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Chronic Kidney Disease:Chronic Kidney Disease:Collaborative Care Through The Stages.Collaborative Care Through The Stages.

Family Medicine Grand RoundsFamily Medicine Grand Rounds

University of VirginiaUniversity of VirginiaJanuary 23, 2009January 23, 2009

Rasheed A Balogun, MD FACP FASNDivision of Nephrology, University of Virginia

Charlottesville, VA

Chronic Kidney Disease:Chronic Kidney Disease:Collaborative Care Through The Stages.Collaborative Care Through The Stages.

(Part 2) (Part 2)Family Medicine Grand RoundsFamily Medicine Grand Rounds

University of VirginiaUniversity of VirginiaMarch 13, 2009March 13, 2009

Rasheed A Balogun, MD FACP FASNDivision of Nephrology, University of Virginia

Charlottesville, VA

Jan 23 2009 12:30 PM Collaborative Care of CKD 49

Disclosure Statements Current ACCME guidelines state that participants in CME activities

should be made aware of any affiliation or financial interest that may affect the faculty member’s contributions. Each faculty member has completed a statement of disclosure, which includes funding sources other than the honorarium received for this program. The faculty have provided the following information on sources of funding that may be perceived as a potential conflict of interest.

Rasheed Balogun: research funding from National Kidney Foundation-Vas: received honoraria from Abbott Laboratories and Genzyme Therapeutics: board member (chair MAB), NKF-Va: will not discuss any non-FDA approved products


Outline/Objectives Define CKD

Review national and local epidemiology + outcome data

Review CKD: Clinical Action Plan Detect CKD Prevent progression of CKD Diagnosis and treat CVD Treat co-morbid conditions and complications Refer to nephrology: Emphasize role of the non-

nephrologist MD in CKD care


Cardiologist

PCP

Dietician

NephrologistPatient

Nurses and other health care professionals

Teamwork in CKD Care

Jan 23 2009 12:30 PM Collaborative Care of CKD 52Chronic Kidney Disease in USA Zabetakis. Am J Kidney Dis. 2000;36(suppl 3):S31.

Associated Systemic Complications in Chronic Kidney Disease (CKD)

Anemia of CKD

Hypertension

Cardiovascular disease

Dyslipidemia

Osteodystrophy

Metabolic acidosis

Malnutrition

Diabetes mellitus


Work-up of Anemia of CKD: When?

Normal 12 – 14 Hb g/dL (Hct 36-42)

Anemia Men, Postmenopausal women

≤12 Hb g/dL (Hct < 36)

premenopausal women

≤11.0 Hb g/dL

NKF. Am J Kidney Dis. 2001;37:S182.

Guideline 1


Adapted from: Fauci.Harrison’s Principles of Internal Medicine. 1998:334.

Red blood cellsRed blood cells O2 deliveryO2 delivery

ErythropoietinErythropoietinErythroidmarrow

Erythroidmarrow

IronIron

REcellsRE

cells

RE=reticuloendothelial

X

Erythropoiesis in CKD


Anemia of CKD Primary cause: deficiency of erythropoietin

(absolute or relative)

Iron Deficiency (contributory)

Normocytic, normochromic anemia

usually starts when the GFR < 60 (Stage 3)


Assessment of Anemia In Renal Disease

If GFR < 60 ml/min/1.73m2 (Stage 3), consider anemia of renal origin

Folate B12 Iron, saturation, ferritin R/O blood loss Erythropoietin level (?) R/O other chronic disease/inflammatory

states

Jan 23 2009 12:30 PM Collaborative Care of CKD 58NKF. Am J Kidney Dis. 2001;37:S182.

Evaluation of anemia of CKD Hemoglobin and/or hematocrit Red blood cell indices Reticulocyte count Iron parameters

Serum iron Total iron-binding capacity (TIBC) Percent transferrin saturation (TSAT) Serum ferritin

Test for occult blood in stoolGuideline 2


Erslev. N Engl J Med. 1991;324:1339.

