Therapeutic drug use in animals with chronic kidney disease

Introduction

Chronic kidney disease (CKD) represents a significant health challenge in veterinary medicine, affecting a substantial portion of the aging canine and feline populations. One of the primary functions of the kidney is to eliminate metabolic wastes, achieved through passive glomerular filtration and active tubular secretion. As CKD advances, renal function diminishes, resulting in an accumulation of these waste products. Those that have negative physiologic effects are called uremic toxins. Due to the decrease in renal function and the accumulation of these toxins, the majority of the body’s organ systems can be negatively impacted, and most CKD patients require polypharmacy to help mitigate their uremic signs. To complicate matters, the same reduction in kidney function and the effects of accumulated uremic toxins can influence how drugs are absorbed, distributed, metabolized, and eliminated from the body; this is collectively known as pharmacokinetics (PK) (1,2). The altered PK profile in patients with CKD creates challenges for veterinarians to achieve desired therapeutic outcomes while simultaneously minimizing the risk of adverse drug reactions (Figure 1) – but the PK of many drugs in an animal with kidney disease is often unknown. This creates significant difficulty in determining the optimal dosing protocol, and for some drugs it may be best to choose an alternative that has a higher margin of safety; when an acceptable substitute is unavailable, cautious dosing and administration may help increase patient safety.

Figure 1. Most CKD patients will require multiple drug therapies, either to help treat their renal condition and/or because of co-morbidities; however, care must be taken, as many therapeutic drugs can have unwanted side effects.
© Shutterstock

 

Altered drug pharmacokinetics in CKD

Chronic kidney disease may result in significant changes to all aspects of drug PK, namely absorption, distribution, metabolism and elimination. These alterations can lead to unintended drug accumulation within the patient, thereby increasing the risk of adverse effects or therapeutic failure.

Impact on drug absorption

The oral bioavailability of medications can be significantly compromised in CKD patients. Gastrointestinal (GI) disturbances, such as nausea, vomiting and intestinal edema, are common clinical signs associated with uremia, and can directly impede the absorption of orally administered drugs. Uremia may lead to altered activity of drug transporters within the GI tract, resulting in either increased or decreased drug absorption.

Medications commonly prescribed for CKD, such as enteric phosphate binders (e.g., calcium carbonate, aluminum hydroxide, sevelamer), may physically bind to other orally administered drugs, including furosemide and cyclosporine. This binding prevents the absorption of the co-administered drug, thereby reducing its systemic availability.

Impact on drug distribution

Drug distribution, characterized by the volume of distribution (Vd), can be significantly altered in CKD patients. Dehydration, commonly observed in these cases, can decrease the Vd of hydrophilic drugs, resulting in higher plasma drug concentrations. Edematous states, a consequence of iatrogenic hypervolemia and the nephrotic syndrome, may increase the Vd for hydrophilic drugs, effectively diluting the drug and potentially leading to lower plasma drug concentrations. Lipophilic drugs will be less affected by changes in hydration; however, such drugs may have higher plasma concentrations in patients with CKD and low-fat stores.

Most drugs are distributed throughout the body by being bound to proteins, most commonly albumin, and in their free (unbound) state. Uremic toxins can interfere with the binding of drugs to plasma proteins like albumin and alpha-1 acid glycoprotein. This interference leads to a higher free fraction of the drug in circulation. As only the unbound drug is pharmacologically active and available for metabolism and elimination, altered protein binding can impact drug efficacy and toxicity. Drugs with a low magnitude of protein binding will be less affected by uremic toxins and may have more predictable plasma drug concentrations.

Impact on drug metabolism

Kidney disease can impair drug metabolism, primarily by affecting the activity of cytochrome P450 (CYP450) enzymes. These enzymes are predominantly located in the liver and are crucial for the biotransformation (activation or inactivation) of many drugs. Reduced CYP450 activity in CKD can lead to prolonged drug half-lives and the accumulation of parent drugs. It may also result in decreased production of active metabolites.

In some instances, hepatic metabolism may be upregulated as a compensatory mechanism to increase drug clearance. However, this compensatory process is inconsistent and difficult to predict, introducing another layer of variability to drug pharmacokinetics in CKD patients. Whilst this upregulation could potentially mitigate drug accumulation, its unpredictable nature introduces significant variability in drug clearance. This makes standardized dosing challenging, and increases the risk of both subtherapeutic levels and toxicity. 

