September 20, 2020
Perazella, Mark A.
Drugs remain a relatively common cause of acute and chronic kidney injury, with the general population being exposed to a large number of prescribed and over-the-counter drugs. This also includes a variety of substances available at different health food stores. Drug-induced nephrotoxicity is more common in hospitalized patients, specifically among intensive care unit patients. A prospective cohort study of Acute Kidney Injury (AKI) cases revealed a 14 to 26 percent drug-induced nephrotoxicity in adults and 16 percent of hospitalized AKI in the pediatric population. Nephrotoxicity is also associated with different imaging agents used for diagnostic and therapeutic purposes.
In a study by Naughton, C. A., it has been shown that the average patient today is older, has more comorbidity, and is more exposed to diagnostic and therapeutic procedures that have potential risk for the kidney. It also mentioned that approximately 20 percent of community and hospital-acquired cases of acute renal injury is caused by drugs. Patients today, as mentioned in the article have higher incidences of diabetes and cardiovascular disease; hence ingestion of multiple medications and more exposure to procedures that are potentially harmful for the kidney.
Nephrotoxicity due to medications, drugs, and other ingested substances is a complicated process that involves a combination of factors, mainly drugs exerting toxic effects by one or more common pathogenic mechanisms. Other factors include the inherent nephrotoxic potential of the drug, underlying patient characteristics that enhance their risk for kidney injury, and the metabolism and excretion of the potential offending agent by the kidney.
Knowledge of the offending drugs and their pathogenic mechanisms of renal injury are crucial to recognizing and preventing drug-induced renal impairment. Development of kidney injury is initiated by exposure to a potentially toxic and offending agent. Most potentially nephrotoxic drugs are utilized in treating various disease processes. These include antimicrobial agents, anticancer drugs, analgesics, and immunosuppressive agents. In addition, new medications with still unknown nephrotoxic potential make it through clinical trials and are consequently utilized in clinical practice where they cause kidney injury.
The main goal of this study is to review and discuss the clinically relevant aspects of drug-induced nephrotoxicity for the clinical nephrologist and for clinical practice in general. It also aims to discuss different pathogenic mechanisms involved in drug-induced toxicity as well as their outcome with possible prevention and intervention.
The general population is exposed to a variety of potentially harmful (to the kidney) substances which includes prescribed therapeutic agents, over-the-counter products, diagnostic agents, and environmental substances. This is in part due to easy access to some of these medications. Exposure to a potentially toxic offending agent is known as an initial step in developing kidney injury. Alternative products which are made available at most health food stores include herbal remedies, natural products and nutritional supplements. The concern with these products is that some of them often contain a number of harmful chemicals and/or contaminants that are not listed in the label.
Drug dose and duration is another important cause of drug induced nephrotoxicity because of the innate kidney toxicity of the drug. High doses and prolonged courses of certain agents will enhance risk for kidney injury (via excessive exposure) even in patient with minimal or no underlying risk. Drugs that are insoluble in the urine may cause acute crystalline nephropathy, enhanced by reduced urinary flow rates, urine pH, excessive drug dosing, and rapid infusion rates. Other drugs are associated with osmotic nephropathy causing lysosomal dysfunction and cell swelling. Combination of nephrotoxic drugs increases risk for kidney injury and over-all drug toxicity. Other factors considered are drug-induced inflammation and cast nephropathy.
Increased risk for medication-induced nephrotoxicity is related to a number of patient-specific factors. Some of which are nonmodifiable, such as older age and female sex due to their decreased lean body mass and reduced total body water that may lead to excess drug dosing. These patients have lower albumin concentration which leads to reduced drug binding and increased free drug concentration that can be nephrotoxic. Other patient factors that increase risk are the genetic makeup of immune response genes (heightened allergic response), drug metabolizing enzymes and transport pathways, comorbid conditions (liver disease, heart disease, and CKD), and acutely developed diseases (intravascular volume depletion, metabolic perturbations, and AKI).
An important contributing factor to drug nephrotoxicity that is also considered is the mechanism by which the kidney metabolizes and excretes various drugs and toxins. High rate blood delivery (~25% of cardiac output) to the kidneys exposes it to significant drug concentrations. Many tubular cells, specifically in the loop of Henle require high metabolic rates due to its hypoxic environment which also increases risk for kidney injury. Increased concentrations of certain medications in the medulla and interstitium induce kidney injuries through direct toxicity as well as ischemic damage from reduced prostaglandin and increased thromboxane production. Other kidney factors included are biotransformation of drugs to nephrotoxic metabolites and reactive oxygen species and proximal uptake of drugs (apical uptake, basolateral transport and reduced drug efflux).
Medications are extensively prescribed by clinicians and consumed by patients. This remains as common causes of kidney injury. Drug nephrotoxicity is a complicated process that involves a combination of factors. Knowledge of the offending drug and their pathogenic mechanisms of renal injury are critical in recognizing and preventing drug-induced renal impairment. It is also important to seek professional advice before taking any medication to prevent possible renal injury especially to those with comorbidities.