Continuing Education Activity

Numerous drugs used to manage and treat multiple diseases, including hypertension, diabetes, and other pathologies, are nephrotoxic. These agents are in various classes and categories of medication. This activity reviews the indications, action, and contraindications for nephrotoxic drugs as a valuable agent in choosing key treatment strategies. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, monitoring, relevant interactions) pertinent for healthcare team members in the care of patients with renal pathologies and related conditions.

Objectives:

• Describe the most common drug classes that can contribute to an increased incidence of renal damage.
• Identify the main drugs that are more likely to be nephrotoxic and how clinicians should proceed with treatment.
• Outline some renal pathologies that can become a result of nephrotoxic drug administration.
• Review the importance of care coordination amongst the interprofessional team to improve outcomes for patients with renal disease.

Indications

Reports of acute and chronic kidney diseases are increasing in the U.S. and various parts of the world. When looking for a critical metric to understand when not to treat using a nephrotoxic medication, the standard is set at an eGFR less than 60 mL/min per 1.73 m^2.

Nephrotoxic medications can elicit damage to the kidney via various mechanisms, including alteration in its structure and function. When evaluating the primary etiologies in renal injury, the incidence of drug-induced toxicity has accounted for 20% of all-cause incidents. Besides, when nephrotoxicity from pharmacologic agents is further examined, evidence has shown it to be one of the chief etiologies in intrinsic renal failure aside from the second most common cause, infection.[1] Numerous drugs go under the category of nephrotoxic medications. Tables 1 through 3 list the most common drugs that can damage the kidneys and their drug class.

The more significant percentage of individuals affected by these agents come from the over 70-year-old category. With the aging life expectancy in the United States, we need to choose pharmacologically appropriate agents for our aging population with declining renal functions.

Mechanism of Action

Drugs such as those listed previously elicit damage to renal tissue via numerous mechanisms. A few of these mechanisms include impairment of perfusion, inflammation induction, free radicals formation, and many other mechanisms.[2][3] A few of the most common mechanisms of action appear below:

GFR Alteration

• A few examples include the effect of ACE inhibitors, ARBs, cyclosporins, NSAIDs, and tacrolimus that affect the intraglomerular hemodynamics via the alteration of the glomerular filtration rate.[4]

Tubular Cell Toxicity

• The presence of certain pharmaceutical agents may damage the cells of the proximal tubules via free radical formation, mitochondrial damage, and transport systems damage. These agents include aminoglycosides, amphotericin B, adefovir, cisplatin, and foscarnet.[5]

Interstitial Nephritis

• NSAIDs and rifampin are common causes of acute interstitial tissue inflammation. Chronic forms result from agents, including analgesics, anticancer drugs, lithium, and calcineurin inhibitors.[6]

Crystal Nephropathy

• Antivirals such as acyclovir and antibiotics such as ampicillin have been common etiologies of insoluble crystal formation within renal tissue.[7]
• A more detailed list is present in tables 1-3.

Administration

The majority of the drugs described are oral formulations, with a few minor ones available in other dosage forms.

Adverse Effects

As adverse reactions are the main subject, the full list of renal damage locations appears in tables 1 and 2. The primary sites include the glomerulus and proximal and distal convoluted renal tubules.

Contraindications

Contraindications to drug administration include the presence of chronic renal disease or end-stage renal disease.[8] As previously mentioned, the presence of a GFR below 60 ml/min per 1.73 m^2 for the definition of moderate chronic renal disease and a creatinine clearance below 30 mL/min as seen in severe chronic kidney disease are critical metrics for treatment judgment. 

Monitoring

General guidelines recommend determining baseline renal function before and after initiation of nephrotoxic pharmaceutical agents. The most common formula used in the calculation of glomerular filtration rate is the Schwartz formula. Calculation of GFR (mL/min/1.73 m^2= length (cm) X potassium /serum creatinine (mg/dL). To use clinician judgment in determining whether to withdraw a nephrotoxic agent, we aim to keep the GFR above the chronic kidney disease threshold of 60.[2]

Also, many biomarkers have become available to assess renal toxicity further. A few of these are as follows:

Urine Proteins and Enzymatic activity

• Alanine aminopeptidase, alpha-glutathione-S-transferase, γ-glutamyl transpeptidase, alkaline phosphatase, N-acetyl-D-glucosaminidase, and π-glutathione-S-transferase 18294749.

Proteinuria

• An increase in the amount of high or low molecular proteins in urine testing is another key diagnostic tool. Typically high and low molecular weight proteins get reabsorbed before being released into the proximal convoluted tubule of the nephron. High molecular weight proteins that signal renal damage include albumin, transferrin, and immunoglobulin G. Low molecular proteins diagnostic for renal damage include a1-microglobulin, B2-microglobulin, cystatin-C, and retinol-binding protein.[9]

Kidney injury Molecule 1

• KIM1 is a type 1 glycoprotein rapidly detected in urine upon damage to tissue that allows for the measurement of proximal renal tubule damage. Greater sensitivity than traditional methods of measuring renal damage such as BUN, Creatinine, and the presence of proteinuria.[5][10]

Neutrophil Gelatinase-associated Lipocalin

• NGAL is synthesized during granulocyte maturation and as a byproduct of tissue inflammation and damage, especially in the proximal renal tubule. Acute kidney injury can be measured and diagnosed earlier with this biomarker. Caution is necessary as NGAL also elevates general inflammatory and infectious processes.