Clinical Consequences: untreated Anemia of CKD

Cardiovascular Left ventricular hypertrophy (LVH)

Precipitating factor for congestive heart failure (CHF)

Exacerbation of angina

Reduced Aerobic capacity

Overall well-being

Cognition


Pre

vale

nce

of

LV

H(%

Pat

ien

ts)

0

10

20

30

40

50

>50 35 – 49 25 – 34 <2514.1 13.2 12.5 11.4 †

*

Ccr (mL/min)

Mean Hb (g/dL)

* P<0.001 †P<0.0001

Levin. Nephrol Dial Transplant. 2001;16(suppl 2):7.

Anemia and LVH


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

LVH in CKD LVH is an independent predictor of cardiac

death. Hypertension, anemia, and diabetes are

modifiable predictors of LVH. Blood pressure increase of 5 mm Hg is

associated with 3% increase in LVH risk. Hb decrease of 1 g/dL is associated with 6%

increase in LVH risk.

Foley RN et al. Kidney International. 1995;47: 186-192.Levin A et al. Am J Kidney Dis. 1996;27:347-354.

Foley RN et al. Kidney International. 1995;47: 186-192.Levin A et al. Am J Kidney Dis. 1996;27:347-354.


Chronic Kidney Disease in USACPMPM= cost per member per month

Collins. Satellite Symposium.ASN, 2000.

J Am Soc Nephrol 12: 2465–2473, 2001

Clinical and Economic Outcomes by Hematocrit Level: Incident ESRD Patients 1996–1998

<30 30 to <33 33 to <36 36 to <39 390.0

0.5

1.0

1.5

2.0

Rel

ativ

e R

atio

8760 24,465 28,674 4307 555n

reference

MortalityHospitalCost PMPM

Hct

Impact: Anemia of CKD on Outcomes


Treatment: Anemia of CKD Recombinant erythropoietin

Epoetin alfa Darbepoetin

Iron therapy prn

Red-blood-cell transfusion severe anemia

acute anemia


Epoetin and Management of AnemiaEpoetin and Management of Anemia

NKF. Am J Kidney Dis. 2001;37(suppl 1):S182.

NKF-K/DOQI Guidelines Target Hct 33%–36% (Hb 11–12 g/dL)* Supplement with iron to maintain target

Hct/Hb Initiate epoetin alfa (or darbopoetin)


Erythropoietin Treatment Epoetin is administered weekly in an incremental

dose that commonly starts from 50-100units/kg SQ

Rate of rise of Hgb/Hct should be monitored weekly until the patient's condition is stable

hypertension, seizures, and venous thrombosis can occur when it rises too rapidly

Jan 23 2009 12:30 PM Collaborative Care of CKD 66Chronic Kidney Disease in USA

Epoetin Management: Monitoring

Starting dose 50–100 U/kg IV or SC qW (‘tiw’)Ensure good blood pressure controlAdjusting the dose

Reduce as Hct approaches 36% or increases by >4 points in 2 weeks

Increase incrementally if Hct does not increase by 5–6 points in 8 weeks (with adequate iron stores)

Following a dosage adjustment: Measure Hct twice weekly for at least 2–6 weeks until stable


Correction of anemia of CKD:many positive effects Improved/increased energy, physical strength,

appetite, and sleep improved sex life, home

life, and mood improvement in vascular

resistance better immune

responsiveness to antigenic stimuli

improved cognition

Decreased shortness of breath stabilization of left

ventricular hypertrophy and possibly regression

decreased development of left ventricular dilatation

a decrease in high cardiac output

hospitalization rate, length of stay, and cost.


Kausz. Am J Kidney Dis. 2000;36(suppl 3):S39.

St. Peter. American Society of Nephrology Meeting. 2000:A0889.

* Patients not treated with epoetin alfa.

Current Care of Anemia in Patients With CKD is Sub-optimal

Mean Hct at start of dialysis: 29%* Only 28% of patients with CKD

receive epoetin alfa before dialysis.

71

Data to Support Ideal Hemoglobin Target (1):

8 9 10 11 12 13 14 15 16

hemoglobin concentration (g/dL)

Normal Normal hematocrithematocrit

(hemodialysis)(hemodialysis)

CHOIRCHOIR

(pre-dialysis)(pre-dialysis)

1010

1414

11.311.3

13.513.5

↓ morbidity/mortality

↑ morbidity/mortality

?

