(11/2) Galen Lecture: HYPERcalcemia and HYPOphosphatemia Calcium [SCa 8.6-10.6mg/dL]

- Absorption: Occurs in the Gut, Kidney, and Bone o Gut: Enhanced by Vitamin D o Kidney: Reabsorption enhanced by PTH

§ Majority reabsorbed in proximal tubule § Loop diuretics inhibit reabsorption

o Bone: Balance of Deposition and Absorption - Distribution: Freely exchanged between IVFÛISF (ECF)

o ~50% of IVF Calcium is protein-bound, specifically to either anions or albumin

§ Protein-bound = Biologically inactive o Measuring Serum Calcium will calculate both the bound and unbound. o *Corrected Calcium = Measured SCa + 0.8*(4 – measured Serum albumin)

§ This is used to estimate ionized calcium levels in patients with hypoalbuminemia (Alb < 4mg/dL) - Excretion: Feces, Urine

Hypercalcemia [Ca > 10.5mg/dL] –OR- [Ionized Ca > 5.4mg/dL] - Cx: Calcium in circulation > Excretion of Calcium into the urine + deposition into bone

o Primary Hyperparathyroidism and Malignancy account for 90% of the cases of hypercalcemia § Primary Hyperparathyroidism: Most commonly caused by parathyroid adenoma, leading to

excess secretion of PTH. This established a new high “normal” value ( Ca < 11mg/dL) • PTH activates Osteoclasts (bone resorption), increases absorption of Ca in the gut via

VitD, Increases renal synthesis of VitD, increases renal absorption of Ca in Kidneys § Secondary/Tertiary Hyperparathyroidism: Most commonly caused by CKD, and will present as

adynamic bone disease. Due to reduced uptake of Ca in bone, increased Ca load with phosphorous binders, and increased Ca absorption due to Calcitriol administration

• Advanced renal failure à Parathyroid Hyperplasia (Tertiary), Need a transplant! § Malignancy: Solid tumors and Leukemia, every cancer has its own mechanism (Ca > 13mg/dL)

• May directly induce Osteolysis, Cytokines stimulate osteoclast production, and Tumors may secrete a PTH-related protein [RECHECK, she said the word TNFa I think]

• Lymphomas often cause increased GI absorption à PTH-independent CalcitriolÝ o Drug-Induced: Most commonly related to excess ingestion of Vitamin D analogs or Tums

§ VitD (>150ng/mL)- As you know, will increase Calcium absorption and bone resorption § Calcium Supplement: More frequently seen in Dyspepsia or Osteoporosis pt § Lithium: Known to induce mild hypercalcemia via ‘resetting’ the PTH. § Vitamin A: Known to stimulate osteoclastic resorption effect § Thiazide Diuretics: By blocking Na/Cl symport in the distal convoluted tubule of the nephron,

they inhibit urinary calcium excretion à increasing SCa o Accelerated bone resorption, Excessive GI Absorption, Decreased renal excretion of calcium

§ Secondary to Endocrine Disorders (Addisons, Acromegaly, Thyrotoxicosis), Granulomatous Disorder (Sarcoidosis, Tuberculosis)

- Sx: Ca levels do not correlate well with the s/sx. Better to look at Acuity of rise –or- rate of Ca level rise for tx o General: N, V, Fatigue, Thirst (associated with dehydration), Renal failure Sx o In Malignancy, there generally is an acute rise. Normal like 9 or 10…. The BOOM 14! o Primary Hyperparathyroidism causes an acute on chronic rise. Normal like 11 or 12… then BOOM 14!

o CHRONIC: Most commonly involves Ca deposition in blood vessels and organs. Long-standing HyperCa can even cause Primary Hyperparathyroidism, Sarcoidosis, CKD

