Lecture 19-22 CKD-MBD Lau

BACKGROUND:

Systemic disorder manifested by either one or combination of: o Abnormalities of Ca, PO4, PTH or vit D metabolism o Abnormalities in bone turnover, mineralization, volume, linear growth or strength o Vascular or soft tissue calcification

These are all surrogate markers for fractures or mortality

Lab abnormalities begin at eGFR < 40 (kidneys no longer compensate)

PATHOPHYSIOLOGY:

PHOSPHATE:

Mineral essential for cell structure & metabolism

Primarily in bone & teeth (coupled w/ calcium) o Circulating in serum: < 1% o Intracellular: 70% o Skeletal: 29%

Absorbed in GI from foods (70-80%)

Excreted through renal system o Filtered with active tubular reabsorption

Normal range 0.8 – 1.6 mmol/L

AS RENAL FXN DECLINES hyperphosphatemia: Related to:

Secondary hyperparathyroidism (SHPT)

Reduced serum calcitriol levels

Abnormal bone modeling

Soft tissue calcification

Symptoms of pruritus

Poor outcomes & mortality in CKD5D

CALCIUM:

Mineral essential for: o Bone and teeth mineralization o Role in cell signaling (incl. brain nerves) o Contraction of muscle heart (incl. heart) o Blood clotting

Primarily in bone & teeth (coupled w/ PO4) o Circulating serum (bound/unbound) < 1% o 99% stored

Absorbed in GI and excreted from renal o Almost all physiologic and pathologic

changes are due to changes in equilibrium b/w bone & ECF

Normal range: 2.1 – 2.6 mmol/L

AS RENAL FXN DECLINES hypocalcemia

Results from ↓ absorption 2o to ↓ calcitriol

Related to: o Paresthesias o Muscle cramping & spasms o Seizures o iPTH increase & eventual proliferation of

parathyroid cells o Osteocytic bone resorption (osteolysis)

VITAMIN D:

Fat soluble steroid hormone o Major role in maintaining blood

levels of Ca and PO4 o May also protect against

osteoporosis, high BP, cancer & other diseases

Nutritional vit D obtained through exposure to sunlight, food, or dietary supplements

Primarily stored in adipose tissue or stored in liver

“Normal” or ideal vitamin D level unknown o Vit D deficiency < 30 nmol/L

25(OH)VitD in Canada

PARATHYROID HORMONE:

Single chain 84 aminoacid polypeptide, t1/2 is 2-4 mins once secreted o In labs, measure “intact” PTH which is calculated from broken PTH

Actions in serum: o Promote movement of Ca into extracellular fluid by:

Inducing osteocytic (osteolysis) & osteoclastic bone resorption Enhancing renal tubular reabsorption of Ca at distal parts of nephron

↑ production of 1-α hydroxylase to produce calcitriol Augmenting intestinal transport Stimulates FGF23 secretion by osteocytes

Inhibit renal PO4 reabsorption & ↓ renal production of 1-αhydroxylase o Stimulate urinary PO4 excretion via tubular reabsorption

AS RENAL FUNCTION DECLINES:

PTH levels increase progressively with renal failure

Increased bone turnover activity & defective mineralization o Renal osteodystrophy

Results in bone pain

Increased risk of fractures

FIBROBLAST GROWTH FACTOR 23:

Protein secreted by bone osteocytes and osteoblasts

Primary fxn is to maintain normal serum PO4 by: o Decreasing renal PO4 reabsorption at

renal tubular cells o Decreasing calcitriol production to reduce

intestinal PO4 absorption o Decrease PTH secretion

by inhibiting tubular reabsorption

negative feedback loop

Lecture 19-22 CKD-MBD Lau

HYPERPARATHYROIDISM:

