Kidney Dysfunction

Overview: 

Analgesic prescribing for patients with kidney disease must consider that: (1) some analgesic medications, so called nephrotoxic drugs, can cause kidney injury or worsen kidney function; (2) kidney dysfunction may impair drug elimination, causing or augmenting adverse effects. 


Because many of the same considerations apply to patients with acute kidney injury and chronic kidney disease, including those on dialysis, we refer to these entities broadly as “kidney dysfunction” throughout the module. In this this module, our objectives are to:

  • Identify analgesics that require special consideration in people with kidney dysfunction, either due to nephrotoxicity or impaired elimination
  • Identify alternative analgesics that are safer to use in kidney dysfunction
  • Provide recommendations on safer prescribing practices for patients with kidney dysfunction

The first step to kidney-safe prescribing is evaluating a patient’s current and baseline kidney function. Kidney function is usually assessed using serum creatinine, which can be used along with a patient’s age and sex to estimate the kidney’s filtration ability through the estimated Glomerular Filtration Rate (eGFR; in mL/min/1.72m^2).

The most recent guidelines for kidney function estimation recommend the use of the race-free 2021 CKD-EPI estimating equations (Delgado C et al, Journal of the American Society of Nephrology, 2021). In Apex, “eGFRcr”  was implemented March 30, 2022 and refers to the race-free estimating equation. Older estimates available in Apex use the CKD-EPI 2012 equation; the “eGFR high estimate” generally applies to younger and/or more muscular patients, “eGFR low estimate” applies to older patients and those with lower muscle mass. Importantly, eGFR equations assume that creatinine is at steady state--this is not the case during acute kidney injury (AKI) when creatinine rises and falls. In addition, clinicians must interpret any given creatinine value in the context of that patient’s baseline, as severe AKI can occur with values in the laboratory reference range. Measurement of cystatin C to guide eGFR estimation should be considered in older patients and those with lower muscle mass as well. Chronic kidney disease (CKD) is most commonly defined by eGFR < 90 and/or persistent proteinuria/albuminuria. Patients with end-stage renal disease (ESRD) generally require RRT and may be treated with either hemodialysis or peritoneal dialysis. Nephrology and/or pharmacy consultation is recommended to guide drug dosing in the following circumstances: at extremes of muscle mass where eGFR estimates may not be accurate; during AKI when creatinine is rapidly changing; with advanced CKD or ESRD. Drug dose adjustment recommendations (LexiComp) are usually based on creatinine clearance (CrCl), which approximates the eGFR reported in Epic.

Challenges

Potentially nephrotoxic drugs are more likely to cause harm at higher doses, with longer durations of therapy, and/or in combination with other nephrotoxic agents. 

Impaired drug elimination becomes increasingly prominent as kidney function declines and is most challenging for patients on renal replacement therapy (RRT, or dialysis).

Treatment Recommendations

We will first discuss potentially nephrotoxic drugs, followed by agents with adverse effects that worsen in patients with low kidney clearance.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used medications for pain and inflammation, which are available over-the-counter and by prescription. Systemic NSAIDs are usually given orally, and there are IV formulations as well.

  • NSAIDs inhibit cyclooxygenase and thus block the synthesis of vasodilatory prostaglandins necessary for maintaining GFR and providing blood flow to kidney tubules.
    • NSAID use can thus cause transient drops in GFR and tubular ischemia, which if severe or prolonged, can manifest as AKI.
      • NSAIDs are also a relatively common cause of acute interstitial nephritis (AIN), which can cause AKI as well. 
    • In addition to AKI, NSAIDs can cause hypertension, edema/volume overload, and hyperkalemia.
  • Patients with kidney dysfunction are at higher risk for all the NSAID-related adverse effects noted above. 
    • For this reason, NSAID use in patients with CKD (particularly in those with eGFR <30-45) is generally discouraged. However, observational evidence suggests that NSAID use in patients with mild CKD does not incur substantially greater risk than in the general population. 
    • NSAID use in patients with kidney dysfunction should be guided by balance of the risks and benefits in each case. This is particularly true if alternative agents also carry high risks (e.g. opioids).
  • If NSAIDs are to be used, the general rule is to prescribe the lowest effective dose for the shortest possible course, including reducing the frequency of administration if feasible. Per expert opinion, up to 5 days of NSAID therapy may be appropriate in patients with mild to moderate CKD who do not have other risk factors; consider surveillance labs during and after therapy (Baker & Perazella, American Journal of Kidney Disease, 2020). 
    • Ensure euvolemia when initiating therapy and avoid volume depletion during therapy. 
    • Discontinue drugs that may exacerbate NSAID effects, if able (ACE inhibitors, ARBs, tacrolimus, cyclosporine). Iodinated radiocontrast (intravenous or intra-arterial) causes renal vasoconstriction and may also exacerbate NSAID effects.
    • Over-diuresis/volume depletion increases the risk of NSAID-mediated AKI, but some patients are at risk for volume overload due to salt retention in the setting of NSAID use. NPO patients are at increased risk for volume depletion.
  • There is no strong evidence for clinically significant differences in nephrotoxicity between any of the currently available NSAID formulations (Ungprasert, et al. European Journal of Internal Medicine, 2015). Furthermore, celecoxib (a COX-2 selective NSAID) does not appear to be more or less nephrotoxic than non-selective NSAIDs (e.g. ibuprofen, naproxen) with chronic use, as demonstrated in the PRECISION trial (Nissen, et al. New England Journal of Medicine, 2016). 
  • Topical NSAIDs (e.g. diclofenac gel) may be a good alternative to systemic NSAIDs in patients who are at risk of NSAID toxicity.
    • Topical NSAIDs reach therapeutic concentrations locally in soft tissue, but serum concentrations are a small fraction (0.4-2.2%) of the concentration expected with an oral formulation. This avoids nephrotoxicity and minimizes the likelihood of drug interactions (McPherson & Cimino, Pain Medicine, 2013). 
    • Topical NSAIDs may be particularly useful for musculoskeletal pain as in osteoarthritis.

