CHRONIC KIDNEY DISEASE

Reinaldo Rosario MD, FASN Renal Electrolyte & Hypertension Consultants (REHC)

NATURAL HISTORY OF RENAL DISEASE

Initial injury to the kidney Adaptive hyperfiltration Long-term damage to the remaining nephrons proteinuria and progressive renal insufficiency Advanced renal disease dysfunction volume overload, hyperkalemia, metabolic acidosis, HTN, anemia and bone disease End Stage Renal Disease (ESRD)

CKD - DEFINITION
Evidence of structural or functional kidney abnormalities that persists for at least 3 months, with or without a decreased GFR. GFR <60 mL/min/1.73m for 3 months, with or without kidney damage Prevalence 4.7% or 8.3 million

NKF. Am J Kidney Dis. 2002;39(supp1):S1

STAGES OF CHRONIC KIDNEY DISEASE

Stage I Description Kidney Damage with normal or increased GFR Kidney Damage with mildly decrease GFR GFR (mL/min/1.73m) >90

II III

60-89

Moderately decreased 30-59 GFR

IV
V

Severely decreased GFR

Kidney Failure

15-29
<15

PREVALENCE OF CKD
8,000,000 7,000,000 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 >90 60-89 30-59 15-29 <15 GFR (ml/min/1.73m2)

NKF. Am J Kidney Dis. 2002;39(supp 1):S1

ESRD
As of Dec. 31 2006 506,256 dialysis pts In 2006 alone, 110,854 pts entered the ESRD program Medicare expenditure - $22.7 billion in 2006 Projected number of ESRD pts by 2010 651,330 and Medicare cost in excess of $28 billion dollars

U.S. Renal Data System: USRDS 2006

ESRD
Annual mortality rate for all ESRD pts on treatment is 20-fold higher than the general population At age 45 life expectancy: - General population: 34.7 years - ESRD: 6.2 years on dialysis / 19.5 years with a functioning kidney graft

U.S. Renal Data System: USRDS 2002

CAUSES OF DEATH IN ESRD

15% 11% 5%
U.S. Renal Data System: USRDS 2002

4%
Cardiac

39%

Cerebrovascular Other known Unknown Infection Malignancy

26%

MULTIPLE RISK FACTORS FOR CKD

Diabetes Hypertension Autoimmune disease Systemic infections Exposure to drugs associated with acute decline in kidney function Recovery from acute kidney failure Older age Family history of kidney disease Reduced kidney mass Racial/ethnic background Smoking

NKF. Am J Kidney Dis. 2002;39:S46 Pinto-Sietsma. Ann Intern Med. 2000;133:585

EVALUATING PATIENTS AT RISK FOR CKD

Evaluating risk factors and identifying GFR declines are essential to the prompt and appropriate management of CKD GFR or age/weight-sensitive eGFR Blood pressure Glucose Urinalysis Microalbuminuria/proteinuria

COMORBIDITIES AND COMPLICATIONS OF CKD

Anemia Hypertension Cardiovascular disease Diabetes Osteodystrophy Malnutrition Metabolic acidosis Dyslipidemia Deficits in functioning and well-being

Zabetakis. Am J Kidney Dis. 2000;36(suppl 3):S31 NKF. Am J Kidney Dis. 2002;39:S17

DELAYED DIAGNOSIS OF CKD LEADS TO UNDERUSE OF INTERVENTIONS Lack of interventions to treat HTN, CVD, DM, anemia, and malnutrition Under use and delayed consultations with nephrologists, cardiovascular specialists, or dietitians Lack of patient education Lack of a permanent vascular access at initiation of hemodialysis

OPTIMAL CKD PATIENT CARE

Early detection of CKD
Delay progression
ACE inhibitors BP control Blood sugar control Protein restriction?

Prevent complications
Anemia Malnutrition Osteodystrophy Acidosis

Treat comorbidities
Cardiac disease Vascular disease Diabetes

Prepare or RRT
Educate patient Select RRT modality Create access and initiate dialysis in a timely fashion

Pereira. Kidney International. 2000;57:351

MANAGEMENT OF PATIENTS WITH CKD

Blood pressure control Diabetes control Cardiovascular disease management Anemia management Iron management Vitamin D and vital bone protection Eating well and exercise Access planning

CARDIOVASCULAR RISK AND GFR

35 30 25 20 15 10 5 0 >60 45-59 30-44 15-29 <15 GFR (ml/min/1.73m2)

Age-standarized rate of CV events (per 100 persons/year)

Go AS. N Engl J Med 2004;351:1300

CARDIOVASCULAR MORTALITY AND HYPERTENSION

Cardiovascular Mortality Risk
7 6 5 4 3 2 1 0 115/75 135/85 155/95 175/105 Systolic/Diastolic Blood Pressure (mm Hg)

Lewington S . Lancet 2002; 360: 1903-13.

