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Therapeutics III

Drug Induced Kidney Diseases


Manhal A.Amber Lecturer Ass. in Clinical Pharmacy School of Pharmacy, Faculty of Medical Sciences

DIN
Relatively common complication Inpatient and outpatient settings

Variable presentations depending on the drug

and clinical setting Manifestations of DIN include: Acidbase abnormalities, Electrolyte imbalances, Urine sediment abnormalities, Proteinuria, pyuria, and/or hematuria.

Manifistations
Decline in the glomerular filtration rate (GFR)

raise serum-creatinine (Scr) and blood urea nitrogen (BUN). Initial diagnosis of DIN is often delayed as it typically involves detection of elevated Scr and BUN, for which there is a temporal relationship between the toxicity and use of a drug

Epidemiology of DIN
Outpatient or communityacquired DIN are

not well understood. Up to 20% of hospital admissions, as a result of AKI, have been attributed specifically to community-acquired DIN 8% to 60% of all cases of in-hospital AKI is due to DIN. The incidence of antibiotic-induced nephrotoxicity alone may be as high as 36%

Mechanisms of DIN
Tubular epithelial cell damage Hemodynamically mediated kidney injury Obstructive nephropathy Glomerular disease Tubulointerstitial disease Renal vasculitis, thrombosis, and

cholesterol emboli

Renal tubular epithelial cell damage


Direct toxic or ischemic effects of drugs The most common presentation of DIN in the

inpatient setting. EX:


Aminoglycosides, cisplatin, amphotericin B Osmotically active agents such as immunoglobulins, dextrans, and mannitol

AG Nephrotoxicity
A gradual progressive rise in the serum creatinine

concentration and decrease in creatinine clearance after 6 to 10 days of therapy. Nonoliguria (maintaining urine volumes greater than 500 mL/day) Severe kidney injury does not usually develop if aminoglycoside therapy is stopped promptly upon notation of a signficant rise in serum creatinine. Not all AKI during a course of therapy is caused by the aminoglycoside

Risk Factors
A. Related to aminoglycoside dosing Large total cumulative dose Prolonged therapy Trough concentration exceeding 2 mg/L Recent previous aminoglycoside therapy A. Related to synergistic nephrotoxicity Amphotericin B Cyclosporine Diuretics Vancomycin

C. Related to predisposing conditions in the patient: Dehydration or shock Gram-negative bacteremia Hypoalbuminemia Increased age Liver disease Obstructive jaundice Preexisting kidney disease Poor nutrition Potassium or magnesium deficiencies

Prevention of AG induced Nephrotoxicity


Discriminating selection of patients in whom

the drugs are used. Alternative antibiotics should be used whenever possible. Avoid volume depletion, limit the total AG dose administered Avoid concomitant therapy with other nephrotoxic drugs. High intermittent dosing of aminoglycosides, termed once-daily dosing

Management
S.Cr. should be measured frequently (every

2 to 4 days) during therapy. AG use should be discontinued or the dosage regimen revised if a Scr increase of 0.5 mg/dL or more is noted. Other nephrotoxic drugs should be discontinued if possible, and The patient should be maintained adequately hydrated and hemodynamically stable. Short-term dialysis may be necessary

HEMODYNAMICALLY MEDIATED KIDNEY INJURY


The kidneys constitute only 0.4% of body weight,

but receive approximately 25% of resting cardiac output. This enhances the kidneys exposure to circulating drugs Within each nephron, blood flow and pressure are regulated by glomerular afferent and efferent arterioles to maintain:

intraglomerular capillary hydrostatic pressure, glomerular filtration, urine output

Pathophysiology
Afferent and efferent arteriolar vasoconstriction are

primarily mediated by angiotensin II. Afferent vasodilation is primarily mediated by prostaglandins Hemodynamically mediated kidney injury results from a decrease in intraglomerular pressure.
Mechanisms commonly include: a decrease in renal blood flow, vasodilation of glomerular efferent arterioles.

Hemodynamically Mediated Kidney Injury


Angiotensin-converting enzyme inhibitors Cyclosporine, tacrolimus Nonsteroidal antiinflammatory drugs Angiotensin II receptor blockers

ACEIs
ACEI-induced AKI has accounted for 9% of

all cases of AKI requiring hospitalization


Hospitalized patients with CHF, and those

with CKD, including diabetic nephropathy


Up to one-third of patients with bilateral

renal artery stenosis demonstrate a rise in serum creatinine >30% after starting ACEI therapy

Clinical Presentation
Moderate rise in serum creatinine of 0.1 to

0.3 mg/dL should be anticipated


Dose-related elevations in serum creatinine

should be anticipated in most patients prescribed ACEIs


A rise in Scr of 0.5 mg/dL or more in the

course of 1 to 2 weeks may necessitate discontinuance of the offending drug

Pathogenesis
Decrease in glomerular capillary hydrostatic

pressure sufficient to reduce glomerular ultrafiltration.


