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Special Thanks to …. For sponsorship of LMEF programs. This activity supported in part by an educational grant from Genzyme. Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org.

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special thanks to
Special Thanks to…

For sponsorship of LMEF programs

This activity supported in part by an educational grant from Genzyme

Did you know that you could be receiving credit for attending today? For membership information, please visit our website: www.Lafmeded.org

chronic kidney disease and ckd mbd
Chronic Kidney Disease and CKD-MBD

Akram Al-Makki, MD, FACP, FASNNephrology Department

chronic kidney disease ckd
Chronic Kidney Disease (CKD)
  • A CKD diagnosis is made when
    • Kidney damage is present for ≥3 months, with or without decreased glomerular filtration rate (GFR), manifested by either
      • Pathologic abnormalities, or
      • Markers of kidney damage, including abnormalities in blood, urine, or imaging tests
    • A GFR level <60 mL/min/1.73m2 persists for ≥3 months, with or without kidney damage

National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and diseasein chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

staging of ckd
Staging of CKD

National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and diseasein chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.

prevalence of ckd
Prevalence of CKD
  • In 2000, approximately 26 million adults in the US had chronic kidney disease and most were unaware of their condition1
  • Contributors to the growing prevalence2,3:
    • Aging population
    • Increasing prevalence of diabetes mellitus
    • Increasing prevalence of hypertension
  • Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States. JAMA. Nov. 7, 2007;298:17.
  • U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Diseasein the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007.
  • National Kidney Foundation. Part 4. Definition and classification of stages of chronic kidney disease.American Journal of Kidney Diseases. 2002;39(Suppl 1):S46-S75.
us prevalence breakdown based on ckd stage
US Prevalence:Breakdown Based on CKD Stage

1

1

*

1

1

2

1995-1999 estimates

Year 2000 estimates

* >20 years old

  • Coresh J, Selvin E, Stevens LA, et al. JAMA. 2007;298:2038-2047.
  • Coresh J, et al. Am J Kidney Dis. 2003 Jan;41(1):1-12.
risk factors for ckd
Risk Factors for CKD
  • Diabetes (type 1 and type 2)
  • Hypertension
  • Advancing age
  • Proteinuria
  • Family history of kidney disease
  • Environmental nephrotoxins
  • Race

Healthy People 2010; Nelson NA et al, Am J Nephrol, 1999; US Renal Data System. 2001 Atlas of ESRD in the United States.

prevalence of ckd contributors
Prevalence of CKD Contributors*

Urologic disease2.8%

Other known cause10.2%

Unknown cause3.9%

Cystic kidney disease4.6%

Missing cause1.2%

Glomerulonephritis16.2%

Diabetes36.9%

Hypertension24.2%

*Based on 2005 data

United States Renal Data System 2007 Atlas. Bethesda, MD: National Institutes of Health National, National Institute of Diabetes & Digestive & Kidney Diseases, 2007.

consequences of ckd
Consequences of CKD

DeathFrom Any Cause

Hospitalization

CV Events

eGFR (mL/min/1.73 m2)

eGFR (mL/min/1.73 m2)

eGFR (mL/min/1.73 m2)

eGFR = estimated glomerular filtration rate

*Age-standardized rates per 100 person-years

N=1,120,295 ambulatory adults

Adapted from Go AS et al. N Engl J Med. 2004;351:1296-1305.

abc of ckd management
ABC of CKD management
  • Appropriate screen and diagnose early CKD.
  • Be aware of complications and comorbidities:
  • Anemia
  • Bone and mineral abnormalities
  • Cardiovascular and renal.
  • Consult nephrologist in a timely manner
definition of ckd mbd and renal osteodystrophy
Definition of CKD-MBD And Renal Osteodystrophy
  • Definition of CKD-MBD
    • A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or the combination of the following:
      • Abnormalities of calcium, Phosphorus, PTH, or Vitamin D metabolism
      • Abnormalities in bone turnover, mineralization, volume, linear growth, or strength.
      • Vascular or other soft-tissue calcification
  • Definition of Renal Osteodystrophy
    • Renal osteodystrophy is an alteration of bone morphology in patiens with CKD.
    • It is one measure of the skeletal Component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy.
    • Uhlig et al, AJKD Vol 55, No 5, May 2010.
alterations in mineral metabolism occur in early stages of ckd

