number Age >70 year 34 million (8.8%) Diabetic patients 17 million (3%) Hypertensive patients 78 million (20%) Ethnicity 54 million (14%) Family history of ESRD ~ 3 million

14. Overview: CKD and ESRD in the United States USRDS 1972 <15,000 patients were receiving dialysis therapy Patient profile: young (< 50 years old ), white, male secondary education, employed 2002 308,910 patients on dialysis therapy on 12/31/2002 122,374 patients with renal transplants Average age > 50 (83%)

15. Overview of CKD and ESRD in the US cont’d CKD Stage-related COMORBID CONDITIONS - Metabolic abnormalities: acidosis, bone disease, phosphatemia - Endocrinopathies: parathyroid gland dysregulation, vitamin D deficiency, testosterone deficiency - Anemia: erythropoietin deficiency, erythropoietin resistance, iron malabsorption and dysutilization - Endothelial cell dysfunction and inflammatory state: malnutrition and altered metabolism - Neuropathy

16. Overview of CKD and ESRD cont’d COMORBIDITY: LEFT VENTRICULAR HYPERTROPHY AND ANEMIA - Incidence of left ventricular hypertrophy (LVH) is epidemic; 70% of ALL patients starting dialysis /40% have congestive failure - For every decrease in GFR of 5 mL/min there is a 3% increase risk of LVH (< 25 mL / min / 1.73 m 2 – rate of LVH 45.2%) - Anemia prevalence in CKD is parallel to that of LVH

18. CKD and Mortality CKD: GFR 3 months duration - Cardiovascular disease is 2 X as common versus the general population - Cardiovascular disease accelerates 2 X as fast in this population - Age matched standardized mortality in general population versus patients with a SCr ≥ 1.7 mg / dL > 65 years of age: 2 X general population 50 – 64 years of age: 12 X general population 16 – 49 years of age: 36 X general population

19. ESRD and Mortality ESRD: GFR < 10 – 15 mL / min - 50% of deaths due to cardiac events - 50% of ESRD patients who have had an MI are dead in 2 years - Age-matched controls for overall cardiovascular mortality > 75 years of age: 5 X higher > 65 year of age: 5 year survival rates are 20% 25 – 35 years of age: 375 X that of age matched controls

20. CKD, ESRD, and Mortality cont’d Nephrol Dial Transplant (2005) 20: 1048-1056 Overall Risk Assessment: A decreased GFR ( < 75 mL / min – ie CKD stage 2 ) correlates with increased cardiovascular disease risk and mortality. This applies in the setting for adjustment of risk factors 1)Gender 2)Age 3)Diabetes 4)Vascular disease at time of diagnosis of CKD 5)Hypertension 6)LV dysfunction 7)Chronic medication ingestion ( anti-inflammatory drugs) 8)Tobacco Use 9)Hyperlipidemia

21. Copyright restrictions may apply. Vanholder, R. et al. Nephrol. Dial. Transplant. 2005 20:1048-1056; doi:10.1093/ndt/gfh813 Relative Risk of Mortality (RR_mortality) vs GFR

22. CKD, ESRD, and Mortality cont’d Why kidney failure ?: Uremic solute retention 1)Oxidative stress product retention 2)Pro-coagulant factors 3)Increased IL-6 4)Phosphorous retention 5)Increased vascular calcium deposition 6)Asymmetric dimethylarginine (ADMA) accumulation 7)Chronic elevation of parathyroid hormone, homocysteine levels neuropeptide Y hormone Other factors 1)Increased sympathetic nervous system activity ( sleep apnea ) 2)Other candidates: - Phenylacetic acid - Indoxyl sulphate and p-cresol - Guanidines

23. HOW DO WE DEFINE? s ē s ē k ā k ā d ē d ē k â r k â r

24. Is therapeutic nihilism the way to go ? Death (premature) CKD ESRD - ACE I - ACE I / ARB II combination therapy - Diabetes control - HMG CoA reductase inhibitors ( beyond hyperlipidemia ) - Smoking cessation - Obesity management - Treatment of hypertension

25. Parachute use to prevent death Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: Systematic review of randomised controlled trials. Br. Med J 2003; 327: 1459-1461.