Primary Secondary Tertiary

Mechanism Unregulated overproduction of PTH

Overproduction of PTH from chronic abnormal stimulus for production

State of excessive PTH secretion

Cause secondary to

Adenomas Phosphate retention

Decreased free ionized Ca concentration

Decreased calcitriol concentraiton

Chronic renal failure

Parathyroid hyperplasia no longer responsive to negative

Labs ↑ Ca ↓ PO4 ↑ PTH

↑ Calcitriol

↓ or Ca ↑ PO4 ↑ PTH

↓ Calcitriol

↑ Ca ↑ PO4 ↑ PTH

↓ Calcitriol

Explanation of labs

Kidney is still functioning so excess PO4 is excreted

Hypercalcemia occurs

Kidney is unable to excrete PO4

Ca binds to excess PO4 and forms deposits, so it becomes low or remains normal

Vit D is low because kidney is unable to activate calcidiol

FEEDBACK LOOPS are still working – normalized calcium will prevent increasing PTH levels (but remains high)

Parathyroid hyperplasia no longer responsive to negative feedback loop from plasma Ca decreased expression of Ca sensing receptors and vit D receptor

Results in: o Muscle weakness, bone and joint pain o Severe hypercalcemia o Proliferation & increase in parathyroid gland mass o Progressive extraskeletal calcification

Management Parathyroidectomy Manage PO4 = phosphate binders

Manage calcitriol = vitamin D3

Manage PTH = calcimemtic

Maximize vit D3 analogues

Phosphate binders

Consider calcimemetics

Parathyroidectomy

Parathyroid-ectomy

Involves removal of one or more of the parathyroid glands may sometimes autotransplant part of tissue to forearm

Postoperative “hungry bone syndrome” o Hypocalcemia, hypophosphatemia, hypomagnesemia may occur due to marked increase in bone production o Prevent with Ca and Vit D supplementation prior to and after surgery

Vit D supplementation preferred as calcitriol is often low, because it is fat-soluble any excess will be stored in fat tissue until it is needed to absorb calcium from diet

Calcium not recommended if they already have hypercalcemia o Monitor Ca and PO4 daily for first 3 days post surgery then subsequent labs as needed

HYPERPHOSPHATEMIA:

PREVIOUS guidelines: limit dietary PO4 to 800-1000 mg/d o Study showed possible increased mortality with dietary restrictions

NEW GUIDELINE: reasonable to consider PO4 in making dietary recommendations o Limit high PO4 foods (additives or preservatives, dairy, nuts, etc)

PO4 binder approach: treat when 2 consecutive levels > 1.45 mmol/L for CKD3/4

When starting meds, consider PO4 & Ca levels o If Ca normal, consider starting Ca carbonate with largest meals o If Ca elevated, evaluate exogenous vit D & Ca sources, consider Ca acetate or non-Ca binder

Although high PO4 linked with mortality, no data to show lowering will impact outcomes

HYPERCALCEMIA:

In CKD3-5D avoid hypercalcemia (linked to increased mortality and non-fatal CVE) o May be ok with hypocalcemia

If need to use phosphate binders, switch to non-calcium based binders o When choosing which agent, think

about pt preferences and co-morbidities o Sevelamer may decrease LDL,

cholesterol, A1C

VITAMIN D DEFICIENCY:

Affects 80 – 100% of dialysis patients (although is present in 20-50% of overall population)

Cause of low serum calcitriol multifactorial o Poor nutrition, reduced UV exposure

causing lack of adequate vitamin D intake, uremic toxins affecting liver hydroxylation step

Vitamin D deficiency associated with insulin resistance, HTN, CVD, auto-immune disease and various types of cancer

1-α hydroxylase function decreases as functional renal mass decreases o Decrease in biologically active vit D

leads to low Ca

CKD MBD:

DIAGNOSIS/MONITORING:

Biochemical – Ca, PO4, PTH and Alk Phos monitoring beginning at CKD 3; frequency dependent on presence and magnitude of abnormalities o Bone disease in CKD different from post-menopausal osteoporosis (which is related to

increased bone turnover but mineralization is normal)