Steady decline in urine phosphate excretion1

Progressive depletion of 1,25(OH)2D31

Decline in urine calcium excretion1

1400

50

250

1200

40

200

*

1000

*

*

30

150

Urine calcium (mg/24 hours)

1,25-dihydroxyvitamin D(pg/mL)

800

Urine phosphate (mg/24 hours)

20

100

600

10

50

400

200

0

0

n=

CKD114

CKD275

CKD3180

CKD443

CKD57

n=

CKD115

CKD287

CKD3221

CKD4156

CKD543

n=

CKD114

CKD274

CKD3179

CKD443

CKD57

CKD Stage

CKD Stage

CKD Stage

(n=319)

(n=522)

(n=317)

*P<0.05 CKD2 vs CKD3†P<0.05 CKD3 vs CKD4

*P<0.05 CKD2 vs CKD3†P<0.05 CKD3 vs CKD4

‡P<0.05 CKD4 vs CKD5

*P<0.05 CKD2 vs CKD3†P<0.05 CKD3 vs CKD4

Alterations in Mineral Metabolism Occur in Early Stages of CKD

An increasingly compromised system leads to disturbances in mineral metabolism

Shading=statistical significance between levels.

  • Urine phosphate excretion decreases and leads to phosphate retention
  • 1,25D production decreases, leading to 1,25D depletion and contributing to elevated PTH
  • Urine calcium excretion decreases, impacting calcium balance

Adapted from Craver L, et al. Nephrol Dial Transplantation. 2007;22:1171-1176.

serum phosphorus levels and mortality in ckd non dialysis patients
Serum Phosphorus Levels and Mortality in CKD Non-Dialysis Patients

Mortality rates by phosphate category

72% of patients

(n=3,289)

  • Mortality risk increases as phosphorus levels rise, even within normal range
  • Each 0.5 mg/dL increase in serum phosphorus was associated with increased mortality
  • Statistically significant increases in mortality were noted when phosphorus levels reached 3.5 mg/dL or above

Adapted from Kestenbaum B, Sampson JN, Rudser KD, et al. J Am Soc Nephrol. 2005;16:520-528.

elevated serum phosphorus and mortality risk in dialysis patients

<3

3-4

4-5

5-6

8-9

>9

6-7

7-8

Elevated Serum Phosphorus and Mortality Risk in Dialysis Patients

2.2

N = 40,538

2.0

1.8

Relative risk of death*

1.6

Referent Range

1.4

1.2

1.0

0.08

0.00

Serum phosphorous concentration (mg/dL)

*Multivariable adjusted

With permission from Block GA, Klassen PS, Lazarus JM, et al. J Am Soc Nephrol. 2004;15:2208-2218.

kdigo focus normal treatment target ranges for phosphorous and calcium
KDIGO Focus: Normal Treatment Target Ranges for Phosphorous and Calcium

Emphasis on individual levels of serum calcium and phosphorus

rather than Ca x P product

  • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):S1-S130.
  • National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
slide18

Survival according to phosphate levels relative to KDOQI guidelines.

Eddington H et al. CJASN 2010;5:2251-2257

©2010 by American Society of Nephrology

common phosphate binders
Common phosphate binders
  • Aluminum hydroxide
  • Calcium carbonate
  • Calcium acetate
  • Lanthanum carbonate
  • Sevelamer
summary slide
Summary Slide
  • Despite early phosphate retention, many patients have serum phosphorus levels within normal range
  • Mortality risk increases as phosphorus levels rise, even when levels remain within normal range
  • Increased serum phosphorus levels are associated with CV events and mortality
hepatic and renal metabolism of vitamin d 2 and d 3

Normal metabolism of vitamin D: production of active hormone1,2

Dietary sources

Sunlight

Vitamin D(parent compound)

Liver

Hydroxylation of the 25 carbon

25(OH)D or 25D–Inactive metabolite–

In a CKD patient, the ability to convert 25D to 1,25D is lost as kidney function declines. This would require treatment with vitamin D hormone (1,25D).

