Mortality in patients with Chronic Mortality in patients with Chronic Kidney Disease Kidney Disease Why there are more patients requiring Why there are more patients requiring renal replacement therapyrenal replacement therapy

John R Brouillette MD FASNNephrology Associates, PC

Birmingham, AL

CRIOS CRIOS CKD Participant Council

Philadelphia Marriott Downtown Meeting Room 403November 9, 2005

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?

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

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)

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

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/1.73m2

Stages of Chronic Kidney Disease

GFR Stage Description ( mL/min / 1.73 m2 )

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

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 m2 for ≥ 3 months, with or without kidney damage

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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%

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

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

MM OO E SE S R R DD BB II C K C K DD II M O R M O R T T A L I T YA L I T Y YY

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%)

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

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 m2 – rate of LVH 45.2%)

- Anemia prevalence in CKD is parallel to that of LVH

CKD and Mortality

CKD: GFR < 60 mL / min > 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

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

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)Gender2)Age3)Diabetes 4)Vascular disease at time of diagnosis of CKD5)Hypertension6)LV dysfunction7)Chronic medication ingestion ( anti-inflammatory drugs)8)Tobacco Use9)Hyperlipidemia

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

CKD, ESRD, and Mortality cont’d Why kidney failure ?: Uremic solute retention

1)Oxidative stress product retention 2)Pro-coagulant factors3)Increased IL-64)Phosphorous retention5)Increased vascular calcium deposition6)Asymmetric dimethylarginine (ADMA) accumulation7)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

HOW DO WE HOW DO WE DEFINE?DEFINE?

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Is therapeutic nihilism the way to go ? 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

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

CKD stages I – V SCr MDRD

C. C. R. A. P. :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

Does one size fit all ?:Does one size fit all ?: The “ Polypill ” Concept The “ Polypill ” Concept

Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326: 1419.

Polypill: StatinPolypill: Statin ½ doses of beta blocker, diuretic, ACE inhibitor½ doses of beta blocker, diuretic, ACE inhibitor Aspirin 75 mgAspirin 75 mg Folic acid .8 mgFolic acid .8 mg

Patient profile: 1) 55 of years of age and olderPatient 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 disease3) Any adult with cardiovascular disease

Is there hope ? Steno-2 Is there hope ? Steno-2 N Engl J Med 348: 383-393, 2003N 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 intake2) Increased exercise 3) Smoking cessation4) ACEI or ARB therapy5) MVI supplements6) ASA 150 mg per day7) Intense glucose control: Hemoglobin AIC of < 6.58) Intense hypertension control: goal BP < 140 / 80 mm Hg (< 130 / 80

mm Hg)9) Anti-lipid therapy with statins and fibrates

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

CKD I – V ESRD CKD I – V ESRD

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 106 308 333 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% )

Does CKD Prevalence Predict ESRD Incidence? Does CKD Prevalence Predict ESRD Incidence? Ann Intern MedAnn Intern Med 2004;141: 95 2004;141: 95

NHANES II: 1976 – 1980 USRDS 1983 - 1996 NHANES III: 1988 – 1994CKD 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%

)

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)

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

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 WHAT ARE THE SOURCES OF INCREASED NUMBERS OF PATIENTS WITH ESRD BEYOND CKD?PATIENTS WITH ESRD BEYOND CKD?

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 / m2 2001: 9.3 ml / min / m2

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

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