Written by Julie Bick, Ph.D.
March is Kidney Disease Awareness Month, a month dedicated to increasing awareness about kidney health and improving treatment strategies for those affected by chronic kidney disease (CKD). One of the most promising advancements in nephrology today is pharmacogenomics (PGx)- the study of how a person's genetic makeup affects their response to medications. As kidney disease continues to impact millions worldwide, personalized medicine through PGx offers a real opportunity to optimize treatments and improve patient outcomes.
Chronic kidney disease (CKD) affects over 37 million Americans, with millions more at risk due to conditions such as diabetes and hypertension. Kidney disease is often referred to as a "silent killer" because it can progress without noticeable symptoms until significant damage has occurred. Standard treatments include medications to control blood pressure, reduce proteinuria, and manage complications. However, patients frequently experience adverse drug reactions (ADRs) or inadequate responses due to genetic differences in drug metabolism.
When we think of the areas of medicine that are the most closely associated with pharmacogenomic testing (PGx), the first to mind is probably mental and cardiovascular health. However, the field of nephrology should also be high on this list since so many of the medications used to manage kidney diseases have PGx guidelines associated with their use; and given that kidneys play a crucial role in drug metabolism and excretion, understanding genetic influences on drug response is vital for optimizing treatments for many nephrology patients. This blog explores the clinical applications of PGx in nephrology, discussing how genetic variations affect drug metabolism, treatment efficacy, and adverse drug reactions in patients with renal disorders.
It is not uncommon for nephrology patients to require medications for hypertension, chronic kidney disease (CKD), transplant immunosuppression, and other conditions. However, drug responses vary significantly among individuals due to genetic factors as well as the combination of medications that are prescribed. PGx provides valuable insights into how genetic differences influence drug metabolism, efficacy, and toxicity, and using medication safety tool, these genetic profiles can be overlaid with drug-drug interactions to more effectively guide clinicians in selecting the most appropriate medications and dosages for each of their patients. Nephrologists are familiar with using biomarkers to optimize medications, but traditionally this has taken the form of measurements such as creatinine clearance to monitor kidney function. However, now PGx is providing nephrologists with the tools to preemptively identify risks of adverse drug reactions, or non-responsiveness to medications and deliver more precision prescribing to their patients.
The cytochrome P450 (CYP450) enzyme family is responsible for metabolizing numerous nephrology-related drugs, and genetic polymorphisms in these enzymes significantly influence drug metabolism, influencing their safety and efficacy.
One of the most relevant of these enzymes for nephrology is CYP3A5. This enzyme metabolizes tacrolimus, a key immunosuppressant drug that is employed both pre- and post-kidney transplantation. Knowing a patient’s CYP3A5 profile at the initiation of tacrolimus therapy enables the clinician to make more informed decisions about dosing and therefore provide safer and more effective treatment for their patients. For example, the CYP3A5*3 allele results in reduced enzyme activity and a poor metabolism profile for tacrolimus that requires dose adjustments for optimal immunosuppression. More recently, CYP3A4 status has also been implicated in tacrolimus response, and therefore PGx profiling of CYP3A4 is being included to assist in reaching optimal therapeutic dosing more rapidly (Birdwell et. al. 2015)
Another drug that is often employed post-transplantation for long-term maintenance immunosuppressive therapy is azathioprine, a pro-drug -meaning it must be metabolically converted to the active drug form known as mercaptopurine. Mercaptopurine is toxic and must be efficiently metabolized by polymorphic thiopurine methyltransferase (TPMT) to prevent severe myelosuppression. Poor or non-functional TPMT enzyme activity is associated with the toxic build-up of mercaptopurine compounds, and therefore patients with TPMT gene variants associated with poor metabolic profiles should receive lower initial doses of any thiopurine medication, or in the case of homozygous non-functional TPMT variants, these drugs should be avoided completely (Relling et. al. 2011).
Post-kidney transplantation therapy may also include Mycophenolic Acid (MPA) that helps to prevent organ rejection by suppressing the immune system response to the transplanted kidney. It is usually administered in combination with other immunosuppressive medications such as steroids and cyclosporine. However, dosing adjustments are recommended based on the patient’s estimated glomerular filtration rate (eGFR) and variations in the UGT1A9 and UGT2B7 genes that are responsible for MPA metabolism and of the gene encoding inosine 5’-monophosphate dehydrogenase (IMPDH), the target of MPA. All of these factors influence the drug efficacy and toxicity in transplant patients (Genvigir et. al. 2020) and although not yet the standard-of-care, PGx guided dosing is recommended.
