2

Course Outline

Chapter 1 Kidney and Hormone Function

Chapter 2 SHPT and Chronic Kidney Failure

Chapter 3 Bone Basics

Chapter 4 Vitamin D Treatment for SHPT

Appendix

3

Chapter 1 Outline: Kidney and Hormone Function

Kidney function and hormone production

Vitamin D hormone: receptors and function

Parathyroid feedback mechanism

Vitamin D hormone, PTH and kidney failure

PTH, SHPT and mortality

4

Kidney Function

Excretion Excess fluid

Mineral balance

• Calcium, phosphorus, potassium, sodium, chloride

Metabolic toxins

• BUN, creatinine

5

Kidney Function

Endocrine Erythropoeitin - stimulates

blood cell production

Renin-angiotension - blood pressure control

D hormone - • Calcium/phosphorus balance and bone

metabolism

• Effect on various other organs with vitamin D hormone receptors (VDR)

6

Vitamin D Hormone Receptors (VDR)

A protein located in the nucleus of the cell

Active D hormone must bind to the VDR, stimulate the VDR, so an action can take place on the target tissue

Active D hormone stimulates the VDR on the parathyroid gland to cease production of PTH

7

Ca2+

PO4

Intestine

PO4

Ca2+

Kidney

D hormone

Blood Ca2+

(& PO4)

Bone

Osteoclast

XParathyroid Gland

8

Reproductive Organs

Kidneys

Intestines

Bones

Immune System

Skin

Bone Marrow

Pancreas

Parathyroid Glands

Vitamin D Receptors (VDR) are Spread Throughout the Body

9

Kidney Failure Mortality Rates

2001 USRDS Annual Report

10

Kidney Failure Mortality Rates

2001 USRDS Annual Report

11

PTH is Directly Related to Mortality

Relative Risk of Death vs. PTH levels(Analysis of 40,000 patients)

0.60

0.70

0.80

0.90

1.00

1.10

1.20

1.30

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

PTH levels (pg/mL)

RR

RR

Chertow et al, ASN Renal Week Abstracts

12

Chapter 1 Review Questions

1. What are some of the actions D hormone is responsible for?

a. PTH suppression and bone mineralization

b. Adequate hemoglobin production

c. Good potassium and phosphorus balance

d. Adequate hydration

2. D hormone deficiency contributes to what?

a. Anemia of chronic disease

b. Autoimmune disorders and hepatitis

c. Secondary hyperparathyroidism

d. Lymphogenesis

13

Chapter 1 Review Answers

1. What are some of the actions D hormone is responsible for?

a. PTH suppression and bone mineralization

2. D hormone deficiency contributes to what?

c. Secondary hyperparathyroidism

14

Chapter 2 Outline: SHPT and Chronic Kidney Failure

Causes of SHPT

Progression of SHPT

Effects of SHPT

15

Causes of SHPT in Chronic Kidney Failure

D hormone deficiency

Hypocalcemia

Phosphorus retention

Acid-Base balance

Diminished degradation of PTH by kidney

Autonomous parathyroid nodules

16

When SHPT Begins

Martinez I, Saracho R, Montenegro J, Llach F: A deficit of calcitriol synthesis may not be the initial factor in the pathogenesis of secondary hyperparathyroidism. Nephrol Dial Transplant 11 Suppl 3:22-28, 1996.

17

Normal Parathyroid Gland Physiology

Make, store and release parathyroid hormone

Regulate serum calcium, D hormone and phosphorus levels

Vitamin D receptors (VDR) and calcium receptors are present on the parathyroid gland and help regulate parathyroid hormone production

18

Progression of Parathyroid Gland Pathology with CKD

Hypertrophy Hyperplasia

Diffuse Nodular

Down-regulation of vitamin D receptors (VDR) Decreased D hormone levels Low dietary calcium Hypocalcemia Increasingly non-responsive to calcium and D

hormone levels

19

Bro S, Olgaard K. Effects of Excess PTH on Nonclassical Target Organs. AJKD 1997.

Side Effects of Elevated PTH

Cardiovascular Left ventricular hypertrophy

Myocardial fibrosis

Hypertension

Calcification in the cardiac and peripheral vascular systems

Immune dysfunction

20

Side Effects of Elevated PTH

Extraosseous calcifications “calciphylaxis”

Pruritis

Bone pain and fractures/altered bone metabolism

Pain and swelling in and around joints

Muscle weakness

Spontaneous tendon rupture

Bro S, Olgaard K. Effects of Excess PTH on Nonclassical Target Organs. AJKD 1997.

21

Side Effects of Elevated PTH

Corneal-conjunctival calcification

Skeletal deformities, retardation of growth

Anemia

Impotence

Altered platelet function

Insulin resistanceBro S, Olgaard K. Effects of Excess PTH on Nonclassical Target Organs. AJKD 1997.

22

Electron Beam Computed Tomography (EBCT) Scan

New noninvasive tool

Allows highly sensitive quantification of calcium deposits in living patients

Allows earlier diagnosis of calcification

Can be used for whole body scanning

23

Yellow indicates calcium deposition

Slide courtesy of P. Raggi.

EBCT Scans Reveal Coronary Artery Calcification in a Dialysis Patient

Bone

24

Mitral Valve Calcification in a Dialysis Patient

Scan courtesy of P. Raggi.