Impact on drug elimination

Drugs are renally eliminated through passive glomerular filtration, active tubular secretion, or both. For drugs whose main mechanism of elimination is via filtration, the rate of drug elimination significantly declines as the glomerular filtration rate (GFR) decreases, leading to a prolonged plasma elimination half-life (t½) and potentially increased plasma drug concentration and cumulative drug exposure.

A decrease in drug filtration not only causes an increase in plasma drug concentration, it will simultaneously also result in reduced concentration of the drug in urine. This is particularly problematic for treating urinary tract infections (UTIs), as bacteria within the urinary system may not be exposed to sufficiently high drug levels to achieve antimicrobial effects, thereby increasing the risk of treatment failure and antimicrobial resistance. This presents a significant therapeutic paradox: a veterinarian might reduce the systemic dose to prevent toxicity, but this could further diminish urine concentration, potentially leading to treatment failure and antimicrobial resistance for UTIs. 

Clinical consequences of pharmacokinetic alterations

The alterations in drug PK in CKD patients therefore challenge the ability to predict plasma and urine drug concentrations. The most adverse outcome is the accumulation of drugs to toxic levels, particularly for those with a narrow therapeutic index. Conversely, reduced drug elimination can lead to drug concentrations in the urine that are below the effective therapeutic range, resulting in treatment failure. This unpredictability of altered PK, with the paradox of systemic toxicity versus local subtherapeutic levels, suggests the need for an individualized therapeutic approach, and requires the clinician to move beyond static dosing guidelines to incorporate real-time patient monitoring and adaptive strategies. Adjusting the dosage or administration frequency of a drug might help reduce the chance for toxicity, but does not guarantee adequate drug concentrations within urine, so there is no “one-size-fits-all” solution for pharmacotherapy in CKD. Veterinarians must carefully weigh a specific drug’s properties, the patient’s kidney function (typically through IRIS staging), comorbidities, and the drug’s target site of action. 

What drugs require cautious use or dosage adjustment?

The general rule is that a comprehensive evaluation of every medication administered to a patient with renal disease must assess the drug's potential nephrotoxicity and its margin of safety. Drugs with a narrow therapeutic index, where the difference between an effective dose and a toxic dose is minimal, pose a significantly higher risk for complications in patients with CKD, as the PK is unpredictable. Furthermore, drugs that are predominantly eliminated by the kidneys may exhibit a prolonged elimination half-life when GFR is reduced, leading to increased plasma concentrations unless the dose or frequency is appropriately adjusted. Medications with potential nephrotoxic effects should be avoided whenever possible in CKD patients, as they can exacerbate renal injury. Similarly, drugs that do not cause nephrotoxicity but may affect kidney function, such as angiotensin converting enzyme (ACE) inhibitors, should be used cautiously in CKD. A variety of drug classes require cautious use or dosage adjustment in dogs and cats with CKD due to their PK profiles and potential for adverse effects, and some examples are given below, with a summary in Tables 1 and 2.

Table 1a. Recommendations for antibiotic usage in CKD patients.

 

Table 1b. Recommendations for antifungal usage in CKD patients.

Table 2. Recommendations for some drugs requiring cautious use or dosage adjustment in CKD patients.

Antibiotics

Aminoglycosides (e.g., gentamicin, amikacin) antibiotics are highly nephrotoxic, being primarily eliminated by the kidneys. Reduced GFR leads to a prolonged half-life and an increased risk of systemic toxicity, including nephrotoxicity and ototoxicity. Therapeutic drug monitoring (TDM) of these drugs is essential in patients with moderate renal impairment, and they should be avoided if an alternative is available. Beta-lactams (e.g., ampicillin, cephalosporins) are generally considered to have a larger margin of safety, but reduced renal function prolongs the elimination half-life, resulting in increased serum drug concentrations and decreased urine concentration (3). Fluoroquinolones (e.g., enrofloxacin) rely on renal excretion but also undergo hepatic metabolism; studies in dogs and cats with reduced GFR did not show prolonged half-life, and these drugs may be dosed normally (4,5).

Cardiovascular drugs

ACE Inhibitors (e.g., enalapril, benazepril) and Angiotensin Receptor Blockers (ARBs) help manage proteinuria and hypertension, and are expected to produce a reduction in GFR. Benazepril undergoes more hepatic elimination than enalapril, so does not require dose adjustment until the later stages of CKD. Telmisartan, an ARB, does not undergo significant renal elimination, so no adjustment needs to be made with its usage to account for kidney disease; however, the effect of the drug should be considered when selecting a dosage. Atenolol, a beta-blocker, may require dose reduction in more advanced stages of CKD to prevent an excessive response. Spironolactone, a potassium-sparing diuretic primarily eliminated by the kidneys, requires dose reduction with more advanced CKD, and should be avoided if hyperkalemia is present. Furosemide may exhibit decreased clearance, but requires higher dosage to achieve the desired concentration at its site of activity (i.e., the luminal side of the thick ascending loop of Henle). Digoxin is a cardiac glycoside with a narrow therapeutic index, and because it is eliminated by the kidneys, monitoring is essential to ensure therapeutic drug concentrations in patients with CKD. Amlodipine, a calcium channel blocker used to treat hypertension, requires no dose adjustment.

