10/27/2010. CKD in the United States. Management of The Patient With Chronic Kidney Disease. CKD Patients Are More Likely to Die Than Progress to ESRD

Management of The Patient With Chronic Kidney Disease

Paul J. Scheel, Jr., M.D., FASN Director,Division of Nephrology

CKD in the United States

An estimated 26 million adults have CKD

• Many are unaware of their condition Prevalence is increasing

– 1988-1994: 14.5%

– 1999-2004: 16.8%

Persons ≥ 60 years: 39.4%

Risk factors

– Diabetes, CV disease, hypertension – Mexican Americans, non-Hispanic blacks

http://www.kidney.org/kidneydisease/ckd/index.cfm#facts.

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5608a2.htm

6.6%

60%

70%

80%

90%

100%

of Patients

Event free

CKD Patients Are More Likely to Die Than Progress to ESRD

5-Year Follow-up

74.8% 63.3% 64.2%

27.8%

10.2% 19.5% 24.3%

45.7%

1.0% 1.2%

19.9%

14.9%

16.2% 10.3%

0%

10%

20%

30%

40%

50%

60%

Stage 1 Stage 2 Stage 3 Stage 4

Percentage o Disenrolled

RRT Died

Adapted from: Keith DS et al. Arch Intern Med. 2004; 164:659-663.

RRT = renalreplacement therapy

Management Goals

• 1) Diagnose

• 2) Delay Progression

• 3) Treat Complications

• 4) Prepare For Renal Replacement Therapy4) Prepare For Renal Replacement Therapy

What is Chronic Kidney Disease (CKD)?

Structural or functional abnormalities of the kidneys > 3 months, as manifested by either

– Kidney damage, with or without decreased glomerular filtration rate (GFR) defined by glomerular filtration rate (GFR), defined by

• Pathologic abnormalities

• Markers of kidney damage in blood, urine, or imaging tests

– GFR < 60 mL/min/1.73m²

CKD Stages

Stage Description GFR

mL/min/1.73 m²

Prevalence (×1000) 1 Kidney damage

with normal GFR ≥90 5900

Kidney damage 2

y g

with mildly decreased GFR

60-89 5300

3 Moderately

decreased GFR 30-59 7600

4 Severely

decreased GFR 15-29 400

5 Kidney failure <15 or on dialysis 300

Serum Creatinine (mg/dL) Corresponding to GFR of 60 mL/min/1.73m²(Stage 3 CKD)

Age (years) European-American African-American

Men Women Men Women

40 1.39 1.08 1.65 1.27

50 1.34 1.03 1.58 1.22

60 1.30 1.00 1.53 1.18

70 1.26 0.97 1.49 1.15

80 1.23 0.94 1.46 1.12

Using simplified (4-variable) MDRD equation

Risk Factors for CKD

CLINICAL FACTORS

• Diabetes mellitus

• Hypertension

• Autoimmune diseases U i t t b t ti /

SOCIOEPIDEMIOLOGIC FACTORS

• Older age

• Ethnicity:

• Urinary tract obstruction/

infection/stones

• Family history of CKD/ESRD

• History of AKI

• Reduced kidney mass

• Low birth weight

• Exposure to certain medications/toxins

– African American – American Indian – Hispanic – Asian – Pacific Islander

• Low income

• Lower educational level

Determining GFR

Serum creatinine is a POOR measure of kidney function

– Significant kidney disease may be present with near- normal serum creatinine -- especially in older women C ti i l

Creatinine clearance

• CCr = (140-age) x wt (in Kg) (x 0.85 in women) 72 x Cr

• 24-hour creatinine clearance

• Mean of 24-hour creatinine and urea clearances

Determining GFR,

• MDRD equation (estimated GFR in mL/min/1.73m²) – GFR=186 X (Cr)^-1.154x (Age)^-0.203x (0.742 if female) x

(1.210 if African American)

– Not validated in Hispanic, certain other populations

• CKD-EPI equation(estimated GFR in mL/min/1.73m²) – GFR = 141 X min(Scr/κ,1)^αX max(Scr/κ,1) ^{– 1.209} X

0.993^AgeX 1.018 [if female] X 1.159 [if black]

• κ is 0.7 for females and 0.9 for males

• α is –0.329 for females and –0.411 for males

• Min indicates the minimum of Scr/κ or 1

• Max indicates the maximum of Scr/κ or 1

Levey AS et al. Ann Intern Med. 2009;150:604-612.

Available online: http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class_g1.htm

Calculated eGFR is an “estimate”…..