Observational data, by association only

↓ morbidity/mortality

↑ morbidity/mortality


“Epo Resistance” Poor response to Epoetin Rx

Fe deficiency Fe deficiency Fe deficiency Chronic inflammatory states Severe hyperparathyroidism Poor (inadequate) dialysis Multisystem dysfunction (hematological,

neurological, cardiac, immunological etc) Iron deficiency


• Poor nutrition• Blood loss

Increased iron needs

NKF. Am J Kidney Dis. 2001;37(suppl 1):S182.

Iron Deficiency WithEpoetin alfa

Iron Deficiency in CKD

Preexisting Iron Deficiency


NKF. Am J Kidney Dis. 2001;37(suppl 1):S182.Macdougall. Curr Opin Hematol. 1999;6:121.

Goodnough. Blood. 2000;96:823.

Frequently used tests

• Serum ferritin >100 ng/mL

• Transferrin saturation >20%

• Additional measurements

• Reticulocyte Hb content

• % Hypochromic RBCs

• Erythrocyte ferritin

Frequently used tests

• Serum ferritin >100 ng/mL

• Transferrin saturation >20%

• Additional measurements

• Reticulocyte Hb content

• % Hypochromic RBCs

• Erythrocyte ferritin

Target

Assessment of Iron Status


100 mg

125 mg

1000 mg

Maximum Single Dose

100 mg x 10 doses

125 mg x 8 doses

100 mg x 10 doses

RecommendedDosage

Iron sucrose

Iron gluconate

Iron dextran

Iron Compound

NKF. Am J Kidney Dis. 2001;37(suppl 1):S182.Van Wyck. Am J Kidney Dis. 2000;36:88.

• 1 gram iron required to– Increase Hct from 25% to 35%– Maintain iron stores over 3-month period

• Recommended dose: 1 gram

Administration of IV Iron: Dosage


Bailie. Am J Kidney Dis. 2000;35:1.Collins. J Am Soc Nephrol. 1997;8:190A.

Administration of IV Iron: Safety

Adverse Events Reported Hypotension Nausea, diarrhea, vomiting, headache,

fever Hypersensitivity reactions (anaphylaxis) Increased infectious complications


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

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.


Iron Therapy: Summary Likely need for iron during Epoetin therapy Oral iron

Ease of administration Safe Possibly ineffective

IV iron Less convenient administration Safety concerns More costly than oral iron Effective



Anemia of CKD

Hypertension


Dyslipidemia

Osteodystrophy

Metabolic acidosis

Malnutrition

Diabetes mellitus


CKD Hypertension

Zabetakis. Am J Kidney Dis. 2000;36(suppl 3):S31.

Hypertension and CKD


Coresh. Arch Intern Med. 2001;161:1207.

130/85 mm Hg

11%

27%62%

140/90 mm Hg

140/90 mm Hg

Blood Pressure Is Poorly Controlled in CKD

Jan 23 2009 12:30 PM Collaborative Care of CKD 83Chronic Kidney Disease in USA

Zabetakis. Am J Kidney Dis. 2000;36(suppl 3):S31.

Benefits of BP Control in CKD

Rate of progression of kidney disease, especially in patients with diabetes

Cardiovascular complications


JNC VII. JAMA 2003;289:2560.

140/90 mm Hg130/80 mm Hg

Without CKDWith CKD

HTN: Goal Blood Pressure Control


JNC VI. Arch Intern Med. 1997;157:2413.

130/85 mm Hg125/75 mm Hg

Without ProteinuriaWith Proteinuria

Blood Pressure Control in CKD: Goals


Del Vecchio. J Nephrol. 2001;14:7.JNC VI. Arch Intern Med. 1997;157:2413.

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


ACE Inhibitors Recommended for Slowing the Progression of CKD

Unless contraindicated, patients with hypertension who have CKD should receive

an ACE inhibitor to control hypertension and to slow progressive renal failure

JNC VI. Arch Intern Med. 1997;157:2413.


