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DIN
Relatively common complication Inpatient and outpatient settings
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
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
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
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:
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.
ACEIs
ACEI-induced AKI has accounted for 9% of
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
Pathogenesis
Decrease in glomerular capillary hydrostatic
initiated, the synthesis of angiotensin II is decreased, thereby preferentially dilating the efferent arteriole.
This reduces outflow resistance from the
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
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
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.
Prevent the compensatory vasodilatation by PGs Leaves the activity of renal vasoconstrictors unopposed
RFs
CKD, hepatic disease with ascites, decompensated
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
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
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
(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
(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,
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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