Botev R et. al. Clin J Am Soc Nephrol. 2009; 4: 899–906.

Available online: http://cjasn.asnjournals.org/cgi/rapidpdf/CJN.05371008v1.pdf

eGFR 45 mL/min/1.73m²

= true GFR of 25‐80  mL/min/1.73m²

True GFR could be > 55  mL/min.1.73m²

…even with the “new and improved version”— CKD-EPI

True GFR could be > 55  mL/min.1.73m²

…or < 15 mL/min.1.73m…or < 15 mL/min.1.73m²²

Levey AS et al. Ann Intern Med. 2009;150:604-612.

Screening for Microalbuminuria, Albuminuria or Proteinuria

• Standard urine dipsticks detect total protein >

30 mg/dL—not sensitive enough for microalbuminuria screening

• Albumin-specific dipstick is useful for screeningAlbumin specific dipstick is useful for screening

• Untimed, random “spot” urine for ACR or protein/creatinine ratio (first morning void preferred)

GFR, Proteinuria, and CKD Progression

Hemmelgarn BR et al. JAMA. 2010;303(5):423-429.

Available online at: http://jama.ama-assn.org/cgi/data/303/5/423/DC1/1

ACR: Normal<30mg/g; Mild 30-300mg/g; Heavy>300mg/g

Albuminuria, GFR, and Death

GFR and albuminuria:

• eGFR < 60-75 mL/min/1.73m²

• Urine albumin > 10 mg/g creatinine

• Are INDEPENDENT predictors of all-cause and cardiovascular death

Chronic Kidney Disease Prognosis Consortium. Lancet. 2010;375(9731): 2073 – 2081.

Initial Assessment of Patient with Proteinuria and Elevated Creatinine

• History—is the proteinuria and elevated creatinine new?

– Often old labs that can be helpful

– Rule out acute kidney injury (AKI) vs. CKD – Recent events

• Diabetic vs. non-diabetic renal disease

• Is the proteinuria persistent

• Other urinalysis findings?

• Quantify proteinuria

Delay Progression

Can

Cannot

Hypertension Age

Albuminuria/proteinuria Ethnicity

Progression of CKD

Dyslipidemia Gender

Hemoglobin A_1C Genes

Smoking Dietary protein intake

Anemia

Renoprotection

• Blood pressure

– < 125/75 mmHg if proteinuria > 1 g/d – < 130/80 mmHg if proteinuria < 1 g/d – STILL CONTROVERSIAL !!

• Proteinuria – < 0.5-1 g/d

• Control lipid and blood glucose levels, stop smoking, lose weight

Peter son JC et al. Ann Intern Med. 1995;123:754-762.

AASK: Effect of CCB vs ACEI on Renal Outcomes

Person-yr

41% 44% 38%

Adapted from: Agodoa LY et al. JAMA. 2001;285:2719-2728.

Events per P

Meta-analysis of the Effects of Dietary Protein Restriction on Rate of Decline in Renal Function

• 13 randomized controlled trials

• Mean follow-up 21.8 months

• Mean dietary protein intake (DPI) ~ 0.6-0.7 mg/kg/d vs. ~1-1.2 mg/kg/d g g g g

• Protein restriction decreased rate of GFR decline by 0.53 mL/min/yr

Kasiske BL et al. Am J Kidney Dis. 1998;31(6):954-961.

Avoiding Acute Renal Injury

• Volume depletion

• Iodinated radiographic contrast media

• Sodium phosphate bowel prep

• Nephrotoxic antibiotics

• NSAIDs

Lower BP Slows Decline in GFR

95 98 101 104 107 110 113 116 119

MAP (mmHg)

/year)

0 -2 -4 6

GFR (mL/min/

130/85 140/90

Untreated HTN -6

-8 -10 -12 -14

Bakris GL et al. Am J Kidney Dis. 2000; 36(3):646-661.

Multiple Agents are Required to Achieve BP Goals

3.8

3.6 3.3

2 8

Number of Agents Needed 2.8

2.7 3.0 3.1 3.0

Bakris GL, et al. Am J Kidney Dis. 2000; 36(3):646-661.

Our RAAS Blockade Tools

• ACE inhibitors

• ARBs

• Aldosterone receptor antagonists

• Direct renin inhibitors

RAAS=renin-angiotensin-aldosterone system

RAAS Blockade in Type II Diabetes

• Most placebo-controlled studies in type 2 DM have been in patients with either microalbuminuria or established nephropathy treated with ARB

• ARB and ACEi appear to be equivalent for microalbuminuria and proteinuria reduction

• No mortality benefit demonstrated

Parving HH et al. NEJM.2001;345:870-878.