§ Vessel deposits lead to atherosclerotic lesions à Heart disease

§ Skin deposits à Calciphylaxis § Kidney deposits à Nephrocalcinosis

o WHAT IS SEVERE? - Symptomatic - Treatment Goals:

o Reverse the signs and symptoms o Restoring Normocalcemia: Each treatment option

is involves 1 or more of these biological processes – we need to be able to understand and recognize what action our treatment provides

§ Inhibit Bone Resorption (Prevent Calcium from leaking out of bones into plasma) § Increase urinary Calcium Excretion § Decrease Intestinal Calcium Absorption

o Treat the underlying cause o Prevent long-term consequences

- Tx Methods: If symptomatic, treat as severe, if asymptomatic, categorize by plasma level o Mild/Asymptomatic (Ca< 12mg/dL):

§ Reduce dietary Ca < 400mg/day, Avoid Thiazides, lithium, VitD § Stay well hydrated to avoid nephrolithiasis (K stones brahh), and avoid immobilization

o Moderate (12-14mg/dL) If Asymptomatic à Tx as Mild. Symptomatic à Tx as Severe § This is just a Ca level range depiction, go up or down from here.

o Severe (Ca > 15mg/dL) Hypercalcemic Crisis – Acute and Symptomatic – Parenteral therapy is required! § Volume Expansion with NS – Used to restore Euvolemia § Calcitonin – Must be (Ca > 14mg/dL) – because rapidly decreases serum Ca § Bisphosonates – most important – provides the long-term effect in lower Ca § Dialysis: Last Resort! (Make sure you use Ca free dialysate)

- Tx Options- Realize these are not all independent of one another, tx may be concurrent! o DRUG: Normal Saline (0.9% NaCl)

§ MoA: Increases renal calcium Excretion, Corrects volume depletion § Dosing: Adjusted to maintain urine output at 100-150mL/hour

• Monitor: UO, Ca, Sx improvement § AE: Fluid overload, edema, electrolyte abnormalities

o DRUG: Calcitonin – both endogenous (parafollicular cells) and exogenous forms are available § MoA: does all 3! Efficacy 48 hour

• Decreases intestinal calcium absorption through functional antagonism of PTH • Inhibits Bone resorption by inhibiting osteoclasts • Increases renal calcium excretion

§ Dosing: 4 units/kg SubQ or IM (theyre equal), repeat in 4-6 hours if responsive • Limited efficacy promotes us to use bisphosphonates concurrently (like in severe cases) • Monitor: Ca

§ AE: N, Hypersenstivity, Tachyphylaxis § Special: Lowers Ca 1-2mg/dL within 4-6 hours! (But don’t use the nasal formulation)

o CLASS: Bisphosphonates – More potent than calcitonin and NS! § MoA: Inhibits bone resorption. Adsorbs to the surface of bone hydroxyapatite and inhibits Ca

release by inhibiting osteoclast-mediated bone resorption § Dosing: These guys work for 2-4 weeks!!! Monitor for Renal toxicity, acute phase rxn (flu-like) § AE: May experience osteonecrosis of the jaw, potential acute phase reactions (flu/bone pain) § Special: CANT USE IN RENAL FAILURE § DRUG: Zolendronic Acid – Preferred. Most potent. IV over 15 mins (every 3-4 weeks!) § DRUG: Pamidronate – Preferred. IV over 2 hours. SCa<13.5 use 60mg, >13.5 give 90mg § DRUG: Ibandronate – people complain of dyspepsia and back pain

- Tx: HyperCalcemia secondary to Hyperparathyroidism – Ready to learn about the Calcimemetics? o Reason for Treatment: Not treating can have long-standing consequences (osteoporosis, calcification) o DRUG: Cinacalcet (Sensipar) – Available as 30, 60, 90mg tabs