Anti-inflammatory drugs

NSAIDs (Non-steroidal Anti-inflammatory Drugs) have nephrotoxic potential due to their inhibition of prostaglandin synthesis, which is critical for maintaining renal blood flow. They are often safely prescribed in patients with CKD, but low dosages should be initially used and escalated depending on patient comfort and tolerance (6). They should be avoided in dehydrated CKD patients.

Immunosuppressants

The use of mycophenolate can lead to an accumulation of inactive metabolites, causing GI intolerance, so a dose reduction is needed. Cyclosporine and leflunomide do not require any dose adjustment.

Chemotherapeutic agents

If using carboplatin, the dose must be adjusted to prevent drug accumulation, and formulae to guide dosage based upon GFR measurement have been published (7,8). Cisplatin has a high potential for nephrotoxicity and should be avoided in patients with CKD if possible; the dosage should be reduced if another drug is not available. Cyclophosphamide carries a risk for sterile hemorrhagic cystitis and is usually given alongside furosemide to shorten contact with the bladder urothelium; the dose should therefore be reduced with CKD.

Other relevant medications

Famotidine, an H2 blocker, requires dose reduction in CKD. For phenobarbital, both the parent drug and metabolites are renally excreted, so dose reduction may be needed in advanced CKD, and therapeutic drug monitoring should be performed to maintain target serum concentrations. Omeprazole, a proton pump inhibitor, undergoes hepatic elimination, and dose adjustment is not needed in CKD cases.

Careful pharmacotherapy

Safe pharmacotherapy in CKD patients requires a systematic and individualized approach, encompassing comprehensive evaluation, strategic dosing and diligent monitoring. The suggested changes to drug dosing that may be considered for dogs and cats with CKD in Tables 1 and 2 are generally based on human recommendations, unless the PK of a drug has been studied in veterinary patients with kidney disease. The PK aberrations observed in many drugs when administered to CKD patients are difficult to predict and cannot be accounted for by changes in elimination alone, and whilst drug elimination may correlate to some degree with an animal’s GFR, other aspects of PK are more challenging to measure. 

Adjustments to a drug dosage or dosing frequency for CKD cases is often based on the human situation, which in turn relies heavily on GFR assessment. However, direct measurement of GFR in animals (using methods such as iohexol clearance, creatinine clearance, or inulin clearance) is rare. Instead, surrogate markers such as serum creatinine (sCr), urea nitrogen, and symmetric dimethylarginine (SDMA) are often used, but these markers have inherent limitations in accuracy, and predicting GFR reliably from them is imprecise. That said, rough extrapolations from human GFR and the corresponding sCr concentration suggests the International Renal Interest Society (IRIS) CKD staging scheme provides a practical framework that may serve as a reasonable starting point for guiding drug dosing in animals (Box 1). The clinician should bear in mind that this approach does not consider any possible effects of CKD on drug absorption distribution, or metabolism, and reliance on such imprecise surrogate markers, and human-derived GFR correlations for veterinary dosing, introduces a significant margin of error, effectively transforming renal dosing from a precise calculation into an informed estimation. This underscores the critical need for vigilant clinical monitoring, and clinicians must approach dosing with caution, recognizing that the calculated dose is a starting point, not a definitive answer. The clinician must weigh the risks of failing to reach therapeutic drug concentrations if dosage modification is unnecessary, as well as considering the possibility that therapeutic concentrations may be exceeded if dosage modification is not performed. Whenever possible, therapeutic drug monitoring should be performed to confirm the dosing strategy meets the target plasma drug concentration.

Box 1. GFR and its relation to IRIS CKD staging.

