According to a report by the US Food and Drug Administration (FDA), 2.2 million adverse drug reactions (ADRs) occur in the US annually. On the other hand, the healthcare cost and morbidity associated with ineffective medication cause unnecessary burdens as well as patient confidence in treatment. Clinicians continuously strive to strike a balance between medication choices and doses that are too high and cause toxic side effects and those that are dosed too low and become ineffective. Here, we will discuss the role of pharmacogenomics in prescribing for kidney patients.
By Lara Zakaria, RPh MS CNS CDN IFMCP
Variability in response to pharmaceutical therapy is due to multiple, complex individual variations in basic physiological differences like age, sex, and weight, as well as metabolism, absorption, organ function, and disease state. These variables mean patients require monitoring, dose adjustments, and sometimes alternative therapy (drug switch).
This is why medications come in various doses, formulations, and options exist within a drug class. Prescribers follow “best practice guidelines” that allow them to choose an alternative when one drug therapy fails or is not tolerated due to side effects or ADR. But even with these well-researched guidelines, the choice and dosage of a medication can still be a guess.
Wouldn’t it be a relief to be able to predict in advance how someone might respond to a medication, avoiding guessing, saving time and improving patient outcome?
Thanks to advances in a field of genetics called pharmacogenomics (PGx), clinicians are starting to use genetic information to personalize drug therapy. Though this has a broad range of benefits, our focus here will be how this impacts those who have kidney disease (KD) or kidney transplant.
Defining Pharmacogenomics
DNA is made up a sequence of four nucleotides, (adenine, cytosine, guanine, thymine). The genetic sequence serves as a template which our cells use it to make thousands of proteins which are essential for carrying out all biological functions that maintain life. This includes the enzymes, receptors, and channels that are involved in the absorption, transport, and metabolism of drugs.
Alterations in the sequence, like single nucleotide polymorphisms (SNPs), or errors in the original code, may affect the efficiency of protein production. In turn, this may alter the efficacy or toxicity of a medication for an individual with that SNP.
When scientists began exploring pharmacogenetics in the 1950’s, clinical research focused on connecting single genetic variations with a predictable outcome in drug therapy. In the last decade and a half, it has lead to an evolution of pharmacogenomics, exploring the complex interplay of genetic and environmental influences on individual genetic expression.
Aside from being a relatively new area of focus, this nuanced difference is what makes “omics”research more challenging to translate into clinical application. Even though we’re only at the tip of the proverbial iceberg of this revolutionary approach to individualized medicine, useful clinical implications are already emerging, in particular when it comes to medications often used in kidney patients.
Pharmacogenomics of kidney disease management
To date, there are approximately 300+ medications with FDA-approved PGx labeling recommendations. Of these, a handful are common in kidney disease patients. These categories include*:
- Cardiovascular Disease (CVD) – including clopidogrel (CYP2C19), simvastatin (SLOCO1B1) among other HMG-COA inhibitors, also known as “statins,” and warfarin (multiple, including CYP2C9, CYP4F2, VOKORC1, and potentially APOE, ABCB1, and UGT1A1)
- Transplant medications – including azathioprine (TPMT), tacrolimus (CYP3A4/3A5), and the antifungal agent voriconazole (CYP2C19)
- Hyperuricemia (elevated circulating uric acid) – allopurinol (HLA-B)
- Diabetes, with metformin being the most well-known (SNP rs11212617).
| Therapeutic Category | Drug | Genetic SNP |
| Cardiovascular Disease (CVD) | Clopidogrel | CYP2C19 |
| HMG-CoA inhibitors (statins) | SLOCO1B1 | |
| Warfarin | CYP2C9, CYP4F2, VOKORC1, and potentially APOE, ABCB1, and UGT1A1 | |
| Transplant medications | Azathioprine | TPMT |
| Tacrolimus | CYP3A4/3A5 | |
| voriconazole (antifungal agent) | CYP2C19 | |
| Hyperuricemia (elevated circulating urea) | Allopurinol | HLA-B*58:01 |
| Diabetes | Metformin | SNP rs11212617 |
* This is a list narrowed down limited to strength of available evidence and relevance to KD by Adams et al.