 

Opioid pharmacodynamics/pharmacokinetics are altered in patients with kidney dysfunction, especially those with renally-cleared active metabolites. 

  • In patients with CKD and ESRD, opioid use is relatively common and associated with increased risk of poor outcomes, including fractures, hospitalization, and death (Lambourg E, et al, British Journal of Anaesthesia, 2022).
  • Within the opioid drug class, some agents may be preferred in kidney dysfunction due to having fewer active metabolites that can accumulate in kidney dysfunction (Roy P, et al, Current Opinion in Nephrology and Hypertension, 2020). When these metabolites accumulate, they can cause altered mental status and sedation as well as neuroexcitation and seizures.
    • In order of most acceptable to least acceptable for use in kidney dysfunction: dilaudid = fentanyl > oxycodone > morphine. Morphine should generally be avoided in patients with kidney dysfunction, especially those on dialysis.
  • Methadone and buprenorphine are safer for use in kidney dysfunction, including patients on dialysis.
  • Individualized risk vs. benefit should guide decision-making. Special considerations include use in end-of-life care or concurrent substance abuse/addiction disorders.

 

Neuropathic agents & centrally-acting muscle relaxants

  • Gabapentin and pregabalin are frequently prescribed for neuropathic pain or as adjunctive agents with other analgesics. Lower doses and reduced frequencies are necessary in kidney dysfunction, due to impaired clearance. Accumulation of gabapentin or pregabalin causes sedation, obtundation, and myoclonus.
  • Baclofen is contraindicated in patients with ESRD on dialysis and should be used with caution in patients with CKD and significant kidney dysfunction. Impaired renal clearance of baclofen results in systemic adverse effects including sedation/obtundation, confusion, and hypotension.

 

There are several analgesics and adjunctives for which renal function is less relevant: ketamine, topical lidocaine, carbamazepine, and tricyclic antidepressants.

 

Acetaminophen (APAP) is widely accepted as a safe analgesic for patients with all stages of kidney dysfunction. Usual dosing guidelines, including maximum daily dose, apply to patients with kidney dysfunction. 

  • However, kidney injury has been observed in APAP overdose, and some have speculated nephrotoxicity with chronic, high-dose use though data are conflicting. 
  • APAP is unlikely to substantially exacerbate hypertension and edema, commonly seen in patients with kidney dysfunction. 
  • Severe gap metabolic acidosis may occur with APAP use (due to accumulation of its metabolites, pyroglutamic acid/5-oxoproline), typically in patients with concurrent liver disease or malnutrition and with chronic use.

Special Considerations

Patients with kidney dysfunction are at higher risk for nephrotoxicity (e.g. AKI/progressive CKD from NSAIDs) and for adverse effects from impaired elimination of renally-metabolized medications (e.g. oversedation from baclofen or morphine). 

CKD can be diagnosed by eGFR or persistent proteinuria, so both parameters should be considered when evaluating kidney function. Some patients may have normal creatinine and preserved eGFR but also have proteinuria and increased risk of nephrotoxicity. For example, this pattern is common in patients with early diabetic kidney disease.

References: 

UpToDate Lexicomp® Drug Interactions & recommendations for renal dosing.

 Delgado C et al, “A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.” Journal of the American Society of Nephrology, 2021; 32:2994-3015.

Davison S. “Clinical Pharmacology Considerations in Pain Management in Patients with Advanced Kidney Failure.” CJASN, 2019; 14: 917-931.

Davison S & Rathwell S. “Safe and Effective Management of Pain in People with CKD.” CJASN. 2019; 14(11): 1551-1553.

Roy P, et al. “Pain management in patients with chronic kidney disease and end-stage kidney disease.” Current Opinion in Nephrology and Hypertension. 2020; 29; 671-680.

Baker M. & Perazella M.A. “NSAIDs in CKD: Are They Safe?” American Journal of Kidney Disease, 2020; 76(4): 546-557.

Sriperumbuduri S & Hiremath S. “The case for cautious consumption: NSAIDs in chronic kidney disease.” Current Opinions in Nephrology and Hypertension. 2019; 28:163-170.

Ungprasert P, et al. “Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies.” European Journal of Internal Medicine, 2015: 26: 285-291.

McPherson ML & Cimino NM. “Topical NSAID Formulations.” Pain Medicine, 2013;14:S35-S39.

Lambourg E, et al. “Analgesic use and associated adverse events in patients with chronic kidney disease: a systematic review and meta-analysis” British Journal of Anaesthesia, 2022;128: 546-61.

Author: 
Anna Malkina
Kathleen D Liu
Jonathan G Amatruda