PHAR 520: PK in Renal Disease

Learning Objectives:

• Describe antimicrobial dosing principles for patients with chronic kidney disease

• Recall additional dosing considerations for patients receiving hemodialysis

• Describe antimicrobial dosing principles for patients with acute kidney injury

• Compare antimicrobial dosing principles for patients with chronic kidney disease versus acute kidney injury

• Identify patients at risk for augmented renal clearance

• Describe antimicrobial dosing principles for patients with augmented renal clearance

Antimicrobials are either classified as what two categories?

1) Time-dependent

• % Time > MIC

2) Concentration dependent

• AUC/MIC

• Peak/MIC (same as C_max/MIC)

For PK/PD of a drug to be affected by renal disease, then…

It must be predominantly a renally cleared drug

What are types of renal disease?

• Impaired renal function

  • Chronic kidney disease (CKD)

  • Acute kidney injury (AKI)

    • Transient AKI

  • Acute on chronic kidney injury

• Enhanced renal function → Augmented renal clearance (ARC)

What are some dosing considerations in CKD?

• CKD patients have an increased risk of developing AKI

• Daily monitoring of SCr/CrCl is typically recommended

  • When feasible, urine output monitoring should be assessed

  • Normal urine output → 0.5-1 mL/kg/hour

• Recovery of renal function should not be anticipated in CKD

  • Renal function is generally more predictable in CKD than AKI

• For agents with a wide therapeutic index, empiric renal dose adjustments may be needed

  • Renal dose adjustments still recommended for maintenance dosing

How should we approach hemodialysis dosing?

• First determine the patient’s normal HD schedule (almost always either M/W/F or T/Th/S)

• Assess whether or not the patient is anuric

  • Some HD patients still produce urine and will need modified doses accounting for this residual renal function

• Drugs that are removed by HD should be scheduled for administration AFTER completion of HD

How much vancomycin is removed by hemodialysis?

• General rules to estimate vancomycin removal by HD

  • Each hour of HD removes 10% of vancomycin (40% removal for a 4-hour HD session)

  • A typical 4-hour HD session removes one-third of vancomycin

HPI: A 56 y/o male weighing 74 kg presents to the hospital with concerns for sepsis. HD is planned to be performed later today. (Labs are all indicative for infection)

What initial vancomycin dose would you recommend for this patient?

A. 15 mg/kg administered after HD ends today

B. 20 mg/kg administered before HD starts today

C. 25 mg/kg administered after HD ends today

D. 30-35 mg/kg administered before HD starts today

D. 30-35mg/kg

• Patient needs emergent treatment, start vanco immediately, eliminate A and C

• HD removes ~1/3 of vancomycin, so give a larger dose

Is rapid recovery from an AKI possible?

Yes, rapid recovery is possible, unlike CKD

What is the definition of a transient AKI?

If there was resolution of KDIGO criteria of an AKI within the first 48 hours of hospitalization

How does Biagi like to approach antimicrobial dosing for patients with a transient AKI?

For patients with an AKI who are critically ill and/or have concerns for sepsis..

1) Defer renal dose adjustments for empiric dosing of wide therapeutic index antimicrobials (beta-lactams, daptomycin, fluconazole) for the first 24-48 hours of therapy

2) Renal dose adjustments are recommended for empiric dosing of nephrotoxic agents (AGs, vanco, etc)

What is acute on chronic kidney injury?

A patient with CKD at baseline undergoes an AKI

• CKD increases risk of developing AKI → AKI then contributes to further progression of CKD

How does Biagi like to approach antimicrobial dosing on AKI with CKD?

• Still defer renal dose adjustments for empiric dosing of antimicrobials for first 1-2 days

• For nephrotoxic agents, either:

  • 1) Dose based on package insert or institutional protocol

  • 2) Change to alternative agent that is not predominantly cleared

What is augmented renal clearance (ARC)?

• The “opposite” of an AKI, resulting in a sudden improvement in renal function

• Most commonly defined as CrCl > 130mL/min

  • Some studies define as urine output >1.5 mL/kg/hr

What are risk factors for augmented renal clearance?

• Being less severe than critically ill (the healthiest of the critically ill)

• Male sex

• Pregnancy

• Trauma

• Younger age

What are the strategies dosing for augmented renal clearance?

• 1. Use maximum approved dosing regimen

  • Applies to both time- and concentration-dependent agent

• 2. Administration via prolonged or extended infusion

  • Applies to time-dependent agents (i.e., β-lactams)

• 3. Therapeutic drug monitoring

  • Primarily applies to aminoglycosides and vancomycin

• 4. Use alternative agent not primarily renally eliminated