Kidney

1 α hydroxylation

1,25(OH)2D or 1,25D–Active hormone–

Released into plasma and carried to target organs where it binds to vitamin D receptors

Hepatic and Renal Metabolism of Vitamin D2 and D3
  • Drueke TB, Moe SM, Langman CB. Treatment approaches in CKD. In: Olgaard K, ed. Clinical guide to bone and mineral metabolism in CKD. New York, NY: National Kidney Foundation;2006:119-127.
  • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guidelines for the diagnose, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MED). Kidney Int. 2009; 76(suppl 113):S1-S130.
impact of ckd on vitamin d
Impact of CKD on Vitamin D

Normal

1,25(OH)2D

25(OH)D

1-hydroxylase

Decreasing Renal Mass

CKD

25(OH)D

1,25(OH)2D

1-hydroxylase

In a CKD patient, the ability to convert 25D to 1,25D is lost as kidney function declines.

  • Levin A, et al. Kidney Int. 2007;71:31-38.
  • Holick MF. N Engl J Med. 2007;357:266-281.
physiologic effects of vitamin d throughout the body

25(OH)D

Major Circulating Metabolite

1,25(OH)2D

Biologically Active

Kidney

Calcium and

Phosphorus Homeostasis

Bone Health

Physiologic Effects of Vitamin D Throughout the Body

Colon

Prostate

Macrophages

Keratinocytes

Breast, etc.

Immunomodulatory

Effects

Multiple Sclerosis

Type 1 Diabetes(via ß-islet cell destruction)

Psoriasis

Rheumatoid Arthritis

Inflammatory Bowel Disease

Periodontal Disease

Cardiovascular

Effects

Renin-Angiotensin

Regulation

Decreased Risk for:

Hypertension

Type II Diabetes(via stimulation of pancreatic insulin production)

Heart Failure

Growth & Regulation

Antiproliferation

Prodifferentiation

Apoptotic

Anti-angiogenic

Prostate,

Colon,

Breast Cancers etc.

Neuromuscular

Effects

Muscle Mass

Muscle Strength

Better Balance

Adapted from: Holick MF. Mayo ClinProc. 2006;81:353-373.

25 oh d vs 1 25 oh 2 d deficiency
25(OH)D vs 1,25(OH)2D Deficiency

Patients with CKD have a high prevalence of both 25(OH)D and 1,25(OH)2D deficiency1

Nutritional vitamin D supplements can replete diminished 25(OH)D substrate in stages 1-5 CKD2

A single monthly 50,000 IU ergocalciferol capsule safely repletes almost all vitamin D-deficient dialysis patients within 6 months3

The ability to convert 25(OH)D to its active form (1,25(OH)2D) in the kidney is lost as renal function declines4

Active vitamin D therapy is given to correct 1,25(OH)2D deficiency in stages 3 to 5 CKD2

  • Wolf M, et al. Kidney Int. 2007;72:1004-1013.
  • Jones G. Semin Dial. 2007;20:316-324.
  • Saab G, et al. Nephron Clin Pract. 2007;105:c132-138.
  • Levin A, et al. Kidney Int. 2007;71:31-38.
progressive vitamin d deficiency in ckd
Progressive Vitamin D Deficiency in CKD

Prevalence of 1,25(OH)2D3 and 25(OH)D3 deficiency by GFR

100

25 (OH)D3 <15 ng/mL

1,25 (OH)2D3 <22 pg/mL

80

60

Patients (%)

40

20

0

≥80

(n=61)

79-70

(n=117)

69-60

(n=230)

59-50

(n=396)

49-40

(n=355)

39-30

(n=358)

29-20

(n=204)

<20

(n=93)

GFR level (mL/min)

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

1 25 oh 2 d 3 levels and mortality in dialysis patients
1,25(OH)2D3 Levels and Mortality in Dialysis Patients

A

B

10

8

6

4

2

0

10

8

6

4

2

0

Active vitamin D therapy

Active vitamin D therapy

No active vitamin D therapy

No active vitamin D therapy

*

*

*

Odds ratio of CV mortality

Odds ratio of all-cause mortality

R

R

<5 6–13 >13

<5 6–13 >13

1,25-dihydroxyvitamin D (pg/mL)

1,25-dihydroxyvitamin D (pg/mL)

1,25-dihydroxyvitamin D levels and 90-day all-cause (A) and CV mortality (B) in hemodialysis patients according to whether patients received active vitamin D therapy

*P<0.05 for the comparison of the individual vitamin D level―vitamin D treatment groups with the corresponding referent groups.

