HypoCalcemia --\> PTH release --\> CaSR receptors on PTGland Kidney: ↑ Renal Absorption of Ca ↑ Renal EXCRETION of Phos ↑Synthesis of Calcitriol

Which type of BONE DISEASE? _HIGH CALCIUM & low PTH levels (\<150) _ Occurs from the: Supression of PTH via Phos Binders / Vit D treatment / Calcimimetics low turnover bone state normal or reduced Osteoid thickness no mineralization defect low Osteoclasts & osteoblasts

_ADYNAMIC BONE DISEASE_ low everything , except for Calcium PTH / osteioid / osteoclasts+blasts Treatment: _ D/C or reduce dose of Vitamin D or Calcimimetic _ since it is caued by the supression of PTH by: phos binders / vit D / calcimemetics

24 - CKD 3 Bone Disease Flashcards by Karlo Sison

Pathophysiology

CKD - Mineral & Bone Disease

w/ progressive CKD, imbalance occurs with:
PHOS / Calcium / VIT D
VV
Secondary HypoThyroidism
&
↑FGF-23 / Bone Disease / Soft Tissue Calcification

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ParaThyroid Gland

CKD - Mineral & Bone Disease

3 Receptors;
Vitamin D + FGF-23
Ca-Sensing Receptor = CaSR
main regulator of PTH

PTH = Maintains Calcium Levels
Acts on:
Kidney / Intestine / Bone
Directly Stimulated by:
HypoCalcemia, PTH –> CaSR on PTGland

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PTH Action on
KIDNEY

HypoCalcemia –> PTH release –> CaSR receptors on PTGland

*Kidney:**
*↑ Renal Absorption of Ca**

↑Renal EXCRETION of Phos

↑Synthesis of Calcitriol

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PTH Action on
INTESTINE

HypoCalcemia –> PTH release –> CaSR receptors on PTGland

indirectly:
↑Absorption of BOTH
Ca & P
in small intestine

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PTH Action on
BONE

HypoCalcemia –> PTH release –> CaSR receptors on PTGland

↑OsteoClasts
breakdown bone –> MORE Calcium

_↓OsteoBlasts_
inhibit “building” = bone formation

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Secondary HyperParathyroidism

Causes an INCREASE in PTH due to WHAT?

↑PTH due to:
_↓serum Ca_ & ↓production of Calcitriol
indirectly ↑Phos

Progressive & starts @ GFR < 60 (CKD)
VVV
leads to HYPERplasia of Parathyroid Gland
lose sensitivity to:
CaSR & VDR
possible adenomatous transformation of the gland
–> HYPERcalcemia in some patients

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*Reduction in GFR**
Nephron LOSS*

has WHAT EFFECTS on

PTH

Phosphorus

Calcium

Calcitriol

↑PTH & ↑PHOS

↓CALCIUM*** & ↓***Calcitriol

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FGF-23

What Increases its production?

What is its function?

↑Phosphate & ↑Calcitriol [1,25(OH)2D]
leads to release of–> ↑FGF-23

FGF-23 –> feedback loop ↓Calcitriol
by supressing 1-a-hydroxylase @ proximal tubule

FGF-23 regulates:
Phosphate & Vitamin D homeostasis
&
INHIBITS PTH PRODUCTION

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Consequences of HYPERParaThyroidism

*#1 = CARDIOVASCULAR ISSUES**
Artery calcification –> ↑*Atherosclerotic load–> ↑MI risk

Vascular Calcification

Osteoporosis

Anemia / Itching

Parathyroidectomy
hungry bone syndrome / recurrence of HYPERparathyroidism

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Types of Bone Disease
&
How are they Classified?

Dependent on the :
Degree of Abnormal bone turnover & imparied mineralization of the extracellular matrix

Osteitis Fibrosa Cystica

Adynamic Bone Disease

MIXED Uremic Bone Disease

Osteomalacia

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Which type of BONE DISEASE?

Occurs when PTH is constantly ELEVATED

Woven Appearance
caused by increased # of osteoid

Accelerated formation & resorption of bone due to:
INCREASED # & activity of
OsteoClasts/Blasts+Marrow Fibrosis

*OSTEITIS FIBROSA CYSTICA**
*iPTH > 300**

WOVEN
Constant PTH elevation

INCREASED:
OsteoClasts + OsteoBlasts + OSTEOID + Marrow Fibrosis

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Which type of BONE DISEASE?