Bone – bone biopsy reasonable if type of renal osteodystrophy impacts treatment options o Bone mineral density (BMD) testing can assess fracture risk to impact treatment decisions

(mortality 50%)

Vascular calcification – lateral abdominal radiograph and echocardiogram to detect presence/absence of vascular or valvular calcification

RENAL OSTEODYSTROPHY:

Defined as abnormal bone histology in CKD pt

Quantifiable by TMV classification o Turnover: skeletal remodeling (bone resorption and formation)

Affected by hormones, cytokines, mechanical stimuli and growth factors o Mineralization: how well collagen becomes calcified (measured by volume and thickness)

Affected by vit D, mineral deficiency, acidosis or Al toxicity o Volume: amount of bone per unit tissue

Affected by age, gender, race, genetics, nutrition

TMV system 4 differential diagnoses o OF – osteitis fibrosa (high turnover, high volume) = high PTH = softening of bone o OM – osteomalacia (low turnover, abnormal mineralization = Al toxicity o MUO – mixed uremic osteodystrophy (high turnover, abnormal mineralization) o AD – adynamic bone disease (low turnover, low mineralization) = low PTH (suppressed via meds)

CKD-MBD CALCIFICATION:

Soft tissue o Eye, skin, joints, visceral organs

Vascular: o Medial / intimal calcification of arteries o Valvular calcification o Coronary artery calcification

Presence of calcification increases with decling kidney function

Lecture 19-22 CKD-MBD Lau

TREATMENTS:

HYPERPARATHYROIDISM:

Ca based binders Sevelamer Lanthanum

Ca carbonate Ca acetate

MOA: Reduces bioavailability of dietary PO4 in GI tract

PO4 is anionic and will be attracted to Ca to bind together and precipitate PO4 out of solution to an insoluble compound excreted in feces

Insoluble cationic hydrogel which becomes protonated in GIT to bind anionic phosphate

Because it’s non-selective, it can bind bile acids and medications

May lower LDL, serum cholesterol, A1C, FGF23 in CKD pts

Dissociates in acidic GIT to a trivalent cation that binds to dietary PO4 in stomach & upper small intestine

Binds 97% of available PO4 at pH 3-5 (in vitro)

At dose of 1g TID shown to reduce 1/3 daily PO4 absorption

Absorption 40% elemental Ca

Most readily available

25% elemental Ca

Less palatable

Less Ca absorbed in GI

More potent PO4 binder

Not absorbed systemically Naturally occurring element not absorbed systemically

Excreted as insoluble lanthanum phosphate in faeces

Starting doses 1250 mg TID with meals (500 mg elemental Ca TID)

667 mg tablets (1-2 tabs TID with meals = 169-338 mg elemental Ca)

800 mg tablet TID with meals (max 4 g TID cc)

500 mg po TID with meals (max 1 g TID cc)

Admin Taken before or with meal to ensure binding of PO from foods

May take extra with snack or largest meal if necessary

Cannot be crushed or chewed

Drug Interactions Abx (FQs, tetracyclines)

Iron

Levothyroxine

Ciprofloxacin ↓

Calcitriol ↓

Ciprofloxacin ↓

Contraindications Hypercalcemia

Renal calculi

Bowel obstruction None

Warnings/ precautions

Mild to severe ↑ Ca (esp. if also on vit D)

Limit use in pt with arterial calcification and/or adynamic bone disease

Caution in pt with GI disorders (dysphagia, constipation, GI surgery, swallowing or GI motility disorders)

May decrease absorption of ADEK vitamins or folic acid

Caution with Ulcerative colitis, Crohn’s Disease or bowel obstruction

Adverse events Nausea +

Abdominal pain +

Constipation (carbonate): ++

Diarrhea (acetate): +++

Flatulence: +

Nausea ++

Abdominal pain ++

Constipation: +++

Diarrhea: ++

Flatulence: ++

Nausea +++

Abdominal pain ++

Constipation: +

Diarrhea: +

Flatulence: +

Annual cost $ 116.30 $408.20 $5767.28 $3817.04

OTHER PHOSPHATE BINDERS (not really used in BC)