Another CYP450 enzyme with significant implications in nephrology is encoded by the CYP2C19 gene. Variants in CYP2C19 affect the metabolism of proton pump inhibitors (PPIs), commonly used in CKD patients, as well as clopidogrel, a commonly prescribed antiplatelet agent. This is very significant since cardiovascular disease is a leading cause of death for patients with CKD, and therefore many patients are prescribed antiplatelets and anticoagulants with PGx guidelines associated with their use. Clopidogrel is used for patients who receive kidney artery stenting (Mousa et. al. 2012) and CYP2C19 PGx profiling is imperative for the safe and effective use of this drug. Clopidogrel is another pro-drug, that is metabolized into its active form by CYP2C19. Patients with CYP2C19 variants that result in a poor or low metabolic profile could experience decreased platelet inhibition (Scott et. al. 2011). In contrast, patients with CYP2C19 variants resulting in rapid or ultra-rapid metabolic profiles for CYP2C19 may experience higher risk for bleeding based on the level of platelet inhibition (Scott et. al. 2013).
As previously mentioned, patients with CKD are at a greater risk of cardiovascular disease, as well as stroke and atrial fibrillation (SF) and traditionally warfarin was the drug of choice to address these risks since the drug undergoes extensive hepatic metabolism into inactive compounds, therefore posing less risk to renally impaired patients (Soliman et. al. 2010). In the case of warfarin use, PGx profiling of the genes for CYP2C9, CYP4F2 and VKORC1, coupled with INR monitoring is assisting clinicians in safer dosing of the drug, and clinical trials implementing PGx testing into warfarin therapy are demonstrating its value in its safety and efficacy (Gage et. al. 2017). CPIC has provided clear and evidence-based guidance for warfarin dosing and Gage et. al. (2008) established a web-based application that incorporates genetic and clinical data to tailor warfarin dosing (www.warfarindosing.org).
Many patients with CKD have comorbidities that require polypharmacy. As such, all drug selection and dosing must consider renal clearance, PGx profiles and drug-drug interactions to avoid toxicity and ensure efficacy. There are many commonly prescribed drugs that are primarily renally cleared and therefore when prescribing to patients with CKD, PGx profiling for these drugs can provide an extra layer of safety and dosing efficacy. This includes azathioprine and mercaptopurine that have previously been discussed in this blog, but in addition beta blockers such as Atenolol, Nadolol and Sotalol are renally cleared and careful monitoring of dosing should be employed at following initial treatment. Similarly, codeine and tramadol for pain management are also renally cleared, and CKD patients with impaired kidney function are at risk of the accumulation of morphine-6-glucuronide; this may be further influenced by the OPRM1 gene variants of the patient and therefore PGx testing can help determine if this individual is even a good candidate or not for morphine-based pain management. Other drugs that may be potentially harmful to CKD patients include medications used to manage diabetes such as Metformin, Glyburide, Glipizide and Glimepiride- all of which are cleared through the kidneys and have PGx-guidance associated with their use. This PGx profiling can help ensure any individual with CKD is a suitable candidate for these medications, or if they should be completely avoided.
There are several drugs for which renal function monitoring is essential when prescribed to CKD patients to prevent the increased risk of drug accumulation and toxicity. These include over the counter medications including NSAIDs such as ibuprofen that can worsen kidney function and potentially result in acute kidney injury (AKI). Aminoglycosides such as gentamicin and antibiotics including penicillin and fluoroquinolones should be carefully dosed to prevent nephrotoxicity and ototoxicity.
Drugs that have very narrow therapeutic windows and are processed through the kidney such as digoxin and lithium should be carefully monitored to avoid toxicity and alternative drugs selected wherever possible.
Although PGx is revolutionizing nephrology by enabling precision medicine approaches in drug selection and dosing, its adoption as the standard of care is much slower than it should be. Understanding genetic variations in drug metabolism, transport, and response can enhance treatment efficacy, reduce adverse effects, and improve outcomes for all nephrology patients. Given that CKD alters the pharmacokinetics of so many drugs, nephrologists should be incorporating PGx profiling into their patient care to provide an additional layer of precision and medication safety. The hope is that as this technology advances, integrating PGx into routine nephrology practice will become increasingly feasible and automatically integrated into patient’s treatment programs.
This Kidney Disease Awareness Month, let’s highlight the role of PGx in nephrology. By incorporating genetic insights into kidney disease treatment, we can pave the way for personalized nephrology care and transform the lives of millions living with kidney disease….one tailored prescription at a time.
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