25

Sanders C, et al. Am J Roentgenol. 1987;149:881-887.Kuzela DC, et al. Am J Pathol. 1977;86:403-424.

Slide courtesy of E. Slatopolsky.

CalcifiedNoncalcified

Calcification of the Lung

26Slide courtesy of H. Malluche.

Cutaneous/Subcutaneous Calcification

27

Chapter 2 Review Question

1. Why is an elevated PTH a concern?

a. It leads to bone disease.

b. It leads to cardiac disease.

c. It causes immunosuppression.

d. All of the above

28

Chapter 2 Review Answer

1. Why is an elevated PTH a concern?

d. All of the above

29

Chapter 3 Outline: Bone Basics

Bone function

Bone cell types

D hormone and bone remodeling

Bone turnover and renal bone disease

30

Bone Function

Support and movement of the body

Protection of internal organs

Mineral storage

Production of blood cells

31

Bone

Bone-lining cells Osteoblasts

Osteoclasts Osteocytes

32

Bone

33

Osteoblasts

Small, bone-builder cells that secrete collagen fibers

Precipitate calcium and phosphorus from the blood to mineralize the bones, the creation of the osteocyte

Located at sites where bone remodeling needs to occur

34

Osteoblasts

Affected by elevated PTH levels and D hormone deficiency

Osteoblast activity can be indirectly measured by alkaline phosphatase

35

Osteocytes

Mature bone cells - mature osteoblasts that are embedded in the bone matrix

No longer able to form bone actively

Maintain bone matrix

Play an active role in releasing calcium into the blood

36

Osteoclasts

Large, irregularly shaped, multinuclear cells that consume bone with enzymes

By digesting collagen and releasing bone minerals into the bloodstream, osteoclasts erode the bone surface causing small shallow pits or cavities, which are named Howship’s lacunae

37

Osteoclasts

Activity is increased by PTH, D hormone, and thyroid hormone

Many other local growth factors play an important role in bone remodeling Calcitonin inhibits the release of calcium from

bone D hormone increases intestinal absorption of

calcium PTH and prolactin stimulte D hormone production Interleukin-6 stimulates osteoclast development Estrogen inhibits bone resorption

38

Bone Turnover

A term used to describe the interaction between various hormones and bone formation and resorption

“High Bone Turnover” vs “Low Bone Turnover” disease High Bone Turnover results in a decrease in bone

density with porous and coarse-fibered bone

Low Bone Turnover results in non-uniform bone remodeling

39

Role of D Hormone in Bone Remodeling

D hormone stimulates formation of osteoblasts from osteoprogenitor cells

Activation of D hormone receptor on osteoblast enhances synthesis of osteocalcin, a requirement for new bone formation

D hormone may also indirectly stimulate osteoclast activity

40

Development of Renal Bone Disease

GFR

D hormone metabolism

Plasma HPO4

Ca++ absorption from GI tract

Plasma Ca++

PTH

osteoclasts

Ca++ & HPO4– resorbed from bones

OSTEODYSTROPHIES CaHPO4 product

METASTATIC CALCIFICATIONS Core Curriculum for Nephrology Nurses, 1998

41

Renal Osteodystrophy

42

Effects of SHPT on Bone

Increases osteoclast activity increasing bone resorption

Increase bone weakness and pain

Increase fracture rate

43

Chapter 3 Review Question

1. What are the two categories of bone disease we see in renal patients and what typically is the PTH level?

a. High turnover bone disease with a low PTH and Low turnover bone disease with a low PTH

b. Low turnover bone disease with a low PTH and renal osteodystrophy with an elevated PTH

c. Osteitis fibrosa with a low PTH and adynamic bone disease with an elevated PTH

d. High turnover bone disease with an elevated PTH and low turnover bone disease with a low PTH

44

Chapter 3 Review Answer

1. What are the two categories of bone disease we see in renal patients and what typically is the PTH level?

d. High turnover bone disease with an elevated PTH and low turnover bone disease with a low PTH

45

Chapter 4 Outline: Vitamin D Hormone Treatment for SHPT

Treatment option for SHPT

Pharmacokinetic profiles

Effective treatment modalities

46

*2001 USRDS Annual Report

Percentage of New Chronic Dialysis Patients Treated with D Hormone Therapy*

-D (30)

+D (70)

Treated withD hormone

-D (32)

+D (68)

Hemodialysis Patients Peritoneal Dialysis Patients

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Treatment Option for SHPT – Vitamin D Hormone Therapy

Calcitriol Rocaltrol® - Oral

Calcijex® - Injectable

Calcitriol (generic) – Oral and Injectable

Doxercalciferol Hectorol® - Oral and Injectable

Paracalcitol Zemplar™ - Injectable

48

Treatment Option for SHPT IV Vitamin D Hormone Therapy*

Hectorol®

doxercalciferol

Zemplar®

paricalcitol

Calcijex®

calcitriol

Half-Life (hr) 32-37 16±9 19±3

Time to max conc.

8-9 hours 5 minutes 5 minutes

Elimination Hepatic Hepatic Hepatic

Protein Binding High High High

Removed by HD?

NO NO NO

*No Clinical Significance*No Clinical Significance

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Summary

The development of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease begins early in the disease process and has an impact on mortality and morbidity

Bone disease has a large impact on chronic kidney failure patients

Vitamin D hormone therapy is recommended for the treatment of SHPT in chronic renal failure patients on dialysis