Is More RAAS Blockade Better?

• Supra-high doses

• ACEi + ARB

• ACEi or ARB + aldosterone receptor antagonist

• ACEi + ARB + aldosterone receptor antagonistACEi + ARB + aldosterone receptor antagonist

The COOPERATE Trial

• Double-blind RCT of 336 pts with non-diabetic renal disease treated with ACEi or ARB or both

– ACEi + ARB resulted in greater reduction in proteinuria and fewer patients with doubling of serum creatinine or ESRD

• Similar BP control

• The only study to show improved CKD progression and ESRD outcomes with dual RAAS blockade

• Retracted by Lancet, October, 2009

Nakao, et al. (Lancet. 2003 Jan 11;361(9352):117-124) Lancet. 2009 Oct 10;374(9697):1226.

Combined ACEi + ARB Treatment

• No long-term studies showing improved renal outcomes (CKD progression, ESRD)

– Likewise for aldosterone receptor blockade

• No demonstrated mortality benefit in patients with CKD

• Risk > benefit, especially in patients at low risk for progression to ESRD

• In all patients on RAAS blockade, low Na⁺diet potentiates proteinuria reduction and BP management

Summary

• Use ACEi or ARB as first-line therapy for diabetics and nondiabetics with microalbuminuria or proteinuria

– Titrate doses to maximally reduce proteinuria – Diuretics, low salt diet

• Consider dual therapy only in patients with high risk of CKD progression and significant proteinuria despite reasonably high doses of single ACEi or ARB

– ACEi + ARB

– ACEi or ARB + spironolactone or eplerenone – Add 2^ndagent in lowest doses

• Carefully monitor BP, eGFR, K⁺

Treat Complications

• Metabolic Acidosis

• Secondary Hyperparathyroidism

• Anemia ?

Metabolic Acidosis

• Often becomes apparent at GFR < 25-30 mL/min – Higher protein diet  more acidosis

• May contribute to bone disease, protein catabolism

• Maintain serum bicarbonate > 22 mmol/L – Start with 0.5-1 mEq/kg per day – Sodium bicarbonate tablets

• 325 mg (3.9 mEq) or 650 mg (7.8 mEq) tablets – Sodium citrate solution

• 1 mEq/ml

• Avoid if patient on aluminum phosphate binders – Baking soda

• 54 mEq/level tsp

Vitamin D

Phosphorous ^Calcium

PTH

Consequences of PTH Elevation in Patients With CKD

PTH PTH

Decreased Vitamin D Receptors and Ca-Sensing Receptors

 Ca⁺⁺

1,25 D Calcitriol

Pi Bone Disease

Renal Failure

Systemic Toxicity

.

Bone Loss Cardiovascular

Disease

1(25)OH

D Decline and PTH Elevation as CKD Progresses

300 400

30 40 50

pg/mL)

H2D (ng/mL)

P<0.01

Stage 3

Stage 2 Stage 4

CKD Stage 1

lower limit

eGFR (mL/min/1.73 m²)

15 25 35 45 55 65 75 85 95 105

100 200

0 10

20 iPTH(p

1(25)OH

P<0.01

N = 150.

eGFR = estimated glomerular filtration rate; iPTH = intact parathyroid hormone.

Martinez et al. Nephrol Dial Transplant. 1996;11(suppl 3):22-28.

25

65 lower limit

upper limit

Prevalence of Abnormalities of Mineral Metabolism, PTH in CKD

CKD Stage 3

CKD Stages 4 and 5

Patients

50 60 70 80 90 100

iPTH >65 pg/mL Phosphorus >4.6 mg/dL Calcium <8.4 mg/dL

(n = 61)       (n = 117) (n = 230) (n = 396)      (n = 355) (n = 358)      (n = 204) (n = 93)

% of P

eGFR (mL/min/1.73 m²)

0 10 20 30 40 50

79‐70 69‐60 59‐50 49‐40 39‐30 29‐20 <20

iPTH = intact parathyroid hormone

>80

Adapted from: Levin A et al. Kidney Int. 2007;71:31-38.

CKD-MBD and Mortality

• All-cause and CV mortality increase 30-60% with each 1 mg/dL higher phosphorus level above normal

• Mortality impact of calcium and PTH levels inMortality impact of calcium and PTH levels in CKD patients not on dialysis is unknown

• No studies showing benefit of treatment

• Low phosphorous and calcium levels also associated with higher mortality

– Likely related to nutritional status

Covic A et al. NDT. 2009;24:1506-1523.