PREVALENCE OF HYPERTENSION IN CKD

Normotensive

17%

1795 patients with kidney diseases were screened GFR range 13-55 mL/min/1.73m BP in 83% of patients (n=1494)
Hypertensive

83%

Buckalew. Am J Kidney Dis 1996;28:811.

BLOOD PRESSURE IS POORLY CONTROLLED IN CKD

11% 27% 62% >140/90 <140/90 <135/90

Coresh. Arch Intern Med. 2001;161:1207

Aggressive Blood Pressure Goals: Consensus Across Treatment Guidelines

Organization
ADA(American Diabetes Association)
ISHIB(Isolated Systolic Hypertension in Blacks) JNC 7(Joint National Committee) NKF(National Kidney Foundation)

Patient Type
Diabetes
ISHIB(Isolated Systolic Hypertension in Blacks) Uncomplicated HTN With DM, CKD Albuminuria (>300 mg/d or >200 mg/g creatinine), with or without diabetes Low risk for CVDPresence of Diabetes Mellitus, target organ damage

BP Goals (mm Hg)

<130/80
<140/90<130/80

<140/90<130/80 <130/80Consider even lower than <130/80

WHO-ISHWorld Health Organization Isolated Systolic Hypertension)

SBP<140 <130/80

BLOOD PRESSURE CONTROL IN CKD: GOALS

Target population
CKD stages 1-4 with proteinuria(>1g/day)or diabetic kidney disease

SBP
<125

DBP
<75

CKD stages 1-4 without proteinuria

<135

<85

CKD stage 5

<140

<90

NKF. Am J Kidney Dis. 2002;3a(suppl 1):S1

GFR = BP MEDS
4 3.5 3 2.5 2 1.5 1 0.5 0 90-99 80-89 70-79 60-69 50-59 40-49 GFR Diabetic Studies Non-Diabetic Studies

Number of Blood Pressure Medications

Nephsap. American Society of Nephrology 2005; 4:101

BP CONTROL: INTERVENTIONS
ACE inhibitors Angiotensin-receptor blockers (ARBs) Calcium channel blockers (CCBs) Diuretics Low-sodium diet Combination therapy

DIABETES MELLITUS: PREDICTIONS

In the next 10 years there will be a 50%

increase in the number of diabetics. 25 to 40% of these individuals will develop kidney disease. Obesity, poor dietary habits, lack of physical activity, family history are risks.

THE EPIDEMIC OF DIABETES

Prevalence increased by 40% 1990-99.
Estimated increase by 165% 2000-2050. Individuals born in 2000: risk developing

diabetes 32.8% males, 38.5% females. Hispanic lifetime risk 45.4% males, 52.5% females.

Adults With Diagnosed Diabetes*

1990

No data available

Less than 4%

4%6%

Above 6%

*Includes women with a history of gestational diabetes.

Mokdad AH et al. Diabetes Care. 2000;23(9):1278-1283.

Adults With Diagnosed Diabetes*

2000

4%6%
*Includes women with a history of gestational diabetes.
Mokdad AH et al. JAMA. 2001;286(10):1195-1200.

Above 6%

DIABETIC KIDNEY DISEASE SIGNIFICANCE

Accounts for 40-50% total kidney failure in

the United States 40-50% of TYPE 1 Patients and 40% of TYPE 2 Patients will develop clinical diabetic kidney disease. Diabetes affects certain ethnic groups more frequently than caucasians: native americans 7x, hispanics and latinos 4-5x, african americans 4x.

ANEMIA IN PATIENTS WITH CKD

9%

39%

Hb 10-12 Hb >12 Hb <10

52%

N= 5222 CKD SCr 1.5-6.0 mg/d(women) SCr 2.0-6.0 mg/dL (men)

McClellan, NKF. 2002

Severe Anemia is Common at the Start of Dialysis

43% 57%

HCT >28% HCT <28%

Obrador. Kidney Int. 2001; 60:1875

ANEMIA SIGNIFICANTLY IMPACTS CKD PATIENTS

Cardiovascular system-related morbidity/mortality Increased cardiac output Left ventricular hypertrophy (LVH) Symptomatic angina pectoris Decreased pulmonary diffusion Decreased oxygen utilization Lower aerobic exercise capacity Decreased energy level Impaired functional ability Reduced cognitive function