R=subjects treated with active vitamin D and 1,25-dihydroxyvitamin D levels ≥13 pg/mL.

With permission from Wolf M, et al. Kidney Int. 2007;72:1004-1013.

summary
Summary
  • Patients with CKD have a high prevalence of both 25(OH)D and 1,25(OH)2D deficiency
  • As kidney function declines, patients lose the ability to convert 25(OH)D to 1,25(OH)D
  • Patients with lower levels of 1,25(OH)2D had a higher risk of mortality
compensatory mechanism of pth during disturbances in mineral metabolism
Compensatory Mechanism of PTH During Disturbances in Mineral Metabolism

Median values of 1,25-dihydroxyvitamin D, 25 Hydroxyvitamin D, and intact PTH by GFR levels

50

150

1,25-dihydroxyvitamin D (pg/mL)

45

25 Hydroxyvitamin D (ng/mL)

40

Intact PTH (pg/mL)

35

100

30

1.25-dihydroxyvitamin D (pg/mL)

25 Hydroxyvitamin D (ng/mL)

25

Intact PTH (pg/mL)

20

50

15

10

5

0

0

>80

79-70

69-60

59-50

49-40

39-30

29-20

<20

GFR level (mL/min)

With permission from Levin A, et al. Kidney Int. 2007;71:31-38.

elevated pth levels and cardiovascular disease in patients with ckd stages 3 and 4
Elevated PTH Levels and Cardiovascular Disease in Patients with CKD Stages 3 and 4

P<0.001

Rate of cardiovascular disease, %

Parathyroid hormone level, pg/mL

With permission from Bhuriya R, et al. Am J Kidney Dis. 2009;53 (4 suppl 4):S3-S10.

elevated pth and all cause mortality
Elevated PTH and All-Cause Mortality

CKD Stages 3 to 5 (non-dialysis patients)

N = 515

2

1

0

-1

2

1

0

-1

CKD STAGE 3

CKD STAGE 4–5

Log relative hazard

Log relative hazard

30 55 80 105 130 155 180

50 100 150 200 250 380

PTH (pg/mL-1)

PTH (pg/mL-1)

Estimated log relative hazard

Estimated log relative hazard

95% pointwise CI

95% pointwise CI

With permission from Kovesdy CP, et al. Kidney Int. 2008;73:1296-1302.

kdigo focus consider normal limit for pth
KDIGO Focus: Consider Normal Limit for PTH

*In patients with CKD stages 3-5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, treatment with calcitriol or vitamin D analogs is suggested. (2C)

  • Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD) Kidney Int. 2009;76(suppl 113):S1-S130.
  • Adapted from National Kidney Foundation (NKF). KDOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42(4 suppl 3):S1-S201.
treatment of secondary hyperparathyroidism
Treatment of Secondary Hyperparathyroidism
  • Intact PTH most the earliest and most sensitive marker for abnormal bone metabolism
    • If PTH above recommended range, initiate replacement therapy with active 1,25-OH vitamin D substitute or CaR agonist
      • Calcitriol (Rocaltrol)
      • Doxercalciferol (Hectorol)
      • Paricalcitol (Zemplar)
      • Cinacalcet (Sensipar) Is not a vitamin D but CaR agonist
    • Monitor PTH, Calcium, and Phosphorous monthly while adjusting therapy
summary37
Summary
  • Elevated PTH levels are a compensatory mechanism for 1,25D depletion — both are prominent and progressive across the CKD continuum
  • Elevated PTH levels and 1,25D depletion have each been independently associated with higher mortality
future research the bone kidney endocrine axis
Future Research:the bone-kidney endocrine axis
  • FGF 23 (Fibroblast Growth Factor 23)
  • Klotho

Hu MC, et al. J Am Soc Nephrol. 2011 Jan;22(1):124-36.

thank you questions
Thank YouQuestions?

Akram Al-Makki, MD, FACP, FASN IU HealthNephrology Department Lafayette, Indiana, USA

(765)838-6365