§ MoA: Decrease PTH by increasing the sensitivity of the Ca receptor on parathyroid gland § Dosing: Corrected Ca must be >7.5mg/dL before dose titration. Start 30mg Qdaily w/ food. § Monitor: SCa (anticipate 10% decrease at initiation) § AE: N/V/D Potentially ContraX: It is a strong inhibitor of CYP2D6

o DRUG: Etelcalcetide (Parsaviv) – The newest drug only for secondary hyperparathyroidism in HD pt § MoA: Binds to the Calcium sensing receptor on parathyroid gland, enhancing activation by SCa § Dosing: Only available as IV, Must adjust dose if Ca <7.5mg/d § Monitor: SCa - there are specific dosing requirements

- Tx Hypercalcemia secondary to Hypervitaminosis D –Tx if Sx! This occurs probably because your Vit-D rx o Calcitriol-Induced: D/C the calcitriol (it has a short half-life). Symptomatic? à Increase fluid intake or

administer IV hydration with saline, flush that shit out o Calcidiol-Induced: Uh oh this one is fat-soluble – longer half life. Can’t simply D/C it and begin walking

on water. à Aggressive therapy with Glucocorticoids or IV Bisphosphonates (if symptomatic) - Tx: Preventing Recurrence

o Education: Restrict calcium intake <400mg/day, stay hydrated to avoid kidney stones, avoid thiazides o Must lower the tumor burden – if the disorder is secondary to malignancy, the patient may benefit from

continuous administration of bisphosphonates. o Tx: Metastic Bone Disease à Administer pamidronate or zolendronic acid q3-4 weeks o DRUG: Denosumab – use for refractory hypercalcemia. Benefit? No restrictions in CKD (effect in 2-4d) o CLASS: Glucocorticoids – Often used in chronic granulomatous diseases (like Sarcoidosis) to prevent

hypercalcemia. – Prednisone 20-40mg/day. Effect prominent in 2-5 days, lasting potentially for weeks. § 2-fold mechanism: (Doses may be higher than what we are comfortable with)

• Decrease intestinal calcium absorption • Decrease calcitriol production by the activated mononuclear cells in the lungs and lymph

nodes Phosphate/Phosphorous (P) [2.5-4.5mg/dL]

- Daily Intake: Only need about 800-1500mg per day, deficiencies are uncommon. - Measurement: Only 0.1% of phosphorous is in the serum (ECF), thus, serum phosphorous levels are terrible

indicators of our current status - Absorption: Minimally regulated, the GI tract absorbs it and it generally goes directly to the bone

o There may be ‘absorption’ component overlap in the Kidney excretion regulation. See below. - Distribution: 85% Bone, 15% Cells, 0.1% ECF 70kg man has ~700g P - Excretion: Daily excretion = ~500mg in the feces and ~900mg in the urine

o The Kidney is the most important regulator of Serum P. It maintains the steady state between the: § Amount absorbed from the intestines Û Amount excreted in the urine

o Proximal tubule reabsorption (70-80%) via Na-P cotransport*** (Distal reabsoption 10-15%) § Inhibited by PTH and Calcitriol (1,25-dihydroxyvitamin D) § Stimulated by low serum phosphorous

o If low PO P intake, reabsorption in the kidney will increase Hypophosphatemia [2.5-4.5mg/dL]

- This condition is generally not seen in the general population, more prevalent in hospital (5%) patients and patients who are alcoholic, have severe sepsis, or trauma (30-50%)

- Cx: Most commonly caused by intracellular shifts of Phosphorous (P) in the setting or preexisting P depletion o Redistribution of Phosphate from Extracellular fluid into cells

§ Stimulation of glycolysis increases the formation of phosphorylated complex carbohydrates. It is called a “Phosphoric Shift”. This occurs with the administration of glucose or insulin – Rapidly in DKA, Anorexia, Mega boozers

• Refeeding Syndrome – clinical complication due to electrolyte shifts during nutritional rehab of malnourished/hospitalized patients – Hypophosphatemia is a hallmark Sx

o Phase 1: Acute rapid hypophosphatemia o Phase 2: Gradual Decrease in Serum P over 5-10 days