HIGH CALCIUM & *low PTH levels (<150)*

Occurs from the:

Supression of PTH* via
*Phos Binders / Vit D treatment / Calcimimetics**

low turnover bone state
normal or reduced Osteoid thickness
no mineralization defect
low Osteoclasts & osteoblasts

ADYNAMIC BONE DISEASE

low everything*, except for Calcium
PTH / osteioid / osteoclasts+blasts*

Treatment:
_D/C or *reduce* dose of
Vitamin D or Calcimimetic_

since it is caued by the supression of PTH by:
phos binders / vit D / calcimemetics

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EXTRAskeletal Presentation

of CKD - Bone Disease

occurs from
HIGH CA & PHOS

Medical OVERsupression of PTH by VIT D
inefficient incoportation of Ca -> bone
leading to vascular calcification

HEART
leads to widened pulse pressure / increased AFTERLOAD & LVH

SKIN –> CALCIPHYLAXIS

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MusculoSkeletal Presentation

of CKD - Bone Disease

FRACTURES
hip fracture, highest incidence in stage 5

Tendon Rupture** + **Bone Pain

Calcification of VESSELS
frequent in stage 5, only INCREASES the longer on dialysis
large effects on:
blood vessels / heart valves / SKIN

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Mineral & Bone Disease Goals

Stage 5
is where Phos + Calcium levels CHANGE

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HYPERPhosphatemia

CKD - Mineral & Bone Disease

↑Phos -> ↑PTH & ↓Calcitriol Synthesis

Most Phos comes from FOOD, dialysis is unable to remove it

Need:
*LOW phos Diet* + PHOS BINDER

Symptoms:
Pruritis, Rash / Bone+Joint Paint / Muscle Cramps + Tetany

HIGH Phosphorus leads to what?

indirectly-> ↑PTH Production

↓Inhibits CALCITRIOL synthesis

PHOSPHORUS BINDERS

Important Counseling Advice

dependent on DIETARY phos control:*
*800-1000 mg/day**

try and AVOID:
_Calcium Based products_
due to HYPERcalcemia

*TAKE WITH FOOD**
do NOT take if NOT eating*

Seperate from certain Meds
Antibiotics / LEVOthyroxine

Caution in patients with:
Bowel Obstruction / Ileus-Fecal Impaction / Hypomotility Disorders

Calcium Carbonate

OTC Phosphorus Binder

Try not to use CALCIUM BASED products, due to hypercalcemia, ExtraSkeletal Calcification

1-2 Tabs
WITH EACH MEAL

Max 7 Tabs of TUMS

Calcium Acetate

PRESCRIPTION Phosphorus Binder

Try not to use CALCIUM BASED products*, due to hypercalcemia
ExtraSkeletal Calcification*
*GREATER PHOS BINDING** > Ca Carbonate
but is RX only*

2 caps w/ each meal

Sevelamer Carbomate/HCL

RENVELA / RENAGEL

*Phosphorus Binder**
*PREFERRED -> does NOT induce ACIDOSIS**

Tabs or Packets
_SEPERATE FROM:
Mycopehnolate / Cyclosporine / Tacrolimus_

CONSTIPATION*
nausea / vomiting / diarrhea / dyspepsia*

Lanthanum Carbonate

Phos Binder

Chewable or Powder

Must be taken WITH or AFTER meals

ab pain / NV

Sucroferric Oxyhydroxide
Velphoro

Phos Binder

*Chewable Tabs**
minimal Fe absorption*
DARKENING OF STOOLS*
diarrhea / constipation / NV*

SEPERATE FROM VITAMIN D

Ferric Citrate
Auryxia

Phos Binder

INCREASES TSAT

do NOT use in IRON OVERLOAD

DARKENING OF STOOLS
diarrhea / constipation / NV

**What Drugs do we need to seperate from** **_Phos Binders?_**

* *_Antibiotics_** * *Tetracyclines + Fluoroquinolones** **_Levothyroxine_** For **Sevelamer: Mycophenolate / Cyclosporine / Tacrolimus** for **Sucroferric Oxyhydroxide:** **PO Vit D**

**Aluminum for Phos Binding**

*not used often:* **_Only in in EMERGENT situations_** or **_P \> 7mg/dL_** Al-OH or Al-Carbonate Use no longer than **\< 4 weeks**, due to toxicities: ***bone / bone marrow / CNS***