2° Hyperparathyroidism: Natural History

Multisystemic Toxicity1. nervous system2. cardiac3. endocrine4. immunologic5. cutaneous

Bone Disease1. osteitis fibrosa2. demineralization3. fractures4. bone pain

Calcium

1,25 Vit D Phos

Chronic Kidney Disease

PTH PTH


Renal Osteodystrophy: Full Spectrum

Adynamic bone

Osteomalacia

Normal Mild Osteitis fibrosa

Mixed

Hyperparathyroidism

Calcium, calcitriol

Aluminium

Low boneturnover

High boneturnover

PTH ALP

PTHALPP


Elevated PTH: Multisystemic Toxicity Widespread

systemic effects

Insidious effects

Early Diagnosis & Rx needed

* Bro AJKD November, 1997

PTHPTH

Bone RemodelingBone Remodeling

Red Blood Cell Production

Red Blood Cell Production

Cardiac FunctionCardiac Function

Neurological Function

Neurological Function

Ca, PCa, P


Long-Term Consequences of Secondary Hyperparathyroidism

Osteitis fibrosa Vascular calcification Soft tissue calcification Calciphylaxis Resistance to vitamin D therapy Need for parathyroidectomy EPO resistance


0.92 0.95 0.98

1.08

1.181.24

1.00

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

<50 50-100 100-150 150-300 600-900 900-1200 >1200

PTH levels & Relative Risk of Death

pg/mL Chertow ASN 2000


Block GA, Am J Kidney Dis. 1998;31:607-617.

Higher Phosphorus: Higher Mortality Risk

1.00

1.25

1.50

1.1-4.5 4.6-5.5 5.6-6.5 6.6-7.8 7.9-16.9

Rel

ativ

e M

orta

lity

Ris

k (R

R)

Serum Phosphorus Quintile (mg/dL)

1.00 1.00 1.02

1.18*

1.39**

p=0.03

p=0.0001n = 6407


Higher Ca P Product: Higher Mortality Risk

Block GA, et al. Am J Kidney Dis. 1998;31:607-617.

1.00

1.25

1.50

14-42 43-52 53-60 61-72 73-132

Rel

ativ

e M

orta

lity

Ris

k (R

R)

Ca × P Product Quintile (mg2/dL2)

1.06 1.08

1.13

1.34*

1.00

p=0.01n = 2669

Jan 23 2009 12:30 PM Collaborative Care of CKD 99Llach, et al. AJKD, 32,4 Supp2, 1998:S3-12

GFR, ml/m

Calcitriol, pg/ml

152535455565758595105

Intact PTH, pg/ml

100

200

300

400

CALCITRIOL PTH

P <0.01

P <0.01

When does Renal Osteodystrophy start? Calcitriol & PTH at Various Stages of CKD

0

10

20

30

40

50

n = 150


Phosphateretention

Calcitriol Deficiency

Hypocalcemia

2º Hyperparathyroidism

Chronic Kidney Disease

Renal Osteodystrophy: CKD 3&4


Renal Osteodystrophy: Management

↓P diet (.8-1g/d)+Fix acidosis:HCO3>22 mmol/L

Binders: P>5mg/dl: (CaCO3, Ca Acetate, Sevelamer) taken with meals

1,25 Vitamin D for low Ca + nl P (when iPTH>250 pg/mL)

Rx: calcitriol 0.25 µg/d; doxercalciferol 2.5 µg/3-7d/wk. Target iPTH 80-300(10-65 pg/mL)


CKD stages 3&4: Acid-Base

Monitor serum bicarbonate acidosis:

HCO3>22 mmol/L

Dietary protein

Na Bicarbonate tablets or Na Acetate


Management: Renal Osteodystrophy

Control serum phosphorus (3.0-5.0 mg/dL) Prevent or reverse accumulation of trace

substances i.e., aluminum, calcium, etc. Maintain serum calcium within normal limits

(8.5-9.6 mg/dL) Suppress secondary hyperparathyroidism

using vit D or analogs Prevent the development of parathyroid

hyperplasia Avoid over suppression of PTH (adyn bone dx)


Target Values

Phosphorus: 3.0 - 5.0 mg/dL – ideal

Calcium: normal range ( 8.5-9.6 mg/dL)

Ca X P: < 55

PTH: 150 - 300 pg/ml



Anemia of CKD

Hypertension


Dyslipidemia

Osteodystrophy

Metabolic acidosis

Malnutrition

Diabetes mellitus


Questions?

NKF: www.kidney.orgNKF-Va: www.kidneyva.org NKDEP www.nkdep.nih.gov

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