IPC Kidney Week 3

MBD Pathophysiology

• Phosphate retention

  • excreted by kidneys

• Decreased Calcitriol (activated Vitamin D)

  • proximal tubule cells → 1-a hydroxylase

• Result in hypocalcemia → PTH release → increased calcium mobilization from bone → renal osteodystrophy

Consequences of CKD-MBD

• Parathyroid hyperplasia

• Calciphylaxis

• left ventricular hypertrophy

• ESA resistance

• Immune dysfunction

• Renal osteodystrophy

  • Osteitis fibrosa

  • adynamic bone disease

  • osteomalacia

Non-Calcium Based Phosphate-Binders

• Normal - High [Ca]

• Sevelamer carbonate (Renvela)

  • first line

• Lanthanum carbonate (Fosrenol)

  • chewable

• Ferric Citrate (Auryxia)

  • Can also treat iron deficient anemia

• Sucroferric oxyhydroxide (Velphoro)

  • potent, chewable

Calcium Based Phosphate-Binders

• Low [Ca]

• Calcium Acetate (PhosLo)

  • Rx only

  • 25% elemental calcium

    • 2x binding capacity vs carbonate

  • $$$

• Calcium Carbonate (Tums, etc..)

  • OTC, cheap

  • 40% elemental calcium

  • needs acidic environment

• ***No more than 1500 mg of Calcium from binders***

  • avoid calcium citrate and chloride salts

Tenapanor

• Xphozah

• Indications → add on therapies for:

  • dialysis CKD patients with inadequate response to binders

  • patients not tolerant to binders

• Contraindications → GI obstruction, < 6 yrs old

• ADR → diarrhea

CKD MBD Agents to lower iPTH

• Calcimimetics → normal - high calcium (lower calcium)

  • cinacalcet → PO

  • Etelcalcetide → IV

• Vitamin D Analogs → normal - low calcium (raise calcium)

  • Calcitriol (Rocaltrol) → IV/PO

    • endogenous

  • Paricalcitol (Zemplar) & Doxercalciferol (Hectorol)

    • Paricalcitol → less risk of hypercalcemia / hyperphosphatemia

    • Doxercalciferol → needs hepatic activation

Lab Goals of MBD Therapy

• Calcium → 8.5 to 10.2 or hypocalcemia with no symptoms

• Phosphorous → 2.7 to 4.6 or 3.5-5.5

• iPTH → 2-9x the upper limit of normal assay (around 150-600pg/mL)

Sevelamer

• Renvela

• Hypercalcemia + hyperphosphatemia (FIRST LINE)

• ADR → GI upset, diarrhea

  • Take other medications 1 hour before or 3 hours after taking sevelamer

• Can ↓ LDL and ↑ HDL

Lanthanum

• Fosrenol

• Hypercalcemia + hyperphosphatemia (SECOND LINE)

• Chewable tablet → MUST be chewed

• ADR → GI upset, “coats stomach” can be seen on X-rays

  • Take other medications 1 hour before or 3 hours after taking lanthanum, not as bad as sevelamer

Ferric Citrate

• Auryxia

• ADR → GI, diarrhea, iron overload, stool discoloration

• Increases TSAT by 8.6%, ferritin by 114 ng/mL

  • reduction in IV iron dose, but still need to use IV iron

Sucroferric oxyhydroxide

• Velphoro

• ADR → GI, diarrhea

• Iron based but does not change iron status

• Chewable → MUST be chewed

  • lower pill burden

Aluminum Based Binders

• Amphojel (aluminum hydroxide)

• Last line phosphate binder → risk of aluminum toxicity

• Very effective binding → use < 7 days for severe hyperphosphatemia

• ADR → GI upset, CNS toxicity, microcytic anemia

When should calcitriol / Vitamin D analogs be used / not used in CKD MBD?