The need for individualized therapy in kidney patients through pharmacogenomics
Even when dosing is in line with best practice guidelines, they may still be sub-optimal or nephrotoxic (toxic to the kidney). Either situation for a transplant or KD patient may be life-threatening. Knowing in advance how a patient will respond to a therapy means avoiding the cycle of “guess, assess and adjust,” saving valuable time.
Let’s use the medication tacrolimus as an example. Tacrolimus is a very widely used and preferred immunosuppressant medication used in patients after a kidney transplant. Monitoring is very important because there’s a small margin of error for dosing. Due to this narrow therapeutic window, a little too much of the drug can quickly result in toxicity, while slightly under-dosing will be ineffective and potentially cause transplant rejection. Either situation can be life-threatening for a transplant patient.
Tacrolimus is metabolized by enzymes (part of the cytochrome P450 class) referred to as CYP3A4 and CYP3A5. It’s understood that individuals considered “hyper-metabolizers” – enzymes work faster than average to metabolize (break down) the drug – require higher dosing to achieve therapeutic efficacy. Meanwhile, slow metabolizers require smaller doses to maintain safe and effective therapeutic levels. Because of the narrow therapeutic window, there is a small margin for accuracy, making these variations in metabolic functions particularly relevant to safety and outcome.
It’s interesting to note that there are various factors that influence CYP3A4/3A5 rate of metabolism. Use of other common medications like acetaminophen, clarithromycin, SSRI antidepressants (like fluoxetine and sertraline), and even caffeine, cannabis, and phytonutrient compounds naturally found in foods and herbs can also serve to up or downregulate the function of CYP3A4/3A5– further confounding or contributing to successfully achieving the narrow therapeutic window.
Another interesting example if the case of a transporter gene SLCO1B1 and its effect on statin therapy. This anti-cholesterol medication class (which includes simvastatin, rosuvastatin, pravastatin, etc) is well known for an ADR which causes muscle breakdown, rhabdomyolysis. Risk increases with increased blood concentration or dosage. Furthermore, muscle breakdown can add stress on the kidney.
SLOCO1B1 is responsible for transporting the drug out of the blood and into the liver for detoxification. In individuals with genetic variations that reduce the function of the transporter, accumulations are more likely to occur, and rhabdomyolysis is more likely even at lower drug dosage than typically expected. Combine this with environmental factors or combination drug therapy that may further slow detoxification, liver function, or drug clearance, and you can start to see how multiple factors may contribute to presentations of this ADR.
Should you get genetic testing?
There are a multitude of consumer tests offering direct to consumer genomic and health data like 23andMe, among others. The health reports are limited, and may omit some crucial lifestyle and epigenetic factors, but can be a good starting point. Raw SNP data can be obtained, but interpretation requires a strong understanding of clinical significance so working directly with a healthcare professional with appropriate training is strongly recommended.
There are also professional tests and reports available through your health care provider like IntellexxDNA and MyDNA. Your PGx-literate provider can help you choose the appropriate test, and most importantly guide you in recommendations once you have your results in hand.
It’s essential to remember that the field of PGx is relatively young and complex. When we talk about genetics, we cannot ignore the significance of epigenetics. In a previous blog, we discussed how dietary and lifestyle modifications can affect expressions of these genetic traits.
Another related emerging field is nutrigenomics– a cousin to PGx – focusing on the effect of nutrients on genetic expression. When interpreting emerging findings in omics, clinicians must take into consideration the effect of factors like nutrition, herbal use, as well as environmental toxins, and medication on epigenetics expression. The individualized and integrative approach to managing kidney disease will rely on the nephrologists, pharmacists, and clinical nutritionists of the not-so-distant future working together to layer those factors to maximize therapeutic benefit and reduce harm to patients.