• \, it is important to correct electrolyte deficiencies before refeeding § Acute respiratory alkalosis, phosphofructokinase activity is increasedà phosphorylation events

§ Post parathyroidectomy – may develop hungry bone syndrome, where there is a marked deposition of calcium and phosphorous into bone

o Decreased intestinal absorption of Phosphate § Inadequate intake – often related to gastric bypass or some small bowel disease § Medications: Antacids (especially Al and Mg based), Phosphate binders for CKD tx, Niacin § Vitamin D deficiency - it normally helps Phosphorous absorption in the gut § Steatorrhea and Chronic Diarrhea

o Increased urinary phosphate excretion § Often due to proximally acting diuretics (Acetazolamide, Metalozone)

o Removal by renal replacement therapies - Sx: Symptoms often do not occur until P < 1mg/dL. They are commonly seen with combined IC shifts

o When Red cell 2,3-DPG levels fall, there is a reduction in oxygen tissue release, ATP levels fall, and cell function begins to fail. This ondition can affect almost every organ system

o Kidney – Hypercalciuria o Skeletal and Smooth Muscle – Muscle dysfunction, rickets, osteomalacia o CNS: Metabolic encephalopathy (ATP depletion), irritability, paresthesia, seizures

- Oral Tx: ~~~~~~~~~~~~~~\(-.-)/~~~~~~~~ORAL ARE PREFERRED~~~~~~~~~~~~\(-.-)/~~~~~~~~~~~~~~~ o Asymptomatic (Phos < 2mg/dL): Oral therapies Symptomatic (Phos 1-1.9mg/dL): Oral therapies o -------- Oral therapies administer in 3-4 divided doses. May supplement with a phos rich diet--------

§ Sodium-based formulations are preferred, UNLESS they have hypokalemia (K<3.5) o DRUG: KPhos Neutral and Phospha 250 Neutral: PO4: 250mg Na: 298mg K: 45mg o DRUG: Phos-Na-K Powder PO4: 250mg Na: 160mg K: 280mg o DRUG: Neutra-Phos PO4: 250mg Na: 160mg K: 272mg o Monitor: Phosphorous level, SNa, K, Baseline Ca o AE: Diarrhea, Hyperkalemia, Hypernatremia, Extraskeletal calcifications

- IV Tx: This is reserved for patients who: Symptomatic (Phos <1mg/dL) or Unable to tolerate PO therapies o Phos ³ 1.2mg/dL: 0.08-0.24 mmol/kg (max 30mmol) over 6 hours o Phos < 1.2 mg/dL: 0.25-0.5 mmol/kg (max 80mmol) over 8-12 hours o à SWITCH to oral supplement once Phos > 1.5mg/dL o DRUG: Potassium Phosphate Phosphorous: 93.1mg/mL Phosphate 3.0 K: 4.4 o DRUG: Sodium Phosphate Phosphorous: 93mg/mL Phosphate 3.0 Na: 4.0 o These are administered slowly because the phosphorous will be shifting intracellularly, and we do not

want to overload. Sodium is preferred unless you are also treating hypoK o Monitor: Serum phosphorous every 6 hours, SCa, SMag, SNa, SK. Anticipate decrease in 2 days post

administration. o AE: Calcium Phosphorous ppt in IVPB à Renal Failure

- Dose Adjustments for Hypophosphatemia treatments o Increase Dose if: Acute on chronic Chronic > 1 week o Decrease Dose if: Ca 10.5-12 (reduce 50%) Ca > 12mg/dL (HOLD PO4) Renal Dysfunct

- Urinary Phosphate Wasting: This is a very difficult disorder to treat, because admininistering phosphate will simply result in further phosphorous excretion.

o Dipyridamole is our current weak option. Give ‘em 75mg PO QID GOOD NEWS! Galen said we do not need to know dosing Sorry if this last hypercalcemia, hypophosphatemia lecture review wasn’t as good – I didn’t pay attention as much GOOD LUCK!