CKD-Mineral Bone Density Testing

CKD Stage Calcium, Phosphorus

PTH 25(OH)D

Stage 3 Every 6-12 months

Once then based on CKD

progression

Once then Once, then based on level and treatments Stage 4 Every 3-6

months

Every 6-12 months Stage 5 Every 1-3

months

Every 3-6 months

Use CKD progression, presence or absence of abnormalities, treatment response and side effects to guide testing frequency

KDIGO Guideline. Kidney Int. 2009;76 (113):S1-S130.

CKD-MBD Treatment Goals

• Use trends to guide therapy, rather than single level

• Bone density testing does not predict fracture risk so should not be used routinely for risk so should not be used routinely for assessing CKD-MBD or guiding therapy

• Maintain calcium and phosphorus levels in reference ranges

KDIGO Guideline. Kidney Int. 2009;76 (113):S1-S130.

CKD-MBD Treatment Goals

• Treat 25(OH)D deficiency as in general population – Cholecalciferol 1000-2000 IU/d

– Ergocalciferol 10,000 IU weekly-50,000 IU monthly

• PTH goal unclear

• PTH—goal unclear

– Treat with calcitriol or vitamin D analogue if progressively increasing despite correction of abnormal calcium, phosphorous, vitamin D levels – In stage 5, maintain iPTH 2-9 times upper reference

level

– Calcimimetics not recommended in stage 3-5 CKD

Uhlig K et al. Am J Kidney Dis. 2010;55(5):773-799.

Phosphorus in Stage 3-5 CKD

Dietary restriction to < 600-1000 mg/d – Dietary protein intake ~ 1.2 g/kg/d – Maintain caloric intake of 30-35 kcal/kg/d – Review diet:Review diet:

• Food additives/preservatives

• Meat phosphorus absorption > seeds, nuts, legumes

• Highest P/protein ratio in many cheeses, milk, nondairy creamer

• Many soda, iced-tea have high phosphorus content

Phosphorus Management in Stage 3-5 CKD

• Phosphate binders – Aluminum hydroxide – Calcium carbonate

Least expensive

– Calcium acetate – Sevelamer carbonate

– Lanthanum Most expensive

Tolerability, interactions, and patient adherence also key considerations in binder selection

Calcium and Vitamin D in Stage 3-4 CKD

• More opinion than evidence

• Maintain corrected total calcium within the normal range for the laboratory used, preferably toward the lower end (8.4 to 9.5 mg/dL; 2.1-2.37 mmol/L)

• Supplement vitamin D2 if serum 25-(OH) vitamin D level

<30 ng/mL (75 nmol/L)

– Ergocalciferol 50,000 U weekly-monthly depending on severity

• Treat with active oral vitamin D if serum 25(OH) vitamin D >30 ng/mL (75 nmol/L) and iPTH is above target range

– Calcitriol: 0.25 mcg 3x/wk-daily

Anemia Occurs Early in CKD and Worsens as Kidney Function Declines

ts (%) Hgb ≤12 g/dL

Adapted from: McClellan et al. Curr Med Res Opin. 2004;20:1501-1510.

Patient

GFR (mL/min/1.73 m²)

Pathophysiology of Anemia in CKD

• Erythropoietin deficiency

• Iron deficiency

• “Anemia of chronic investigation”

• Vitamin deficiency (folate, B12)

• Renal osteodystrophy

• Infection/inflammation

• Other illness: malignancy, multiple myeloma, HIV, etc

Impact of Anemia in CKD

• Decreased quality of life

• Increased:

– Morbidity and mortality risk

– Cardiovascular disorders—LVH, angina, CHF,Cardiovascular disorders LVH, angina, CHF, MI, stroke

– Physical and psychosocial impairments—

depression, cognitive impairment – Hospitalization and length of hospital stay – Rate of progression of CKD

McClellan W et al. Curr Med Res Opin. 2004;20:1501-1510.

Morreale A et al. Curr Med Res Opin. 2004;20(3):381-395.

Kinchen KS et al. Ann Intern Med. 2002;137:479-486.

Anemia is Associated with Higher Mortality Rate at each CKD Stage

ate n years)

Anemia Status

Adapted from: Culleton, B. F. et al. Blood 2006; 107(10):3841-3846.

GFR mL/min/1.73m2 Mortality Ra (per 100 person

Anemia and Quality of Life

Lefebvre et al. Curr Med Res Opinion. 2006; 22(10):1929-1937.