Therapeutic drug monitoring (TDM)

TDM plays a vital role in managing drugs with significant toxicity risks or pharmacokinetic variability, particularly those with a narrow therapeutic index. It allows for the determination of whether a dosing schedule produces plasma drug concentrations within a target therapeutic range, and helps identify sub-therapeutic or toxic concentrations. TDM is particularly useful for anticonvulsants (e.g., phenobarbital, bromide, levetiracetam, zonisamide), some antimicrobials (e.g., aminoglycosides, vancomycin and azoles), immunosuppressants (e.g. cyclosporine, mycophenolate and leflunomide), and some others, such as digoxin and theophylline. Unfortunately, TDM is not available for all drugs that may require adjustment in patients with kidney disease, and there is often a prolonged test turnaround time, so there are limitations to its utility. However, the need for ongoing monitoring, whether that be via TDM or other options, cannot be over-emphasized, as it allows for timely adjustments to the dynamic clinical picture of CKD. Discussions with clients may help improve compliance, highlighting the need to monitor their animal for signs of improvement or adverse reactions, and owners must aways be educated as to when certain medications (e.g., ACE inhibitors, ARBs, NSAIDs) should be stopped if their pet appears to be unwell (Figure 2).

Figure 2. Owners must aways be advised if certain medications prescribed for their pet with CKD should be stopped if the animal appears to be unwell.
© Shutterstock

 

Future directions

Despite advancements in veterinary nephrology, significant limitations in PK data for renally impaired patients persist, necessitating continued research and development. Human drug dosing guidelines, often based on estimated GFR, cannot currently be directly applied to veterinary patients, as validated formulas for GFR estimation based on surrogate markers have not been established for dogs and cats. Furthermore, most drugs lack specific PK evaluation in animals with kidney disease. This scarcity of species-specific PK data makes it challenging to design appropriate evidence-based drug schedules in animals with CKD. Kidney disease also results in PK derangements beyond just reduced GFR and altered drug elimination, affecting absorption, distribution, and metabolism, which further complicates dosing strategies. 

Conclusion

Managing pharmacotherapy in dogs and cats with chronic kidney disease is a complex and nuanced endeavor, influenced by the disease’s systemic impact on drug PK. The altered absorption, distribution, metabolism, and, most notably, elimination, necessitate a cautious and individualized approach to drug selection and dosing. While significant limitations persist in species-specific PK data, general principles remain the cornerstone of safe prescribing. These include a proactive evaluation of every medication for its nephrotoxicity potential and elimination profile, prioritizing safer alternatives, and judiciously adjusting doses, often guided by IRIS CKD staging. Therapeutic drug monitoring, despite its practical limitations, serves as an invaluable tool to bridge the gap between theoretical dosing and real-world patient responses, allowing for individualized therapy.

References

1. Lea-Henry TN, Carland JE, Stocker SL, et al. Clinical pharmacokinetics in kidney disease: fundamental principles. Clin. J. Am. Soc. Nephrol. 2018;13:1085-1095. Doi: 10.2215/cjn.00340118
2. Roberts DM, Sevastos J, Carland JE, et al. Clinical pharmacokinetics in kidney disease application to rational design of dosing regimens. Clin. J. Am. Soc. Nephrol. 2018;13:1254-1263. CJN.05150418. Doi: 10.2215/cjn.05150418
3. Benson KK, Quimby JM, Dowers KL, et al. Pilot study of side effects and serum and urine concentrations of amoxicillin–clavulanic acid in azotemic and non-azotemic cats. J. Feline Med. Surg. 2020;22:729-735. Doi: 10.1177/1098612x19881537
4. Lefebvre HP, Schneider M, Dupouy V, et al. Effect of experimental renal impairment on disposition of marbofloxacin and its metabolites in the dog. J. Vet. Pharmacol. Ther. 1998;21:453-461. Doi: 10.1046/j.1365-2885.1998.00174.x
5. Foster JD, Abouraya M, Papich MG, et al. Population pharmacokinetic analysis of enrofloxacin and its active metabolite ciprofloxacin after intravenous injection to cats with reduced kidney function. J. Vet. Intern. Med. 2023;37:2230-2240. Doi: 10.1111/jvim.16866
6. KuKanich K, George C, Roush JK, et al. Effects of low-dose meloxicam in cats with chronic kidney disease. J. Feline Med. Surg. 2021;23:138-148. Doi: 10.1177/1098612x20935750
7. Bailey DB, Rassnick KM, Prey JD, et al. Evaluation of serum iohexol clearance for use in predicting carboplatin clearance in cats. Am. J. Vet. Res. 2009;70:1135-1140. Doi: 10.2460/ajvr.70.9.1135
8. Bailey DB, Rassnick KM, Dykes NL, et al. Phase I evaluation of carboplatin by use of a dosing strategy based on a targeted area under the platinum concentration-versus-time curve and individual glomerular filtration rate in cats with tumors. Am. J. Vet. Res. 2009;70:770-776. Doi: 10.2460/ajvr.70.6.770