Pharmacokinetic Considerations in Patients with Renal Impairment Part 3 of 3 with Dr. Darren Roberts

Summary

This presentation explores the complexities of pharmacokinetics in patients with acute kidney injury (AKI). It highlights how AKI impacts drug dosing, particularly due to its dynamic nature and its association with critical illness and sepsis. The speaker discusses the challenges in drug absorption, metabolism, and distribution, emphasizing marked variability in patient responses. Despite limited data, it stresses the need for individualized dosing regimens and careful monitoring to prevent adverse drug events. The presentation also touches on methods for assessing kidney function in AKI, underlining the limitations of traditional formulas and the importance of alternative biomarkers.

Takeaways

• 😀 AKI (Acute Kidney Injury) complicates drug dosing regimens, requiring different approaches compared to patients with normal kidney function.
• 😀 AKI is a dynamic condition, with its severity, duration, and treatment varying over time, making pharmacokinetics challenging to manage.
• 😀 In patients with AKI, multiple physiological factors, including sepsis, critically affect drug kinetics, often confounding clear dosing guidelines.
• 😀 AKI impacts drug clearance, electrolytes, and uremic toxins, leading to unpredictable drug concentrations and patient responses.
• 😀 Approximately 20-30% of hospitalized patients experience AKI, with a significant mortality rate (up to 23%) in severe cases, particularly those in intensive care.
• 😀 Sepsis is a major cause of AKI, necessitating careful monitoring of antibiotics like meropenem and vancomycin to ensure therapeutic effectiveness.
• 😀 The relationship between creatinine levels and kidney function in AKI is unreliable, as the condition is not at steady state, making traditional eGFR formulas inaccurate for drug dosing.
• 😀 Kidney function estimations during AKI can be misleading, especially during the recovery phase, where creatinine levels may underestimate the true function.
• 😀 Pharmacokinetics in AKI patients show significant variability, particularly with antibiotics, as distribution and elimination can vary widely between individuals.
• 😀 Alternative biomarkers, such as cystatin C and endoglin (Endoglin), are being explored to assess AKI earlier than traditional creatinine-based tests.
• 😀 Compensatory mechanisms, like hyperfiltration in the remaining kidney, may occur in AKI but are poorly understood, further complicating the pharmacokinetic management of these patients.

Q & A

What is the main challenge in pharmacokinetics when treating patients with acute kidney injury (AKI)?

The main challenge in pharmacokinetics when treating AKI patients is the significant variability in drug concentrations and patient responses due to the dynamic and unpredictable nature of the condition. Additionally, AKI often occurs in critically ill patients with multiple comorbidities, making it even more difficult to predict how drugs will behave.

How is AKI diagnosed and staged?

AKI is diagnosed based on serum creatinine levels. The stages are defined as follows: Stage 1 when creatinine is up to 2 times the baseline or increases by more than 0.3 mg/dL, Stage 2 when creatinine increases up to 3 times the baseline, and Stage 3 when it increases more than 3 times the baseline or exceeds 4 mg/dL.

Why can serum creatinine levels be misleading in AKI when estimating kidney function?

Serum creatinine levels can be misleading in AKI because the condition is dynamic, and creatinine does not reach steady state immediately. As kidney function fluctuates during AKI, creatinine concentrations do not accurately reflect the true kidney function in real-time.

How do the kinetics of drug absorption, metabolism, and volume distribution change in AKI?

In AKI, the absorption and metabolism of drugs are poorly understood due to limited data, especially in critically ill patients. The volume of distribution often increases in AKI due to factors like fluid resuscitation, vasoplegia, and capillary leak, which contribute to changes in drug distribution, particularly for hydrophilic drugs.

What role does sepsis play in altering pharmacokinetics in AKI patients?

Sepsis can significantly alter pharmacokinetics in AKI patients by expanding the volume of distribution of antibiotics, such as pipercillin. This leads to lower drug concentrations in the plasma and potentially longer elimination half-lives compared to healthy individuals, complicating dosing and therapeutic efficacy.

How does renal replacement therapy (RRT) impact pharmacokinetics in AKI?

Renal replacement therapy (RRT) can impact drug clearance by removing drugs from the bloodstream during the treatment process. However, the specific effects on pharmacokinetics depend on the type of dialysis and the drug being administered. This adds another layer of complexity to drug dosing in AKI patients, although this topic was not covered in depth in the presentation.

Why are standard formulas for estimating glomerular filtration rate (GFR) not applicable in AKI?

Standard formulas for estimating GFR, such as Cockcroft-Gault or CKD-EPI, are not applicable in AKI because these formulas assume steady-state kidney function. Since AKI is dynamic, creatinine levels do not reflect accurate kidney function at any given moment, making these formulas unreliable for dosing decisions in AKI.

What alternative methods are used to assess kidney function in AKI?

Alternative methods for assessing kidney function in AKI include measured creatinine clearance, which can be estimated through urine collections in intensive care settings, and nuclear medicine techniques like DTPA, MAG3, or inulin, which provide more direct measurements of GFR. However, these methods are not routinely used due to their complexity and the rapidly changing nature of kidney function in AKI.

How does the intact nephron hypothesis relate to AKI?

The intact nephron hypothesis, which suggests that remaining nephrons in chronic kidney disease can compensate for loss of kidney function, may not apply in AKI. This is because the relationship between filtration, secretion, and metabolism is poorly understood in AKI, and compensatory mechanisms may not be as effective or present in the same way as in chronic kidney disease.

What are the key conclusions from the presentation regarding pharmacokinetics in AKI and CKD?

Both AKI and CKD significantly alter the pharmacokinetics of drugs, but data is limited, and variability among patients complicates drug dosing. Accurate monitoring and individualized dosing are crucial to avoid treatment failure and adverse drug events. The development of clear guidelines is challenging due to the dynamic and heterogeneous nature of AKI and CKD.