Lower physical work capacity

Negative impact on daily living

Macdougall. Semin Oncol. 1998;25(suppl 7):40

EVALUATION OF ANEMIA
Hemoglobin and/or hematocrit Red-blood-cell indices Reticulocyte count Iron parameters Test for occult-blood in stool

NKF. Am J Kidney Dis. 2001;37:S192

TREATMENT OF ANEMIA
Iron supplementation (IV/PO) Erythropoiesis stimulating agents

IRON DEFICIENCY IN CKD

Preexisting Iron Deficiency Poor nutrition Blood loss Iron deficiency with erythropoiesisstimulating agents Increased iron needs

ASSESSMENT OF IRON STATUS

Frequently used tests Serum ferritin Transferrin saturation Additional measurements Reticulocyte Hb content % Hypochromic RBCs Erythrocyte ferritin
NKF. Am J Kidney Dis. 2001;37(suppl 1);S182 Macdougall. Curr Opin Hematol. 1999;6:121 Goodnough. Blood. 2000;96:823

Target 100 ng/mL >20%

POSSIBLE INADEQUACY OF ORAL IRON

Low intestinal absorption of oral iron, even in healthy persons Poor patient adherence Intravenous iron has improved anemia in CKD and ESRD when oral iron has failed

NKF. Am J Kidney Dis. 2001;37 (suppl 1):S182 Silverberg. Kidney Int. 1999;55(suppl 69):S79

Anemia and LVH

50 40

Prevalence of LVH (% Patients)

30 20 10

CrCl

0 >50 35 - 49 25 - 34 <25

Mean Hb (g/dL)

14.1

13.2

12.5

11.4

Levin. Nephrol Dial Transplant, 2001;16 Suppl 2) : 7.

LVH and CKD

LVH is an independent risk predictor of cardiac death HTN, anemia and diabetes are modifiable predictors of LVH Blood pressure increase is associated with 3% increase in LVH risk Hb decrease of 1 g/dL is associated with 6% increase in LVH risk

Greaves. Am J Kid Dis. 1994; 24;768 Levin. Am J Kid Dis. 1996; 27:347.

Normal Hematocrit Trial

Study Objective: Whether normal Hct value should be the target level in dialysis patients Study Design : 1233 HD patients with cardiac disease. Baseline Hct. 27- 33%. Mean age 65 years. Primary Endpoint: time to death or first nonfatal myocardial infarction Methods: Patients randomly assigned to achieve and maintain a Hct of 42 or 32% WITH EPO tx Results: Study terminated early (29 months) due to increase mortality in the group targeted for normal Hct level. N Eng J Med 1998; 339:584

CHOIR Study
(Correction of Hemoglobin and Outcomes in Renal Insufficiency)

Study Objective: Whether a normal or near-normal Hb value should be the target level in pre-dialysis pts with CKD Study Design: 1432 CKD patients (eGFR 15-50 mL/min) with Hb < 11g/dL Primary Endpoint: Composite of death, myocardial infarction, stroke, and hospitalization for heart failure Methods: Randomization to achieve target Hb of either 13.5 or 11.3g/dL Results: Study terminated early(16 months) due to higher number of events in the high Hb group.
Drueke, TB et al. N Engl J Med 2006;355:2071

CREATE Study
(Cardiovascular Risk Reduction by Early Anemia Treatment with Epoietin Beta)

Study Objective: Whether a normal or near-normal Hb value should be the target level in pre-dialysis pts with CKD. Study Design: 603 pts with GFRs between 15-35 mL/min Primary Endpoint: Composite of eight CV events Methods: Randomization to normal Hb (13-15 g/dL) or subnormal (10.5 11.5 g/dL) Results: At 3 years similar risk of experiencing the primary endpoint in bot groups ( HR of 0.78, 95% CI 0.53-1.14)
Singh, AK et al. N Engl J Med 2006; 355:2085

Ongoing and Future Studies

TREAT study Randomized, placebo-controlled trial in Predialysis pts with DM type 2 to Hb 13 or greater than9 g/dL. Primary endpoint is overall mortality and nonfatal CV events. NEPHRODIAB2 trial Prospective randomized openlabel trial in CKD stage 3 and 4 with DM type 2. Randomization to Hb 13-14.9 g/dL or 11-12 g/dL. Primary endpoint is decline in kidney function. Secondary outcomes include mortality

Anemia current recommendations

Close monitoring of predialysis Hb levels Erythropoietic agents rather than blood transfusions Target Hb should generally be in the range of 11 12 g/dL and should not exceed 13 g/dL. Supplemental iron

SECONDARY HYPERPARATHYROIDISM
Most common form of renal osteodystrophy Prevalence 47% of 176 patients with ESRD had a PTH level more than three times the normal amount
Mizumoto. Nephrol Dial Transplant. 1994:9:1751 Billa. Perit Dial Int. 2000;20:315