Use → elevated iPTH despite calcium and phos at goal

Don’t use → hypercalcemia and/or hyperphosphatemia

Vitamin D Products

• Ergocalciferol & cholecalciferol

  • inactive forms of Vit D

  • OTC, cheap

  • recommended in CKD and ESRD → vitamin D deficiency (< 30 ng/mL)

• Calcifediol

  • prohormone of active vid D

  • INDICATED ONLY → CKD stage 3 & 4, Vit D deficiency, secondary hyperparathyroidism

Vitamin D Analog Products

• Calcitriol (Rocaltrol) → endogenous, suppresses PTH by ↑ calcium by ↑ gut absorption = ↓ PTH release

• Paricalcitol (Zemplar) → less hypercalcemia risk

• Doxercalciferol (Hectorol) → requires hepatic activation

• ADRs → increase in calcium and phosphate absorption

Cinacalcet

• Sensipar

• ALWAYS start at 30mg qd dose

• MOA → hyper-sensitizes calcium sensing receptors on PT gland to suppress PTH release

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• Use when calcium levels are normal - low

• Metabolized by CYP3A4

• Inhibits CYP2D6

Etelcalcetide

• Parsabiv

• IV Calcimimetic used during hemodialysis (like cinacalcet)

• ADR → QTc prolongation, hypocalcemia, less GI

Anemia in CKD Definition

• HGB < 13 g/dL → males

• HGB < 12 g/dL → females

• begins to develop once GFR declines to around < 45 ml/min/1.73m²

Hepcidin

• Produced by liver

  • renally excreted, ↑ [ ] in CKD

• low hepcidin = increased iron absorption

• high hepcidin = decreased iron absorption

  • decreased iron mobilization from stored sources

Iron Deficiency Goals

• Start therapy

  • Ferritin < 100 and TSAT < 40% or

  • Ferritin 100-300 and TSAT < 25%

  • Hemodialysis

    • Ferritin > 500 and TSAT > 30%

• Hold if TSAT > 40% and ferritin > 1200

PO Iron Overview

• Poor absorption (10-15%)

• ADR → GI, nausea, constipation, dark stool, cramping, drug interactions

• Slow iron replenishment

• inexpensive

IV Iron Overview

• Better absorption, rapid replenishment of iron stores

• Injection site reactions, hypersensitivity

• Infections

Oral Iron Products

• Ferrous Sulfate → most common, 65mg iron

• Ferrous Gluconate → less iron (39mg) , but less ADR

• Polysaccharide and Maltol forms → better F and tolerability

  • dosed in elemental iron

• Once daily → CKD

• Every other day → general population use

  • may reduce hepcidin levels before next dose

IV Iron Products

• LMW Dextran → InFed

• ⭐ Ferric Gluconate → Ferrlecit

• ⭐ ️Iron Sucrose → Venofer

• Ferumoxytol → Feraheme

• Ferric Carboxymaltose → Injectafer

  • risk of hypophosphatemia

• 1 gram loading dose goal

• Do NOT require test dose

• Preferred Therapy in dialysis patients

ESA Comparisons

• Epoetin alfa (Epogen) → once weekly

• Epoetin alfa epbx (Retacrit) → biosimilar of Epogen, 33% cost savings

• Darbepoetin alfa (Aranesp) → every 2 weeks

• Methoxy polyethylene glycol epoetin beta (Mircera) → every 4 weeks

• Non removed by dialysis

Hemoglobin ESA Targets

• CKD Non-dialysis

  • Initiation → Hb < 10

  • Target → Hb = 10, avoid transfusions

• CKD Dialysis

  • Initiation → Hb < 10

  • Target → Hb 10-11, avoid transfusions

ESA Dosing & Response

• Goal change is 1-2 Hb per month

• Dose adjustments every 4 weeks (steady state)

• Reduce ESA dose:

  • Patients Hb approaches towards 11

  • Hb increases > 1 in 2 weeks or less

• Increase ESA dose:

  • Hb below target after 4 weeks of treatment

• Hypo-responsiveness → no increase in Hb after month of ESA or 2 dose increases

• Resistance → failure to achieve target Hb at high dose, common causes:

  • Iron deficiency, folate & B12

  • malignancy, trauma, inflammation, infection → (acute)

ESA ADR’s & Clinical Pearls

• ADRs

  • HTN

  • Hyper coagulability

    • DVT, PE, MI, CVA (stroke)

  • Pure red blood cell aplasia

  • Progression of malignancy

• Pearls

  • Use for → preventing blood transfusions, quality of life

    • transfusions = less transplant compatibility

  • Do not improve mortality

HIF-PH Inhibitors

• MOA → Mimics hypoxia → promotes HIF accumulation → stimulate endogenous EPO and RBC formation, decrease hepcidin

Vadadustat

• Vafseo

• Indication → anemia in chronic dialysis dependent CKD

• Contraindication → uncontrolled HTN (180/120), concomitant ESA

• ADR → HTN, seizures, GI erosion, CV risks (death, MI, TE)

• Avoid co-administration with iron or phos binders

Blood Transfusion

• Severe anemia Hb < 7

• Packed Red Blood Cells given

  • 1 unit = Hb increase of 1 g/dL & 200mg elemental iron

• Risks

  • TRALI, hypervolemia, hypocalcemia, hypersensitivity reaction, immune activation (bad for transplant)

What drugs require TDM?