ESA Options

• Epoetin alfa

– Typically every 1-2 weeks, sometimes every 3-4 weeks

• Darbepoetin alfap – Typically every 2-4 weeks

• Both given subcutaneously in CKD

CHOIR

Epoetin alfa in CKD Open label, RCT, N= 1432;

mean study duration 16 months

• eGFR 15-50 mL/min/1.73m²

• Hgb < 11.0 g/dL

• High Hgb target: 13.0-13.5 initially;

changed13.5 g/dL

• Low Hgb target: 10.5-11.0 initially;

changed11.3 g/dL

Singh AK et al. N Engl J Med. 2006;355(20):2085-2098.

CHOIR

• 34% increased risk of composite outcome of death, MI, hospitalization for CHF, stroke (p = 0.03)

• No significant difference in % of patientsNo significant difference in % of patients requiring RRT

• Similar QOL measures

Singh AZ et al. N Engl J Med. 2006;355(20):2085-2098.

TREAT

Darbepoetin Alfa in CKD and Diabetes

• Double-blind placebo-controlled trial, N=4038

eGFR 20-60 mL/min/1.73m²

Hgb < 11.0 g/dL

• Darbepoetin: adjusted to maintain Hgb ~13.0 g/dL

• Placebo: Darbepoetin only if/when Hgb < 9.0 g/dL

• Primary end points: time to composite of death or a CV event and time to composite of death or ESRD

Pfeffer MA et al. N Engl J Med. 2009 ;361(21):2019-2032.

TREAT

• No significant difference in cardiovascular composite endpoint

– Greater risk of stroke (~ 2X) in darbepoetin group

• No significant difference ESRD composite endpoint

• Similar QOL measures; some measures slightly better in darbepoetin group

• More hypertension and deaths due to cancer in patients with history of cancer in darbepoetin group

FDA ALERT 2009

• The dosing recommendations for anemic patients with chronic renal failure have been revised to recommend maintaining hemoglobin levels within 10-12 g/dL. Quality of life claims in the previous labeling were removed with the exception of labeling were removed, with the exception of improved exercise tolerance and functional ability for chronic renal failure patients

• The revised product labeling includes a strengthened Boxed Warning

Cochrane Review 2010

“Targeting higher hemoglobin levels in CKD increases risks for stroke, hypertension, and vascular access thrombosis and probably increases risks for death serious increases risks for death, serious

cardiovascular events, and end stage renal disease.”

Palmer SC et al. Ann Intern Med. 2010;153(1):23-33.

Prepare For Renal Replacement Therapy

• Modality

• Access

When to Refer for Transplant

• Pre-emptive transplant is best for many patients—avoids dialysis altogether

• Living donor kidney outcomes are superior to deceased donor kidney outcomes

deceased donor kidney outcomes

– Among living donors—except identical twin not much difference among related and nonrelated donors

• Refer for transplant evaluation as eGFR approaches ~ 20 mL/min

Mange KC et al. Am J Transplant. 2003;3:1336-1340.

Rao S et al. CJASN 2009;4:1827-1823.

Dialysis Options

• Home – HD

• Short daily

• Nocturnal – PD

• Center – HD

• Three times per week

• Nocturnal

• Self care

Dialysis: Early vs. Late Start

• RCT of > 800 patients with eGFR 10-15 mL/min – Start HD (early start) or wait until eGFR 5-7

mL/min (late start)

– 76% of late start group started with higher eGFR due to symptoms or other indication

– Mean age 60 yrs

• No difference in survival, other outcomes, QOL

• Conclusion: OK to delay dialysis until GFR < 7.0 mL/min or other specific clinical indicators for the initiation of dialysis are present

Cooper BA, et al. NEJM. 2010; Published Online June 27.

Managing the Patient with CKD

1. Assess GFR

2. Determine etiology; consider renal biopsy, etc.

3. Identify reversible factors Workup: complete H&P; cbc, electrolytes, bicarbonate, calcium, phosphate, albumin, urinalysis, SPEP/UPEP,

Approaching ESRD 1. Patient/family education 2. Chose RRT modality 3. Referral for transplant

evaluation 4. Dialysis access

y , ,

assess proteinuria, renal ultrasound

Progressive CKD 1. Reduce progression 2. Manage comorbid conditions 3. Manage complications:

BP - use ACEI/ARB, screen and treat hyperlipidemia, CA/phos/PTH, anemia; smoking cessation; preserve vessels;

patient education

Questions?