VITAMIN D DEFICIENCY AND PHOSPHATE RETENTION

CKD
Vitamin D Deficiency Phosphate Retention

Hypocalcemia Hyperparathyroidism Osteodystrophy

Liach. In: Brenner. The Kidney. 1996:2187 Schomig.Nephrol Dial Transplant. 2000;15(suppl 5):18

Hyperphosphatemia
Begins early in renal disease Intimately related to secondary hyperparathyroidism which contributes to release of calcium and phosphorus from bone Elevated Ca x PO4 promotes precipitation of such in arteries, joints, soft tissues and the vicera Ca x PO4 >55 associated with increased mortality, similar to that observed with elevated PO4 level alone
Menon, V. Am J Kidney Dis 2005; 46:455.

MANAGEMENT OF VITAMIN D DEFICIENCY AND PHOSPHATE RETENTION Vitamin D analogs Low phosphate diet (800 mg/day) Phosphate binders (calcium and non-calcium based) Calcium

Coburn. J Am Soc Nephrol. 1998;9:S71 Schroeder. Nephrol Dial Transplant. 2000;15:460 Chertow. Clin Nephrol. 1999;51:18

Phosphate Binders
PO4 Binder Blood Ca Blood PO4 Blood level LDL Adverse Effects Calcium acetate Promotes coronary artery calcification Promotes coronary artery calcification Metabolic acidosis; not seen with Renvela Not yet reported

Calcium Carbonate

Renagel/ Renvela

Lanthanum

Aluminum

Anemia, dementia, CNS abn, osteomalacia

ACID/BASE BALANCE
Renal NH4+ Excretion 40 mEq/day Endogenous H+ Production 70 mEq/day Renal Excretion 30 mEq/day Renal Net Acid Excretion 70 mEq/day

Normal Acid/Base Balance [HCO3] = 24 mEq/L Alpem. Am J Kidney Dis. 1997;29:291

CONSEQUENCES OF METABOLIC

ACIDOSIS
Abnormal renal handling of ions
tubular-phosphate reabsorption filtered load of calcium and phosphate tubular-calcium reabsorption

Increased resorption of bone Increased muscle catabolism

Franch. J Am Soc Nephrol. 1998;9:S78

TREATMENT OF METABOLIC ACIDOSIS IN CKD

Goal Serum HCO3- > 20 mEq/L pH > 7.35 Agents Sodium bicarbonate tablets (650 mg = ~ 8 mEq HCO3-) Sodium citrate (Shohls solution) Dose of HCO31.0 1.5 mEq/kg/day Dependent upon initial serum HCO3- and degree of renal insufficiency
Dubose TD. Harrisons Principles of Internal Medicine. 1998:277

Recommendations in Metabolic Acidosis Treatment

Alkali therapy to maintain plasma bicarbonate concentration above 22 meq/L (K/DOQI guideline recommendation) Sodium bicarbonate Agent of choice; may cause bloating. Sodium Citrate Avoid when also taking aluminum-containing anti-acids since it markedly enhances aluminum absoption

EATING WELL AND EXERCISE

Protein malnutrition is common in CKD Consider dietary protein restriction Properly monitored by experienced dietitian and nephrologist May improve long-term survival of patients Exercise Improves physical functioning Improves cardiovascular health

Bailey. Therapy in Nephrology and Hypertension. 1998:474

EXERCISE
Physical functioning Blood pressure control Muscle, bone strength Level of cholesterol and triglycerides Better sleep Control of body weight
NKF. Staying fit with Kidney Disease

VASCULAR ACCESS FOR HEMODIALYSIS

Establish communication between nephrologist and PCP Preserve an arm: no intravenous injections or blood draws Refer to surgeon for fistula when SCr >4mg/dL, CrCl <25 mL/min, or dialysis anticipated within 1 year Fistula may take 3 to 4 months to mature
NKF. Am J Kidney Dis. 2001;37(suppl 1):S147

TEAM APPROACH: ROLE OF PRIMARY PHYSICIAN AND NEPHROLOGIST IN CKD

Primary Physician Screen and identify risk factors of CKD Provide ongoing management of patients with CKD Provide role-specific patient education

Nephrologists Assist in development of care strategy Aid recommendation and implementation of patient care Provide role-specific patient education

BENEFITS OF EARLY INTERVENTION IN THE MANAGEMENT OF CKD

Delayed progression of CKD Improved teamwork between physicians Decreased risk of cardiovascular complications Improved dialysis outcomes Better educated and prepared patients
Pereira. Kidney Int. 2000;57:351.