• Narrow therapeutic index

• Variable pharmacokinetics

• Known concentration effect relationship

  • toxicity or efficacy

Vancomycin Therapeutic Range

• Trough 10-20 mcg/mL

• AUC 400-600

• Initial dose 15-20 mg/kg

• Toxicity

  • trough >15 or AUC >600

Gentamycin & Tobramycin Therapeutic Range

• Peak 6-8 mcg/mL

• Trough 1-2 mcg/mL

Phenytoin Therapeutic Range

• Random → 10 - 20 mg/mL

• Free concentration → 1-2 mg/mL

Warfarin Therapeutic Range

• INR 2-3

Kidney Dysfunction Affect on PD Overview

• Increased permeability of BBB → CNS effects ↑

• Decreased platelet aggregation → bleeding risk ↑

Child Pugh Score

• 5-6 points → Class A

• 7-9 points → Class B

• 10 - 15 → Class C (most severe)

Phenytoin TDM

• Follows Michaelis menten plot

• 90% bound to albumin

  • uremic toxins displace phenytoin from albumin

  • hypoalbuminuria

  • Leads to increased free phenytoin [ ]

• In patients with renal dysfunction → draw FREE concentration when possible

• Only dose increase by 50mg increments

Warfarin TDM

• Onset of affect is 2-3 days

  • t1/2 of thrombin (factor II) is 72 hours

• Wait 2-3 days before making dose changes to see effect

• INR 2-3 desired

When do you not need to change dosing of a drug in kidney dysfunction?

• Large therapeutic index

• Fraction excreted unchanged in urine is < 30 %

• Metabolites are inactive

  • or drug has no metabolites

Pharmacokinetic Changes in CKD Overview

• Absorption → unchanged

• Distribution → increase, decrease, or unchanged

• Metabolism → decreased phase 1

  • CYP capacity lowered due to transporter blocking (uremic toxins)

  • No change in phase 2, however these products accumulate due to low kidney clearance

• Elimination → decrease kidney elimination

Opioids in CKD

• Good

  • Fentanyl

  • Methadone

• Caution (consider dose reduction)

  • Hydrocodone

  • Oxycodone

  • Hydromorphone

• Do NOT use (can give 1-2 initial dosing but never routine dosing)

  • Morphine

  • Codeine

  • Meperidine

Developing Drug Regimens → LD & MD

• Loading dose

  • Affected by Vd

  • Do not decrease in kidney dysfunction

    • may need to increase for AB

  • Examples

    • Digoxin Vd ↓ 50%

    • AB are hydrophilic so Vd ↑ require higher LD

• Maintenance dose

  • Affected by Cl

Which AB do not need renal dose changes?

• M → Metronidazole

• M → Moxifloxacin

• A → Azithromycin

• L → Linezolid

• D → Doxycycline

• C → Clindamycin

• C → Ceftriaxone

“ Mega Man And Little Diddy Crush Cartoons”

Which anticoagulants do not need renal dosing changes

• Warfarin

• Heparin

• Argatroban

Eliquis Renal Dosing

• Reduced to 2.5mg BID if meets at least two of the following:

• Scr >= 1.5 mg/dl

• Age >= 80 years

• BW <= 60 kg

• Go to anticoag in class for someone with kidney dysfunction

  • lowest risk of bleeding

Edoxaban Dosing

• Contraindicated in CrCl >95 ml/min → shown efficacy failure

Drugs that Decrease Iron Absorption

• Antacids

• Tetracyclines

• H2 Antagonists

• PPI’s

• Cholestyramine

Drugs effected by Iron

• Fluoroquinolone’s

• Levothyroxine

• Tetracyclines

• Mycophenolate

• Methyldopa

• Levodopa

IBW Equations

• Male → 50 + 2.3 (inches above 60)

• Female → 45.5 + 2.3 (inches above 60)