Type 4 Collagen

• Type 4 collagen is present in the basement membrane of the glomerulus. The presence of type 4 collagen in the urine may serve as a critical marker in glomerular membrane damage.[11]

Osteopontin

• Osteopontin is a bone phosphoprotein present in the bone that is useful in measuring damage from certain nephrotoxic drugs. A few of these drugs include cisplatin, angiotensin-2 receptor blockers, cyclosporin, gentamicin, and puromycin.[12]

Clusterin

• Clusterin is a glycoprotein used to measure proximal and distal convoluted tubule damage via presence in the urine.

Preventative measures aimed at decreasing the incidence of significant nephrotoxic effects include oral administration, low effective doses, and short therapy. Furthermore, the dose can be reduced or discontinued in the setting of toxicity.[13]

Toxicity

In the event that there is a significant nephrotoxic event that is changing the GFR, isotonic repletion can be provided to help dilute serum drug concentrations during therapy.[2] Infants and young children are also a chief demographic in drug-induced nephrotoxicity. Toxicity can present with many different types of renal pathology:

• Acute and chronic interstitial nephritis
• Proximal renal tubular acidosis
• Acute and chronic tubular necrosis
• Glomerulonephritis 
• Crystal nephropathy
• Nephrotic syndrome
• Rhabdomyolysis 

Understanding the different regions of renal damage may allow for a more targeted approach to renal injury, including the development of pharmaceutical agents with greater benefit and decreased toxicity.[14][15]

Enhancing Healthcare Team Outcomes

Understanding nephrotoxic pharmaceutical agents is a key component of the interprofessional healthcare team and a patient-centered approach. Starting with the clinicians who prescribe the drugs to the pharmacists who dispense the drug and the nurses who administer the drugs, there is a chain of transport where many healthcare providers are a part of patient care. Knowing the toxic effects, these agents may significantly impact the quality of care a patient receives. The nurse should be aware of which drugs are nephrotoxic, especially with patients that already have renal impairment. They can counsel the patients regarding these agents and report any issues back to the prescriber. The pharmacist can reinforce this counsel while also performing total medication reconciliation, checking doses (especially those that require renal adjustment), and contacting the clinician if there are any issues. These types of interprofessional collaborations will prevent renal toxicity from occurring when it need not. [Level 5]

Furthermore, through the understanding of preventative measures and thresholds for toxicity, healthcare providers may enhance patient safety. Lastly, with the development of numerous biomarkers targeting types of renal damage, response to treatment can be monitored when knowledge of the potential renal effects of medication is known. [Level 1] [14][16]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

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2.

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Schetz M, Dasta J, Goldstein S, Golper T. Drug-induced acute kidney injury. Curr Opin Crit Care. 2005 Dec;11(6):555-65. [PubMed: 16292059]

4.

Perazella MA. Drug-induced nephropathy: an update. Expert Opin Drug Saf. 2005 Jul;4(4):689-706. [PubMed: 16011448]

5.

Markowitz GS, Fine PL, Stack JI, Kunis CL, Radhakrishnan J, Palecki W, Park J, Nasr SH, Hoh S, Siegel DS, D'Agati VD. Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int. 2003 Jul;64(1):281-9. [PubMed: 12787420]

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Markowitz GS, Perazella MA. Drug-induced renal failure: a focus on tubulointerstitial disease. Clin Chim Acta. 2005 Jan;351(1-2):31-47. [PubMed: 15563870]

8.

Ingrasciotta Y, Sultana J, Giorgianni F, Caputi AP, Arcoraci V, Tari DU, Linguiti C, Perrotta M, Nucita A, Pellegrini F, Fontana A, Cavagna L, Santoro D, Trifirò G. The burden of nephrotoxic drug prescriptions in patients with chronic kidney disease: a retrospective population-based study in Southern Italy. PLoS One. 2014;9(2):e89072. [PMC free article: PMC3928406] [PubMed: 24558471]

9.

Ferguson MA, Vaidya VS, Bonventre JV. Biomarkers of nephrotoxic acute kidney injury. Toxicology. 2008 Mar 20;245(3):182-93. [PMC free article: PMC4038970] [PubMed: 18294749]

10.

Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol. 2008;48:463-93. [PMC free article: PMC2742480] [PubMed: 17937594]

11.

Nerlich AG, Schleicher ED, Wiest I, Specks U, Timpl R. Immunohistochemical localization of collagen VI in diabetic glomeruli. Kidney Int. 1994 Jun;45(6):1648-56. [PubMed: 7933812]

12.

Alchi B, Nishi S, Kondo D, Kaneko Y, Matsuki A, Imai N, Ueno M, Iguchi S, Sakatsume M, Narita I, Yamamoto T, Gejyo F. Osteopontin expression in acute renal allograft rejection. Kidney Int. 2005 Mar;67(3):886-96. [PubMed: 15698428]

13.

Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve Clin J Med. 2002 Apr;69(4):289-90, 293-4, 296-7 passim. [PubMed: 11996200]

14.

Kim SY, Moon A. Drug-induced nephrotoxicity and its biomarkers. Biomol Ther (Seoul). 2012 May;20(3):268-72. [PMC free article: PMC3794522] [PubMed: 24130922]

15.

Choudhury D, Ahmed Z. Drug-associated renal dysfunction and injury. Nat Clin Pract Nephrol. 2006 Feb;2(2):80-91. [PubMed: 16932399]

16.

Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Next-generation biomarkers for detecting kidney toxicity. Nat Biotechnol. 2010 May;28(5):436-40. [PMC free article: PMC3033582] [PubMed: 20458311]

Disclosure: Janak Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Amit Sapra declares no relevant financial relationships with ineligible companies.