MAGNESIUM BASED BINDERS:

MOA: Mg carbonate is soluble & minimally absorbed, it chelates anionic PO4 in GIT

Drugs used: o MgOH2 (magnesium hydroxide): complicated by diarrhea or mild hyperK o Mg/Ca acetate/carbonate combo:

Mg dose 86 to 214 mg/d elemental used Equivalent PO4 control to Ca acetate with less Ca ingestion

SEs: diarrhea, constipation, upset stomach o Hypomagnesemia: reason it’s not used in BC

> 1.5 mmol/L: NV, skin flushing, weakness, lightheadedness > 2.5 mmol/L: ↓ LOC, respiratory depression, cardiac arrest

ALUMINUM BASED BINDERS:

MOA: bind with PO4 in bowel to form insoluble compound (trivalent cation)

In 1972, reports of neurological toxicity thought to be due to Al binders, but later found likely to be due to dialysis fluid o However, since other binders are available N.

America doesn’t use this o IF USED, ensure plasma level < 1.5 umol/L

Starting dose: Al hydroxide 600 mg tablet po BID

SEs: anorexia, weakness, osteomalacia (deposits into bone), accumulation can cause encephalopathy

Drug interactions: iron and tetracyclines

GOALS OF THERAPY:

Prevent complications o Renal osteodystrophy o Extraskeletal calcifications

Prevent need for surgery (parathyroidectomy)

Normalize biochemical markers to targets

CKD stage Calcium PO4 iPTH

3 Normal range (2.1 – 2.6)

Normal range (0.87 – 1.5)

Optimal unknown

4

5 Towards normal (1.13 – 1.8)

2-9 x upper limit of assay

Lecture 19-22 CKD-MBD Lau

TREATMENTS (CONTINUED)…

VITAMIN D DEFICIENCY:

Sterol Comment MOA Starting dose Side effects Drug interactions

Vitamin D Cholecalciferol D3 (more potent) Requires hydroxylation through LIVER and KIDNEYs before become active vit D

2-3 x the RDA

600 IU/d Common vit D3: 10,000 IU 1x/wk

↑ Ca & PO4

Kidney stones, soft tissue calcification

Bone pain (excessive PTH suppression = adynamic bone)

Ergocalciferol D2

25 Vit D Calcidiol (25(OH)D3)

Prehormone after activation by liver

VDRa (vitamin D receptor agonist)

Calcitriol (1,25(OH)2D3)

ACTIVE VIT D 0.25 mcg po od 0.5 mcg IV 3x/wk

Cholestyramine (decreases vit D)

Thiazides (increase risk of hyperCa)

Digoxin (increase Ca = increase risk of arrhtyhmias)

Alfacalcidiol (1(OH)D3)

Synthetic prohormone

Pre-hydroxylated requiring hydroxylation through LIVER to become active vit D

0.25 mcg po 3/wk

CALCIMETICS:

MOA: organic molecule that allosterically increases the sensitivity of the Ca sensing receptor o Shifts the set point of Ca to the left to inhibit release of PTH o ↓ PTH release across wide range of serum Ca concentrations

Starting dose: Cinacalcet 30 mg po daily (max 180 mg po daily) o Reaches steady state in 7 days

SEs: GI (NVD, constipation); hypocalcemia and hypophosphatemia

After approval by adjustication group ($15,662 annual cost)

CKD-MBD:

Treatment goals should be individualized and based on co-morbidities, long-term benefits expected and QoL o Evaluate goals of therapy when initiating treatment

CKD-MBD is a systemic disorder where treatment focuses on correcting biochemical markers which can be poor surrogates for hard endpoints

Treatment algorithms available from BCPRA website

TREATMENTS SUMMARIZED: