DRUGS INDUCED NEPHROTOXICITY

INTRODUCTION

Nephrotoxicity can be defined as renal disease or dysfunction that arises as a direct or indirect result of exposure to medicines, and industrial or environmental chemicals. Drug nephrotoxicity is therefore any renal dysfunction attributable to drugs. Drug nephropathies are not restricted to a single type of renal injury. Drugs target one or more discrete anatomical regions of the kidney and may affect only one cell type. The resulting insult to the kidney may result in a spectrum of nephropathies that are indistinguishable from those that do not have a chemical etiology.

HISTOLOGY AND PHYSIOLOGY

The nephron is the functional unit of the kidney and consists of a continuous tube of highly specialized heterogeneous cells, which show sub-specialization along the length of nephrons and between them. It is the major organ of excretion and homeostasis for water-soluble molecules; because it is a metabolically active organ, it can concentrate certain substances actively. In addition, its cells have the potential to bio-convert chemicals and metabolically activate a variety of compounds. Since the kidney excretes many drugs, it is routinely exposed to high concentrations of these drugs or their metabolites or both. Furthermore, the kidney has several features that allow nephrotoxins to accumulate. It is highly vascular, receiving about 25% of the resting cardiac output. The proximal renal tubule presents a large area for nephrotoxin binding and transport into the renal epithelium. Reabsorption of the glomerular filtrate progressively increases intraluminal nephrotoxin concentrations, while specific transport pathways in the kidney may engender site-specific toxicity.

MECHANISMS OF TOXICITY

Many drugs can injure the kidney but they cause renal injury via only a few mechanism. Renal injury can be in the form of: acute renal failure nephrotic syndrome chronic renal failure.

ACUTE RENAL FAILURE

Acute renal failure (ARF), characterized by sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes, and maintain fluid balance, is a frequent clinical problem.

NEPHROTIC SYNDROME

The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria. Drugs implicated include gold, NSAIDs, penicillamine, interferon, and captopril. Patients may present with edema, proteinuria, and hypoalbuminemia. Membranous nephropathy is the most common form reported, though minimal change nephropathy has also been seen with NSAIDs, as discussed below. Treatment is by stopping the drug and this often leads to resolution of nephrotic syndrome. However, irreversible injury has also been described.

CHRONIC RENAL INSUFFICIENCY

Chronic renal insufficiency caused by drugs generally presents as tubulointerstitial disease. It is important to note that for some drugs (e.g., cyclosporine, lithium), the mechanism of acute renal toxicity may be different from that of chronic renal injury. Patients may present with slowly progressive elevation of creatinine, with or without renal tubular dysfunction syndromes.These syndromes may manifest as renal tubular acidosis, renal potassium wasting, concentration defects, and tubular proteinuria. These syndromes may also occur without renal failure. In some cases, the renal damage is reversible when the offending drug is stopped, but in other cases it is irreversible. Frequently reversible forms include those due to 5- aminosalicylic acid, 6 mesalamine, and ifosfamide, while lithium and cyclosporine cause irreversible injury.Common drugs and the pathology caused:

DRUGSACUTE RENAL FAILURENEPHROTIC SYNDROMECHRONIC RENAL FAILURE

ACE INHIBITORS

ACYCLOVIR

AMINOGLYCOSIDES

COCAINE

NSAIDS

LITHIUM

DIURETICS

CISPLATIN

NSAIDS:

Each year, up to 5% of people who take NSAIDs will develop renal toxicity, resulting in hospital admissions and an increase in health care spending.All NSAIDs inhibit cyclooxygenase, the enzyme that is required to convert arachidonic acid into prostaglandins. Prostaglandins are not only involved in the inflammatory process but are present in the kidneys. They balance the effects of vasoconstrictors (norepinephrine, angiotensin II, vasopressin) by causing vasodilation of the afferent arteriole and, ultimately, allow adequate renal blood supply and glomerular filtration pressure.Unopposed vasoconstriction of the afferent arteriole in a patient taking NSAIDs causes decreased blood flow to the kidneys, which results in decreased glomerular filtration rate and renal ischemia.

MANAGEMENT:NSAIDs should be avoided or used with caution in patients at high risk of renal failure. COX-2 inhibitors are included in this warning due to similar effects on renal function. Patients should continue taking aspirin for cardio protection, because low doses do not significantly affect prostaglandin levels in the kidneys.Patients taking high doses of NSAIDs, individuals with underlying renal insufficiency, and the elderly are at a greater risk of toxicity. Factors that cause decreased volume and/or blood flow to the kidneys, such as congestive heart failure, cirrhosis, dehydration, and over diuresis, predispose patients to ARF.When dispensing medications that can precipitate ARF, counsel patients on the risk of using over-the-counter NSAIDs without consulting their pharmacist or physician.