26. CKD stages I – V SCr MDRD C. C. R. A. P. : ADMA level hemoglobin level hemoglobin AIC highly sensitive CRP level intact PTH LDL phosphorous uric acid level urine protein / urine creatinine

27. Does one size fit all ?: The “ Polypill ” Concept Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326: 1419. Polypill: Statin ½ doses of beta blocker, diuretic, ACE inhibitor ½ doses of beta blocker, diuretic, ACE inhibitor Aspirin 75 mg Aspirin 75 mg Folic acid.8 mg Folic acid.8 mg Patient profile: 1) 55 of years of age and older 2) Any adult with diabetes mellitus 2) Any adult with diabetes mellitus 3) Any adult with cardiovascular disease 3) Any adult with cardiovascular disease

28. Is there hope ? Steno-2 N Engl J Med 348: 383-393, 2003 Steno-2 Study: multifactorial interventions compared to conventional treatment of modifiable risk factors for cardiovascular disease in patients with microalbuminuria and type II diabetes. Prospective study: 160 patients total with 80 / 80 in each group Intensive treatment: 1)Reduction of total saturated fat intake 2)Increased exercise 3)Smoking cessation 4)ACEI or ARB therapy 5)MVI supplements 6)ASA 150 mg per day 7)Intense glucose control: Hemoglobin AIC of < 6.5 8)Intense hypertension control: goal BP < 140 / 80 mm Hg (< 130 / 80 mm Hg) 9)Anti-lipid therapy with statins and fibrates

29. Kaplan-Meier Estimates of the Composite End Point of Death from Cardiovascular Causes, Nonfatal Myocardial Infarction, Coronary-Artery Bypass Grafting, Percutaneous Coronary Intervention, Nonfatal Stroke, Amputation, or Surgery for Peripheral Atherosclerotic Artery Disease in the Conventional-Therapy Group and the Intensive-Therapy Group (Panel A) and the Relative Risk of the Development or Progression of Nephropathy, Retinopathy, and Autonomic and Peripheral Neuropathy during the Average Follow-up of 7.8 Years in the Intensive-Therapy Group, as Compared with the Conventional-Therapy Group (Panel B) Gaede, P. et al. N Engl J Med 2003;348:383-393

30. CKD I – V ESRD

31. ESRD: Past, Present, and Future Characteristics 1988 1998 2002 2010 %____ # of patients treated for ESRD 136,906 326,217 508,305 651,330 ( 452 %) New patients per year (incident) 37, 906 86,825 100,359 172,667 Patients receiving dialysis ( 12/31) 237,726 308,910 520,240 Patients per 10 6 308 333 2219 # of primary physicians 102,800 121,000 147,600 166,600 ( 62% ) # of practicing nephrologists 3,280 4,816 5,730 7,120 ( 117% )

32. Does CKD Prevalence Predict ESRD Incidence? Ann Intern Med 2004;141: 95 NHANES II: 1976 – 1980 USRDS 1983 - 1996 NHANES III: 1988 – 1994 CKD stage III and IV (GFR: 15 – 59 mL/min) CKD stage V (GFR: < 15mL/min) Year NHANES (total US. Pop.) # CKD per/100,000 ESRD 1978 8305 (129,600,000) 263 (2,560,000) 1970 - 1983 22,929 1991 13350 (158,100,000) 397 (3,890,000) 2460 1996 60,323 ( 70% )

33. Does CKD prevalence predict ESRD incidence? cont’d: New cases of ESRD from 1983 to 1996 extrapolated from number of cases of CKD collected in NHANES II and III from 1978 to 1991 ESRD 1983 ESRD 1996 RR of progression per 1000 NHANES II per 1000 NHANES III 1978 to 1991 Overall 9 16 1.7 (1.1 -2.7) Age 20-60 18 27 1.5 (0.7-3.0) Age 61-74 5 10 2.1 (0.3 to 3.5)

34. Hsu C-y et. al. Ann Intern Med 2004;141:95-101 Numbers of cases of newly treated end-stage renal disease (ESRD) among black and white patients, 25 to 79 years of age, in the United States from 1985 to 1996

35. Does CKD prevalence predict ESRD incidence? Answer: NO - ESRD incidence through 1996 outpaced the INCREASE in CKD prevalence by 70% - Approximately 10% of the growth in ESRD cases is attributable to the increase in cases of CKD in the adult population WHAT ARE THE SOURCES OF INCREASED NUMBERS OF PATIENTS WITH ESRD BEYOND CKD?

36. Factors of beyond CKD contributing to ESRD 1) Gradually rising starting age of patients on dialysis Incident rate outpacing prevalent rate due to dynamic mortality rates ? 2) Improved survival from all causes of death / increased age expectancy of the population as a whole 3) Earlier dialysis initiation criteria based on higher GFR: 1995: 7.5 ml / min / m 2 2001: 9.3 ml / min / m 2 4) Return rate of patients that have been transplanted previously that develop CKD stage V 5) Increased incidence of patients with acute kidney failure 1970 ( 4.9% ) to 1991 ( 7.2% ) that live with ESRD on discharge

37. Summary 1)There is excessive risk for cardiovascular disease in patients with CKD 2) The increased risk of cardiovascular disease is directly related to decline in GFR 3) CKD is a risk factor for cardiovascular disease beyond the established other risk factors such as diabetes, hypertension, and hyperlipidemia 4)Most patients with CKD do not progress to ESRD 5) Increased ESRD incidence can be attributed to improvements in care of patients with cardiovascular disease, increased lifespan, and initiating patients with a higher residual GFR