Nonsteroidal Antiinflammatory Drugs

Kidney Function Restoration Program

Treatment for Kidney Damage

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Patients at risk for NSAID-induced acute renal failure

TRenin-angiotensin axis TAngiotensin II

T Adrenergic nervous system TCatecholamines

Renal vasoconstriction ¿Renal function

"Normalized" renal function

Compensatory vasodilation induced by renal prostaglandin synthesis

FIGURE 11-17

Mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) disrupt the compensatory vasodilatation response of renal prostaglandins to vasoconstrictor hormones in patients with prerenal conditions. Most of the renal abnormalities encountered clinically as a result of NSAIDs can be attributed to the action of these compounds on prostaglandin production in the kidney [31].

Sodium chloride and water retention are the most common side effects of NSAIDs. This should not be considered drug toxicity because it represents a modification of a physiologic control mechanism without the production of a true functional disorder in the kidney.

PREDISPOSING FACTORS FOR NSAID-INDUCED ACUTE RENAL FAILURE

Severe heart disease (congestive heart failure)

Severe liver disease (cirrhosis)

Nephrotic syndrome (low oncotic pressure)

Chronic renal disease

Age 80 years or older

Protracted dehydration (several days)

FIGURE 11-18

Conditions associated with risk for nonsteroidal anti-inflammatory drugs (NSAID)-induced acute renal failure. NSAIDs can induce acute renal decompensation in patients with various renal and extrarenal clinical conditions that cause a decrease in blood perfusion to the kidney [32]. Renal prostaglandins play an important role in the maintenance of homeostasis in these patients, so disruption of counter-regulatory mechanisms can produce clinically important, and even severe, deterioration in renal function.

Mechanism Nsaid Induced Renal Failure

FIGURE11-19

Inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) on pathways of cyclo-oxygenase (COX) and prostaglandin synthesis [33]. The recent demonstration of the existence of functionally distinct isoforms of the cox enzyme has major clinical significance, as it now appears that one form of cox is operative in the gastric mucosa and kidney for prostaglandin generation (COX-1) whereas an inducible and functionally distinct form of cox is operative in the production of prostaglandins in the sites of inflammation and pain (COX-2) [33]. The clinical therapeutic consequence is that an NSAID with inhibitory effects dominantly or exclusively upon the cox isoenzyme induced at a site of inflammation may produce the desired therapeutic effects without the hazards of deleterious effects on the kidneys or gastrointestinal tract. PG—prostaglandin; TxA2—thromboxane A2.

EFFECTS OF NSAIDS ON RENAL FUNCTION

Renal Syndrome

Mechanism

Risk Factors

Prevention/Treatment [34]

Sodium retension

X Prostaglandin

NSAID therapy (most

Stop NSAID

and edema

common side effect)

Hyperkalemia

X Prostaglandin

Renal disease

Stop NSAID

X Potassium to

Heart failure

Avoid use in high-risk patients

distal tubule

Diabetes

X Aldosterone/renin-

Multiple myeloma

angiotensin

Potassium therapy Potassium-sparing diuretic

Stop NSAID

Acute deterioration of

X Prostaglandin and

Liver disease

Avoid use in high-risk patients

renal function

disruption of hemodynamic bal-

Renal disease Heart failure

Dehydration

Stop NSAID

T Lymphocyte recruit-

Old age

Dialysis and steroids (?)

Nephrotic syndrome with:

Fenoprofen

Stop NSAID

Interstitial nephritis

ment and activation

Avoid long-term

Papillary necrosis

Direct toxicity

Combination aspirin and acetaminophen abuse

analgesic use

FIGURE 11-20

Summary of effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function [31].

All NSAIDs can cause another type of renal dysfunction that is associated with various levels of functional impairment and characterized by the nephrotic syndrome together with interstitial nephritis.

Characteristically, the histology of this form of NSAID-induced nephrotic syndrome consists of minimal-change glomerulonephritis with tubulointerstitial nephritis. This is an unusual combination of findings and in the setting of protracted NSAID use is virtually pathognomic of NSAID-related nephrotic syndrome.

A focal diffuse inflammatory infiltrate can be found around the proximal and distal tubules. The infiltrate consists primarily of cytotoxic T lymphocytes but also contains other T cells, some B cells, and plasma cells. Changes in the glomeruli are minimal and resemble those of classic minimal-change glomerulonephritis with marked epithelial foot process fusion.

Hyperkalemia, an unusual complication of NSAIDs, is more likely to occur in patients with pre-existing renal impairment, cardiac failure, diabetes, or multiple myeloma or in those taking potassium supplements, potassium-sparing diuretic therapy, or intercurrent use of an angiotensin-con-verting enzyme inhibitor. The mechanism of NSAID hyperkalemia—suppression of prostaglandin-mediated renin release—leads to a state of hyporeninemic hypoaldostero-nism. In addition, NSAIDs, particularly indomethacin, may have a direct effect on cellular uptake of potassium.

The renal saluretic response to loop diuretics is partially a consequence of intrarenal prostaglandin production. This component of the response to loop diuretics is mediated by an increase in renal medullary blood flow and an attendant reduction in renal concentrating capacity. Thus, concurrent use of an NSAID may blunt the diuresis induced by loop diuretics.

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