When ACEI therapy (e.g., enalapril or ramipril) is

initiated, the synthesis of angiotensin II is decreased, thereby preferentially dilating the efferent arteriole.
This reduces outflow resistance from the

glomerulus and decreases hydrostatic pressure in the glomerular capillaries

Risk Factors
Patients with hemodynamically significant

renal artery stenosis, Those with decreased effective arterial blood volume:

Congestive heart failure Volume depletion from excess diuresis or gastrointestinal fluid loss Hepatic cirrhosis with ascites Nephrotic syndrome

Prevention
Recognizing the presence of preexisting kidney

disease or decreased effective renal blood flow (HF, Volume depletionetc). Initiate therapy with very low doses of a short-acting ACEI (e.g., captopril 6.25 mg to 12.5 mg), then gradually titrate the dose upward and convert to a longer-acting agent after patient tolerance has been demonstrated. Renal function Indices and serum potassium concentrations must be monitored carefully, daily for hospitalized patients and every 2 to 3 days for outpatients. NSAIDs & diuretics should be discouraged and dehydration avoided.

Management
Stop the drug

Patients will require management of severe

hyperkalemia, usually with sodium polystyrene sulfonate suspension.


ACEI or ARB therapy may frequently be reinitiated,

particularly for patients with congestive heart failure, (maintenance of a serum creatinine concentration of 2 to 3 mg/dL) may be an acceptable.

NSAIDs
NSAIDs have an overall favorable safety profile Conventional nonselective NSAIDs and selective

COX-2 inhibitors are unlikely to impair renal function in the absence of renal ischemia or excess renal vasoconstrictor activity.
50 million U.S. citizens report NSAID use, it has

been estimated that 500,000 to 2.5 million people will develop NSAID nephrotoxicity in the United States annually

Clinical Presentation
Kidney injury can occur within days of initiating

therapy, particularly with a short-acting NSAID (ibuprofen).


Patients typically present with complaints of

diminished urine output, weight gain, and/or edema.


Urine volume and sodium concentration are usually

low, and BUN, Scr, and potassium are typically elevated.

Pathogenesis
NSAIDs inhibit COX-catalyzed prostaglandin

production and impair renal function by decreasing synthesis of vasodilatory prostaglandins from arachidonic acid.
PGs have limited activity in states of normal renal

blood flow, but in states of decreased renal blood flow their synthesis is increased and they protect against renal ischemia and hypoxia by antagonizing renal vasoconstriction due to angiotensin II, norepinephrine, endothelin, and vasopressin.

Administration of NSAIDs in the setting of renal ischemia

Prevent the compensatory vasodilatation by PGs Leaves the activity of renal vasoconstrictors unopposed

promotes renal ischemia with loss of glomerular filtration

RFs
CKD, hepatic disease with ascites, decompensated

congestive heart failure, intravascular volume depletion, or systemic lupus erythematosus.


Additional risk factors include atherosclerotic

cardiovascular disease and concurrent diuretic therapy Combined NSAID or COX-2 inhibitor and ACEI or ARB therapy.
Patients older than 65 years of age may increase the

risk of AKI by up to 58%.

Prevention
Recognizing high-risk patients and using analgesics

with less prostaglandin inhibition, such as acetaminophen, nonacetylated salicylates (sulindac & salsalate), aspirin, and possibly nabumetone. Nonnarcotic analgesics (e.g., tramadol) may also be useful, but do not provide antiinflammatory activity. If essential for high risk patient? The minimal effective dose should be used for the shortest duration possible, along with optimal management of predisposing medical problems and frequent renal function monitoring

Management
NSAID-induced AKI is treated by discontinuation of

therapy and supportive care.


Kidney injury is rarely severe and recovery is

usually rapid.

TUBULOINTERSTITIAL DISEASE
Involve the renal tubules and the surrounding

interstitial tissue. The presentation may be acute and reversible with interstitial inflammatory cell infiltrates, rapid loss of renal function, and systemic symptoms. Acute allergic interstitial nephritis is the underlying cause for up to 3% of all cases of AKI. AIN usually manifests 2 weeks after exposure to a drug but may occur sooner if the patient was previously sensitized

Clinical Presentation- -Lactams


AIN is associated with all -lactam antobiotics Methicillin-induced AIN is the protype. Fever (80%), maculopapular rash (25%), eosinophilia

(80%), pyuria and hematuria (90%), low-level proteinuria (90%), and oliguria (20%). Eosinophiluria, an important marker of druginduced AIN, is frequently absent Tubular dysfunction may be manifested by acidosis, hyperkalemia

Clinical Presentation- NSAIDs


Patients are typically older than age 50 years

(reflecting NSAID use for degenerative joint disease), the onset is delayed a mean of 6 months from initiation of therapy. lower incidence of fever, rash, and eosinophilia. These extrarenal symptoms are observed in only 10% of patients Concomitant nephrotic syndrome (proteinuria >3.5 g/day) occurs in more than 70% of patients. Fenoprofen-allergic interstitial nephritis (50%)

Pathogenesis of AIN
Diffuse or focal interstitial infiltrate of lymphocytes,

plasma cells, eosinophils, and occasional polymorphonuclear neutrophils


Granulomas and tubular epithelial cell necrosis Allergic hypersensitivity response \ NSAID interstitial nephritis involves T lymphocytes,

possibly in response to altered prostaglandin synthesis

RFs, Prevention & Management


No specific risk factors have been identified

because these are idiosyncratic hypersensitivity reactions Individuals with other drug allergies may have increased risk Patients must be monitored carefully to recognize the signs and symptoms, because promptly discontinuing the offending drug often leads to full recovery. 1 mg/kg/day for a week, which is then tapered over 3 weeks to discontinuation

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