Renal Dysfunction
Corey Diamond, PharmD
A new guideline is designed to help clinicians adjust doses of anticancer drugs in patients with renal dysfunction and will feature recommendations for over 50 different anticancer drugs. The Cancer Institute of New South Wales (Cancer Institute NSW) has released the draft International Consensus Guideline for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) and aims to roll out the new international guideline in the latter half of 2022.
The guideline will be used as a valuable standardizing instrument that encourages clinicians—even in the United States—to weigh the unique hazards and advantages of kidney drug doses in patients with any degree of kidney dysfunction, on which there has been little consensus, in general, and could represent a significant leap forward for practice standardization.
Scope of the guidelines
The new, comprehensive ADDIKD guideline provides recommendations for standard practice approaches to quantifying and classifying kidney function. It pushes strongly for standard measuring of renal function using highly accurate forms of glomerular filtration rate (GFR) whenever possible, particularly the Chronic Kidney Disease–Epidemiology Collaboration (CKD-EPI) equation (eGFRCKD-EPI). It also seeks to adopt the kidney disease staging categories of the Kidney Disease Improving Global Outcomes as a basis for the ADDIKD guideline’s stepwise approach to drug adjustments.
The guideline will also provide dosing recommendations for the first cycle of anticancer treatment regimens. The ADDIKD guideline committee, which included one member from the United States, reviewed over 2,000 published articles and more than 150 registered product information monographs to provide dosing recommendations for 59 anticancer drugs.
Lastly, Cancer Institute NSW aims to translate its recommendations into an “easy-to-use” format so that it may retain a level of accessibility to all members of a multidisciplinary cancer team who may be less familiar with specific antineoplastic treatment protocols. For example, the guideline features a quick dosing reference table with a “traffic light system,” alerting clinicians to necessary precautions, closer monitoring, dose adjustments, and adverse effects based on a patient’s renal function and other risk factors.
The current landscape
According to the American Cancer Society, approximately one-quarter of patients with cancer have kidney dysfunction at the start of their treatment. However, prevalence is higher in certain patients, such as those with lung, colorectal, prostate, or multiple myeloma cancers.
A study published in January 2014 in the American Journal of Kidney Disease found that there was an 18% increase in the risk of cancer-related mortality with every 10 mL/min/1.73 m2 decline in estimated GFR (eGFR) from 60 mL/min/1.73 m2.
As a result, factors such as a limited therapeutic index, significant pharmacokinetic variability between patients, and the requirement for multi-drug, multi-day chemotherapy regimens make providing safe and effective anticancer therapy difficult. Patients with renal insufficiency are particularly prone to these problems since they frequently require dose adjustments or are unable to take certain medications.
Urgent necessity
Currently, no standardized approach to quantifying kidney function exists for adult patients with cancer. Fifty methods are available today. Additionally, a large percentage of anticancer treatment clinical trials are severely limited due to excluding patients with kidney dysfunction. It may surprise many clinical pharmacists to know that current recommendations for renal dose adjustments of anticancer agents are extrapolated from outdated or theoretical data.
Conversely, the empirical data that do exist come from tiny cohort studies and case reports. This dearth of evidence has caused wide variation in treatment and increased the danger of both under- and overdosing.
It may also surprise pharmacists to learn that creatinine clearance (CrCl)—although ubiquitous in clinical practice—is a rather poor marker of kidney function. Measured GFR (mGFR) is considered the gold standard for renal function, but its associated costs and labor make it impractical to implement into routine practice. Under ideal circumstances, CrCl overestimates mGFR by 10% to 20%.
In fact, some research has shown that—among patients with mild to moderate renal impairment—CrCl overestimates GFR by as much as 50%. The results of these aforementioned problems all compound to significantly increase the risk of toxicity from anticancer agents in patients suffering from even mild kidney disease. The current push by the ADDIKD guidelines to move toward eGFRCKD-EPI over CrCl stems from new highly validated research that the former’s relative accuracy is about 13% higher, which has been deemed by experts as clinically significant. ■