**iPTH**

* *Directly Measures Parathyroid Gland FXN** * **Indirectly Measures*** **Bone Remodeling** * _NOT ACCURATE ASSAY_* * *--\> better to _LOOK AT TRENDS_** rather than individual result **iPTH \> 300** = possible **Osteitis Fibrosa Cystica** **iPTH \<150** = possible **adynamic bone disease**

**Vitamin D & Vitamin D Analogues (Calcitriol)** For: CKD - Mineral & Bone Disease

KDOQI: Only use if: * *Ca \<9.5** --- **P \<5.5** * still used in practice though* **Vitamin D --\> *_supresses PTH_*** Increases: * *_Gut Absorption of PHOSPHORUS_** * *AND _CALCIUM_** ***_caution with HYPERphosphorus_***

**Comparible Doses of** **Calcitriol / Viamin D Analogs**

**"****Alphabetical Order - 1 - 2 - 4"** **_Calcitriol_ - 1 mcg MOST HYPER-Ca & HYPER-Phos** **_DoxerCalciferol_ -** **2 mcg Pro-drug**, *less HYPERcalcemic*, PO is MORE HYPERcalcemic vs IV * *_Paricalcitol_ -** **4 mcg** * **least hypercalcemic & hyperphosphatemic***

**Cinacalcet = Sensipar** 30/60/90 mg tablets **Taken with food & WHOLE** adjust dose in **4 weeks** **_USES_**

***_reduce PTH_*** by ↑**CaSR sensitivity on PT Gland** * *Ca needs to be \> 8.4mg/dL** * may cause HypoCalcemia* Uses: * *PTH is NOT controlled by VitD Analogs** * *HYPERcalcemia** / **Calciphylaxis** ensure med is held 12 hours b4 PTH lab draw *can have FALSELY low PTH levels*

**Cinacalcet = Sensipar** **ADR / Precautions / Drug Interactions**

TAKEN WHOLE & WITH FOOD **Vomiting / Diarrhea** / Nausea Precaution: **SEIZURES** --\> associated with ***_low Calcium_*** DI: * *Strong Inhibitor of CYP2D6 * partially metabolized by 3A4***

**Etecalcetide = Parsabiv** **MoA / Uses**

**_Binds to CaSR_** and **enhances its activation** by **extracellular calcium** **_ONLY FOR HEMODIALYSIS PATIENTS_** IV formulation --\> need to **restart to 5mg/ML** if *missed dose* Calcium should be **\>8.4** b4 starting check q4weeks

**Etelcalcetide** **ADR / Concerns**

**_only for HEMODIALYSIS patients_** **IV, store in FRIDGE** ADR: * **_HypoCalcemia_*** --\> **Worsening heart Failure** * possible IMMUNOGENECITY --\> AB formation* **Better GI Tolerance \> Cinacalcet** **Switching From Cinacalcet --\> D/C for 7 days pror**

**Inactive Vitamin D**

**Serum 25(OH)D goal level \> 30 ng/mL** ***_not for Adjusting PTH_*** role mainly for **preventing: cancer / diabetes / Autoimmune dzs / CV dzs / infxns** Treatments: **_Ergocalciferol_** 50k units qweek - q2week - qmonth **_Cholecalciferol_** 1k-5k QD * *_Calcifediol = Rayaldee_** 30mcg pq qHS * drug interactions with CYP3A & THIAZIDE diuretics*

**Mineral & Bone Disease Goals** **KDOQI - CKD Stage 3 & 4**

Both the SAME for Phos & Ca (normal ranges) Phos = **2.7 - 4.6** Corrected Ca = **8.4 - 10.2** Ca x P = **----** **CKD 3 iPTH = 35 - 70** **CKD 4 iPTH = 70 - 110**

**Mineral & Bone Disease Goals** **KDOQI - CKD Stage 5**

Phos = **3.5 -5.5** Corrected Ca = **8.4 - 9.5** Ca x P = **\< 55** iPTH = **150 - 300**

**Mineral & Bone Disease Goals** **KDIGO 2017** **CKD G5D**

**_iPTH_** **2-9x Upper Limit ~150 - 600** Phos: *lower towards normal range* Ca = *AVOID* HYPERcalcemia