Stage 3 CKD Co‐morbidities: How to Evaluate & Treat Secondary Hyperparathyroidism & 

Anemia

Andrea Easom MA, MNSc, APN, FNP‐BC, CNN‐NP

Instructor, COM, Nephrology Division

University of Arkansas for Medical Sciences

Objectives

• Discuss the relationship between CKD, CV disease and vitamin D deficiency and treatment options to manage Vitamin D deficiency and secondary hyperparathyroidism

• Discuss diagnosis and treatment of CKD related anemia.

• Evaluate treatment goals for CKD anemia in light of black box warnings

CVD Mortality Markedly Increased in ESRD

Foley RN et al. Am J Kidney Dis. 1998;32(suppl 3):S112–S119.

• CVD mortality 10–20 times higher in ESRD than the general population• 120 times higher for ESRD patients aged 25 to 34

Dialysis maleDialysis femaleDialysis blackDialysis white

GP maleGP femaleGP blackGP white

Ann

ual M

orta

lity,

%

Age, years25–34 35–44 45–54 55–64 65–74 75–84 >85

100

10

1

0.1

0.01

GP = General population.

Metabolic and PathologicComorbidities as They Begin to Appear in 

CKD Stage 3

Andress DL. Semin Dial. 2005;18:315-321.Becker B, et al. J Am Soc Nephrol. 2005;16:1091-1098.Elder G. J Bone Miner Res. 2002;17:2094-2105.Kramer H, et al. J Am Soc Nephrol. 2005;16:507-513.

Num

ber o

f Pat

ient

s (m

illio

ns)

≥90 89-60 59-30 29-15 <15

eGFR (mL/min/1.73 m2)

Stage 3

Stage 1Stage 2

Stage 4 Stage 5

0

1

2

3

4

5

6

7

8↓ 1,25 D3

↑ PTH (SHPT)

↑ Insulin resistance

Dyslipidemia

Hypertension

Vascular Calcification

Osteodystrophy

Anemia

CKD &Secondary Hyperprathyroidism

Relative Prevalence of Calcitriol Deficiency and Anemia in Patients With CKD by eGFR

Design• N = 80 patients with CKD• Anemia defined as Hgb <11 g/dL or treatment with erythropoietin replacement therapy

• Calcitriol deficiency defined as serum calcitriol <30 pg/mL

Results• Prevalence of calcitriol deficiency was greater than prevalence of anemia at all stages of CKD

Gutierrez et al. J Am Soc Nephrol. 2005;16. Published online ahead of print. Available at www.jasn.org. Accessed June 8, 2005.

>60 45-60 30-45 <30

eGFR (mL/min/1.73 m2)

100

80

60

40

20

0

Calcitriol Deficiency

Anemia

Subj

ects

(%)

Vitamin D Receptor Is Ubiquitous

System Tissue and CellGastrointestinal Esophagus, stomach, small intestine, large intestine, colon

Arterial vessels Vascular smooth muscle cellsHepatic Liver parenchymal cellsRenal Proximal and distal tubules, collecting duct Endocrine Parathyroid, pancreatic β-cells, thyroid C cellsExocrine Parotid gland, sebaceous glandReproductive Testis, ovary, placenta, uterus, endometrium, yolk sac Immune Thymus, bone marrow, B cells, T cellsCardiovascular Cardiac myocytesRespiratory Lung alveolar cellsMusculoskeletal Osteoblasts, osteocytes, chondrocytes, striated

muscleEpidermis/appendage Skin, breast, hair folliclesCentral nervous Brain neuronsConnective tissue Fibroblasts, stroma

Intimal and Medial Calcification in Patients With CKD

Patient in the general population

Medial CalcificationIntimal Calcification

Patient with CKD

0

50

100

150

200

250

300

>80 79-70 69-60 59-50 49-40 39-30 29-20 <20

eGFR Interval (mL/min/1.73 m2)

iPTH

Lev

el (p

g/m

L)

05101520253035404550

iPTH 1,25 Vitamin D 25(OH) Vitamin D

1,25

Vita

min

D (p

g/m

L)25

(OH

) Vita

min

D (n

g/m

L)

Mean Values of iPTH, 1,25(OH)2D3, and 25(OH)D3 by eGFR

N = 1814

*P<0.001.Bakris et al. Poster presented at: American Society of Nephrology Renal Week 2005; November 8-13, 2005; Philadelphia, PA. Abstract F-PO732.

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

*

*

Stage 2 Stage 4Stage 3

Prevalence of Elevated iPTH by eGFR Intervals

0102030405060708090

100

>80 79-70 69-60 59-50 49-40 39-30 29-20 <20(n = 61)

Patie

nts

With

iPTH

>65

pg/

mL

(%)

iPTH = intact parathyroid hormone.Bakris et al. Poster presented at: American Society of Nephrology Renal Week 2005; November 8-13, 2005; Philadelphia, PA. Abstract F-PO732.

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

N = 1814

eGFR Interval (mL/min/1.73 m2)

Evidence of Renal Osteodystrophy: Bone Loss in CKD Stages 2‐4

-2.25

-2.00

-1.75

-1.50

-1.25

-1.00

-0.75

-0.50

-0.25

0.00Spine Hip Arm

Bon

e M

iner

al D

ensi

ty (Z

-Sco

re)

PTH <60 pg/mL PTH 60-120 pg/mL PTH >120 pg/mL

*P<0.05 compared with patients with PTH in the normal range.Rix et al. Kidney Int. 1999;56:1084-1093.

*

**

Schulz et al. J Clin Endocrinol Metab. 2004;89:4246-4253.

Aortic Calcification in Postmenopausal Osteoporosis

1st

N = 392nd

N = 394th Quartiles

N = 403rd

N = 39

Aor

tic C

alci

ficat

ion

(%/y

)B

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nge

(%/y

)

P<0.03

-6.0

-4.5

-3.0

-1.5

0

15

30

45

60

P<0.002

P<0.001© 2006 The Johns Hopkins University School of Medicine.

.

Kestenbaum B et al. JASN 2005

Serum PO4 and Mortality in CKD

• Increase in mortality risk was noted with phosphate levels >3.5 mg/dl

• After all adjustments; – Each 1‐mg/dl increase was associated with an 23% increased risk for death 

• Linear relationship between serum phosphate and mortality for each 0.5‐mg/dl (0.16 mmol/L) increments. 

Slide courtesy of Dr. Shukla

Serum PO4 and CV events

StudyPhosphorus (mg/dl)

Higher Serum Phosphorus Is Associated With:

The Atherosclerosis Risk in Communities (ARIC) Study 

3.5 CVD events and mortality

Multi‐Ethnic Study of Atherosclerosis (MESA) 

>4.0High ankle brachial index among individuals without CVD

Framingham Offspring Study(FOS) 

 3.5 to 6.2

Increased CVD risk in individuals free of CKD and CVD in the community

Third National Health and Nutrition Examination Survey (NHANES III) 

>4.0Each 1 mg/dl higher phosphorus associated with 31% increase of a first major CV event

Cholesterol and Recurrent Events (CARE) study 

≥3.5Each 1 mg/dl higher phosphorus associated with a 27% increase in all‐cause mortality

(general population)Martin and Gonzalez, CJASN  February 2011

Slide courtesy of Dr. Shukla

Binders and Mortality: calcium role125 dialysis patients

44 months follow up

Absolute deaths 22 vs 11 in calcium vs. sevelamer group

N 2047

Prevalent ESRD population (HD)

Block et al, KI 2007 Suki et al, KI 2007

Total Hip Bone Mass Predicts Survival in CKD Dialysis Patients

Survival (d)1400120010008006004002000

Cum

ulat

ive

Surv

ival

1.0

0.8

0.6

0.4

0.2

Normal

Osteopenia (T-score -1.0 – 2.5 SD)

Osteoporosis(T-score >-2.5 SD)

N = 88P = 0.03

SD = standard deviation.Taal et al. Kidney Int. 2003;63:1116-1120. © 2006 The Johns Hopkins University School of Medicine.

Early Assessment for Treatable Consequences of Altered Mineral Metabolism in CKD

Assessment2

Stage 3: Ca, P, PTH every 12 moStage 4: Ca, P, PTH every 3 moMonitor 25(OH)D levels every 6 mo

Consequences in CKD1

eGFR (mL/min/1.73 m2)

CKD Stage

Vitamin D Deficiency <65 2-3

Hyperparathyroidism <65 2-3

Hyperphosphatemia <40 3-4

Hypocalcemia <30 4-5

1. Courtesy of Dennis L. Andress MD; 2. NKF. Am J Kidney Dis. 2003;42(4 suppl 3):1-201.

Recommended Goals for Hormone and Mineral Metabolism in CKD Stages 3 and 4

Parameter RecommendationiPTH (pg/mL) Stage 3: 35-70; stage 4: 70-110

Serum 25(OH) vitamin D (ng/mL) >30

P (mg/dL) 2.7-4.6

Ca (mg/dL) 8.5-10.2

Ca × P product (mg2/dL2) <55

Ca intake (mg/d)<1500 elemental from Ca-based P-binders<2000 from diet and P-binders

iPTH = intact PTH.NKF. Am J Kidney Dis. 2003;42(4 suppl 3):1-201.

Martin K J , González E A CJASN 2011

Pathways involved in evolution of disordered mineral metabolism in an early course of CKD (dashed lines

indicate counter-regulatory pathways).