ACE Inhibitors and Angiotensin II Receptor Blockers:

ACE inhibitors and angiotensin II receptor blockers are another frequent cause of ARF, especially in patients with severe renal artery stenosis or chronic kidney disease and in those hospitalized for congestive heart failure. Current guidelines recommend ACE inhibitors for patients with chronic kidney disease and systolic heart failure because of their proven benefits on morbidity and mortality; however, low doses should be used initially, and renal function should be monitored frequently.Glomerular pressure is normally high enough to maintain adequate filtration without relying on postglomerular resistance. In the setting of reduced blood flow, however, glomerular filtration is dependent on resistance in the efferent arteriole created by angiotensin IImediated vasoconstriction. ACE inhibitors reduce the outflow resistance from the glomerulus, resulting in decreased pressure and glomerular filtration.

MANAGEMENT:Treatment with an ACE inhibitor should be stopped if SCr increases by more than 30% and reduced if reinitiated. A mild decrease in renal function due to ACE inhibitors is acceptable due to the benefits that result from long-term therapy. Treatment should be started at low dosages, especially in patients with underlying risk factors, and the dose should be titrated gradually. It is important to avoid dehydration and excessive use of diuretics and NSAIDs.

Aminoglycoside Antibiotics:

Aminoglycosides are used to treat infections with gram-negative bacteria. They cause nephrotoxicity in up to 10% to 20% of patients when used for a full course of therapy.The primary mechanism of aminoglycoside-induced ARF is injury to the proximal tubule leading to cellular necrosis. This occurs via binding of cationic charges on amino groups to tubular epithelial cells. Tubular cell death occurs from generation of oxygen-free radicals and subsequent alterations in cellular function.Risk factors for aminoglycoside-induced ARF include aminoglycoside dosing (i.e., large cumulative dose, prolonged therapy, trough concentrations >2 mg/dL), synergistic exposure to other nephrotoxins (especially concomitant vancomycin), and underlying condition of the patient.

TUBULAR CELL DEATH

MANAGEMENT:pharmacists monitor aminoglycoside levels during inpatient treatment. Inherent pharmacodynamics and pharmacokinetic properties of aminoglycosides have led to more frequent use of once-daily dosing as opposed to traditional multiple daily-dosing regimens. Aminoglycosides display concentration-dependent killing and significant "postantibiotic" effect; therefore, giving a higher dose less frequently is at least as effective and may decrease renal toxicity by allowing excretion of aminoglycosides from the tubular cells prior to the next dose.

Radiocontrast Dye:

ARF is frequently caused by administration of radiographic contrast dye (RCD), which is used for diagnostic and treatment procedures. The incidence approaches nearly 50% in patients with combined diabetes and pre-existing renal insufficiency. Other risk factors for RCD-induced ARF include volume depletion, high doses of RCD, and using other drugs that cause nephrotoxicity. Most patients experience a transient rise in SCr within two to five days after receiving RCD, followed by recovery to baseline over the next few days. High-risk patients may experience more severe toxicity and require dialysis. Hospital course is significantly affected due to comorbid conditions that worsen with the onset of ARF.Nephrotoxicity appears to result from a combination of direct tubular necrosis and renal ischemia. Significant injury to the tubular cells and production of toxic-free radicals occur after RCD and may be accompanied by renal vasoconstriction and ischemia.

MANAGEMENT:Adequate hydration and discontinuation of nephrotoxic drugs is an essential part of the prevention of RCD-induced ARF. Many small trials have shown conflicting results regarding the use of various fluids, bicarbonate, and diuretics for prevention of RCD-induced ARF, and there are no clear recommendations based on proven benefit.Isotonic normal saline (1 mL/kg) may provide the most benefit and should be given at least six to 12 hours prior to RCD and continued six to 12 hours after the procedure. In addition, administration of sodium bicarbonate one hour prior to the procedure, with continued treatment for at least six hours after RCD, may also provide additional benefit. Diuretics should be given only if the patient is fluid overloaded.

Cisplatin:Cisplatin enters renal cells by passive and/or facilitated mechanisms. Exposure of tubular cells to cisplatin activates signaling pathways that are cell death promoting (MAPK, p53, ROS, and so on) or cytoprotective (p21). Meanwhile, cisplatin induces TNF-alpha production in tubular cells, which triggers a robust inflammatory response, further contributing to tubular cell injury and death. Cisplatin may also induce injury in renal vasculature, leading to ischemic tubular cell death and decreased glomerular filtration rate (GFR). Together, these pathological events culminate in acute renal failure.

Reference:

Clinical pharmacy and therapeutics (Roger Walker) http://www.uspharmacist.com http://folk.uio.no/imeea/pdf/drug%20nephrotoxicity.pdf http://www.doctorfungus.org/thedrugs/Nephrotoxicity.php http://www.nature.com/ki/journal/v73/n9/fig_tab/5002786f1.html

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