1. Pharmacology behind Common Drug Nephrotoxicities Perazella, Mark A
Pharmacology behind Common Drug Nephrotoxicities Perazella, Mark A. Presentation by: Jana May Marie B. Cruz, MD

2. Objectives

3. 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 come about with possible prevention and intervention.

4. Introduction

5. Drugs remain relatively a common cause of acute and chronic kidney injury
Exposure of the general population to a large number of prescribed and over-the-counter drugs as well as to a wide variety of drugs used for diagnostic and therapeutic procedures.
Commonly prescribed or ingested medications that may cause adverse drug effects including renal impairment are antimicrobials, diuretics, NSAIDs, proton pump inhibitors, supplements, laxatives, analgesics and immunosuppressives.

6. Drug-induced nephrotoxicity is more common in hospitalized patients, specifically intensive care unit patients
In a prospective cohort study of AKI, it revealed there are 14%-26% drug-induced nephrotoxicity in adults and 16% of hospitalized AKI in the pediatric population are due to drugs.
In a study by Naughton, C.A., the average patient today is older and has more comorbidities (higher incidences of diabetes and cardiovascular diseases). It also mentioned that approximate of 20% of community- and hospital-acquired cases of acute renal injury is caused by drugs.

7. Discussion

8. Nephrotoxicity of medications, drugs and other ingested substances is a complicated process that involves combination of factors, drugs exerting toxic effects by one or more common pathogenic mechanisms.
These 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.
Development of kidney injury is initiated by exposure to a potentially toxic offending agent. Most potentially nephrotoxic drugs are utilized in treating various disease process, examples include antimicrobial agents, anticancer drugs, analgesics and immunosuppressive agents.

9. Knowledge of the offending drugs and their pathogenic mechanisms of renal injury are crucial to recognizing and preventing drug-induced renal impairment.
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10. THE DRUG
Exposure to a potentially toxic offending agent is known as an initial step in developing kidney injury
Availability of an expanding variety of potentially harmful (to the kidney) substances which includes prescribed therapeutic agents, over-the-counter products, diagnostic agents and environmental substances
Alternative products which are made available at most health food stores often contain a number of harmful chemicals that are not listed in the label
Toxicity of therapeutic and diagnostic agents may be inherent to the pharmacological compound itself and the potential for toxicity may be heightened in the kidney microenvironment.

11. THE DRUG
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

12. Drug factors associated with increased risk for nephrotoxicity
Drug factors associated with increased risk for nephrotoxicity. Medications cause kidney injury through various mechanisms.
Increased exposure of the kidneyon thebasisof route, dose, anddurationof drug exposure; drug-related immune effects (suchas B-lactams, PPIs,
NSAIDs, and immune checkpoint inhibitors); combined nephrotoxic drug exposure; and drug and metabolite insolubility in the urine (such as
methotrexate, acyclovir, and sulfadiazine) lead to kidney injury. In addition, increased drug concentrations within tubular cells are due to
transport effects (such as tenofovir and cisplatin), intracellular accumulation of certain drugs due to lack of metabolizing enzymes (such as
sucrose and hydroxyethyl starch), innate direct cell toxicity (such as aminoglycosides, colistin, and amphotericin B), and intratubular cast
formation from drugs interacting with uromodulin (vancomycin). ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor
blocker; HES, hydroxyethyl starch; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitor; Tr, transporter.

13. THE PATIENT
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.
Reduced muscle mass is reflected in lower serum creatinine. Depending on the type of estimating equation used to approximate glomerular filtration rate (GFR), this may be falsely interpreted as high GFR, leading to inappropriately high drug dosing.
Decreased total body water increases the concentration of drug in serum.
Hypoalbuminemia also carries the risk of inducing toxic drug levels by increasing the unbound drug fraction in the serum.

14. THE PATIENT
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).
Patient who is on diuretic therapy or has vomiting or diarrhea that results in true volume depletion is vulnerable to toxic drug effects on the kidney
Patient with congestive heart failure or hepatic failure with ascites who has effective volume depletion may experience prerenal AKI and become more susceptible to the nephrotoxic effects of certain agents.
Hepatic failure is a particular risk factor for drug-induced renal impairment because cirrhotic patients tend to have reduced muscle mass and hypoalbuminemia
Presence of hyperbilirubinemia is the highest predictive factor for nephrotoxicity among patients with liver failure, putatively because of tubular damage from bile salts

16. THE KIDNEY
The mechanism by which the kidney metabolizes and excretes various drugs and toxins is another contributing factor in kidney injury
High rate blood delivery (~25% of cardiac output) to the kidneys exposes it to significant drug concentrations.
Some of these agents may have the requisite charge and size for filtration at the glomerulus and subsequently gain entry into renal tubular epithelial cells via pinocytosis or endocytosis.
Other drugs are transported via peritubular capillaries and gain access to renal tubular epithelial cells at the basolateral surface, where they are taken up by organic anion and organic cation transporters (OATs and OCTs, respectively) and eventually effluxed into tubular lumens
Tubular cells in the collecting duct and loop of Henle are at greater risk for nephrotoxicity because they are highly metabolically active and, as a result, reside in a relatively hypoxic microenvironment.

17. THE KIDNEY
Increased concentrations of certain medications in the medulla and interstitium induce kidney injurys through direct toxicity as well as ischemic damage from reduced prostaglandin and increased thromboxane production.
The kidney oxidizes drugs via cytochrome p450 and other enzyme systems into smaller metabolites, suggesting that intrarenal drug toxicity may be mechanistically linked to reactive oxygen species as well as direct effects of drug metabolites.
Other kidney factors included are biotransformation of drugs to nephrotoxic metabolites and proximal uptake of drugs (apical uptake, basolateral transport and reduced drug efflux).

19. Conclusion

20. Medications are extensively prescribed and consumed by patients thus remain as a common cause 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.

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