Nutritional vitamin D: therapy?Author/Year Subjects efficacy Change in Other Relevant Biomarkers

Shah et al., 2005 29 PD <7  to 30  No change in PTH or 1,25(OH)2D. 

DeVille et al., 2006  85 CKD 3 to 5 17.4 to 42.1 PTH decreased by 2.8 pmol/L

Al‐Aly et al., 2007 66 CKD 3 and 4 17 to 27 PTH levels decreased from 231 to 192pg/ml.

Zisman et al., 2007 52 CKD 20 to 31 in CKD 3 18

to 35 in CKD 4 PTH decrease by 13% in CKD 3,  2% in CKD  4.

Saab et al., 2007  119 HD  17 to 53 No change in PTH

Jean et al., 2008 149 HD 30 to 126 nmol/ L Lowered PTH and AP  only in responders

Jean et al., 2008 43 HD  28 to 118 nmol/l1,25(OH)2 D increased from 7 to 30 pmol/l. PTH decreased ,144  to 108, AP unchanged. 

Chandra et al 2008 20 CKD 3 and 4 17 to 49 ng/ml No change in PTH or 1,25(OH)2D 

Blair et al., 2008 344 HD  18 to 42 HbA1c levels fell 6.9 to 6.4 no change in PTH.

Kalantar‐Zadeh et al, CJASN 2009Slide courtesy of Dr. Shukla

Active vitamin D and outcomes?Author/Year No Examined Therapy Main Results

Shoji et al., 04  242 alfacalcidol / placebo  Lower CV mortality 

Teng et al., 03  67,399 Paricalcitol/ calcitriol  16% lower ACM 

Teng et al., 05  51,037 Any VDRA/ placebo  20% lower ACM

Melamed etal. 06  1007 IV calcitriol / placebo Lower ACM

Tentori et al.06 7731Any VDRA / placebo & calcitriol / paricalcitol / doxercalciferol 

Lower mortality with any VDRA. No difference between the types of 

VDRA 

KZadeh et al.06  Lee et al., 07 

58,058 Paricalcitol / placebo  Lower ACM

Kovesdy et al 08  520 Calcitriol / placebo  Lower ACM

Shoben et al.08   1418 Calcitriol / placeboLower ACM and combined 

mortality or ESRD

N‐Diaz et al.08  16,004 Calcitriol / placebo  Lower mortality

Wolf et al.08  9303 VDRA / placebo Lower Mortality 

Tentori et al.09 38,066  Inactive / active vitamin D 7% to 22% lower mortality 

Kalantar‐Zadeh et al, CJASN 2009Slide courtesy of Dr. Shukla

Evaluations of Oral Vitamin D Compounds in CKD Stages 3 and 4

Patients (%)

Vitamin D Compound N

Ca >10.5 mg/dL

P >5.5 mg/dL

Ca × P >55

mg2/dL2

Urinary Ca

% change

Calcitriol 511 64 56 33 100

Alfacalcidol* 1762 11 56 NA 58

Doxercalciferol 553 4 (NS) 9 (NS) NS 42

Paricalcitol 2204 2† (NS) 10† (NS) NS 6 (NS)NA = not assessed.*Alfacalcidol is not available in the US; †Percent of patients with elevation for 2 consecutive lab evaluations.1. Calcitriol NDA, 18-044, 1977. FDA publication; 2. Hamdy et al. BMJ. 1995;310:358-363; 3. Coburn et al. Am J Kidney Dis. 2004;43:877-890; 4. Coyne et al. Am J Kidney Dis. 2006;47:263-276.

© 2006 The Johns Hopkins University School of Medicine.

Develop A Clinical Action Plan

• Check 25(0H) Vitamin D and iPTH levels when eGFR falls below 60 

• Start treatment when indicated by labs• Restrict phosphorus intake when eGFR <40• Start PO4 binders when eGFR is low and PO4 is trending up, even w/n normal range

• Monitor labs, as indicated by therapy

CKD & Anemia

Anemia is a Mortality Multiplier

DM / CHF/ CKD

 / Ane

mia

DM / CKD

 / Ane

mia only

DM / CHF / CK

D only

CKD / Ane

mia only

DM / CHF on

ly

CHF on

ly

DM / Ane

mia only

DM / CKD

 only

CKD only

Ane

mia only

DM only

Non

e

3.6 3.7 3.7

7.3

1.52.0 2.0

2.4 2.42.9

1.0

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

6.3

Adapted from Collins AJ. Adv Stud in Med. 2003;3(3C):S194‐S197.

A reduction in kidney mass and decreased production of erythropoietin, results in decreased RBC mass and anemia

More reticulocytes enter circulating blood

Proerythroblasts in bone marrow mature into reticulocytes

Low delivery of oxygen in the blood stimulates erythropoietin secretion

Larger number of RBCs in circulation

The Role of the Erythropoietinin RBC Production

RBCs = red blood cells; EPO = erythropoietinModified from: Hillman. In: Harrison’s Principles of Internal Medicine. 14th ed. 1998:334‐339.

CHOIR study

• 1432 patients with CKD• 222 primary composite 

end points– 125 in high Hb group

• The use of a target hemoglobin level of 13.5 g as compared with 11.3 g was associated with increased risk and no improvement in the quality of life.

Singh et al, NEJM 2006Slide courtesy of Dr. Shukla

The TREAT study• 4038 diabetic CKD patients• 13 vs 9 Hb• 1234 end points• 632 vs 602 in high vs rescue control 

group• The use of darbepoetin alfa in 

patients with Diabetes, CKD and moderate anemia did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. 

• For many persons involved in clinical decision making, this risk will outweigh the potential benefits

Pfeffer et al, NEJM 2009Courtesy of Dr. Shukla

Please see Important Safety Information including Boxed 

WARNINGS WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLICEVENTS, and TUMOR PROGRESSIONRenal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.Cancer:

ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with advanced breast, head and neck, lymphoid, and non-small cell lung malignancies when dosed to target a hemoglobin of ≥ 12 g/dL.

The risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of < 12 g/dL.

To minimize these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions.Use only for treatment of anemia due to concomitant myelosuppressive chemotherapy.Discontinue following the completion of a chemotherapy course.

Perisurgery: EPOGEN® increased the rate of deep venous thromboses in patients not receiving prophylactic anticoagulation. Consider antithrombotic prophylaxis.

CKD Warning• In controlled trials, patients experienced greater risks of death, serious adverse CV reactions and stroke when administered ESAs to target hemoglobin level greater than 11 g/dL.

• No trial has identified a hemoglobin  target level, ESA dose or dosing strategy that does not increase these risks.

• Use the lowest ESA dose sufficient to reduce the need for RBC transfusions.

Amgen Highlights of Prescribing Information 6/2011

Initial Work Up and Treatment of Anemia Associated With CRF

Treat with ESAif indicated? 

No

Further workup and other necessary labs required

Yes

Treat with irona

CRF patients identifiedwith anemiaWorkup: CBC, indices, retics; iron studies1

Iron deficiency?

CRF Anemia?

aEven with iron therapy, ESAs may still be required.CBC = complete blood count. 1. Modified from: National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1‐S146.2. Aranesp® (darbepoetin alfa) prescribing information, Amgen.

Target hemoglobin : classically recommended 10‐12gm/dl but now ? 9 the lower limit or even lower?

Patients With CHF and Anemia (n = 126, 91% CKD)

NYHA class = New York Heart Association classification; SOB = shortness of breath.Silverberg et al. Perit Dial Int. 2001;21(suppl 3):S236‐S240.

Clinical Benefit of Anemia Correction: CHF and CKD

Parameter Before AfterHgb (g/dL) 10.3 13.1Serum creatinine (g/dL) 2.4 2.3∆GFR (mL/min/mo) -0.95 0.27NYHA class (0-4) 3.8 2.7Fatigue/SOB index (0-10) 8.9 2.7Hospitalizations 3.7 0.2Systolic BP (mm Hg) 132 131Diastolic BP (mm Hg) 75 76

Anemia Treatment Eligibility

• Serum Creatinine (2.0 mg/dl or above) or 

• Creatinine Clearance (45 ml/min or below) and 

• Hemoglobin (10g/dl or below) or

• Hematocrit (30 % or below) or

and

• Symptoms of anemia

CKD Anemia: A Funded Modifiable Risk Factor

Anemia Management Targets

• Hemoglobin : None• If Hg approaches or exceeds 11g/dL, Reduce or stop dose

• Transferrin Saturation: 20‐50 %*

• Ferritin: >100 ng/mL*– Use clinical judgementto continue when ferrtinis >500 ng/ml

Treatment options

• ESAs– Epoetin alpha

– Darbepoetin alpha

• Iron Therapies– Oral irons

– Injectables• Iron dextran

• Iron sucrose

• Sodium ferric gluconate

• Ferumoxytol injection

CKD Anemia Treatment Plan• Successful treatment of anemia involves

– Analyzing current patient data trends

– Evaluating the whole patient to make ESA and IV iron treatment decisions

• Assess inflammation and malnutrition

• Do not rely solely on the serum ferritin marker

– Protocol that balances ESA and IV iron therapy

– System to monitor  response to therapy

• Trending laboratory results

• Adjusting medication doses

Summary

• There are multiple benefits to correcting anemia in CKD patients

• Treatment of anemia is principally aimed at correcting the morbidity and not mortality and the goal is to prevent complications. 

• Use the lowest ESA dose to reduce the need for RBC transfusion

• Monthly labs and titration of doses are needed• Weigh the risk benefit ratio before starting