NSAIDs and the Kidney: NSAID induced Nephrotoxicity Non-steroidal anti-inflammatory drugs (NSAID)
Authors: Kyle Moxham Mehul Gupta Reviewers: Emily Wildman Yan Yu* Adam Bass* * MD at time of publication
Inhibition of Cyclooxygenase COX-1 (expressed in kidney) and COX-2 (expressed in kidney and sites of inflammation)
NSAID induced nephrotoxicity: associated with chronic NSAID usage independent of dosage
COX inhibition ↑ conversion of arachidonic acid (AA) to leukotrienes, causing systemic T-cell dysfunction (unknown mechanism)
Type IV systemic hypersensitivity (delayed
T helper cell mediated) reaction to drug exposure
T cells release inflammatory cytokines into the bloodstream
(see Calgary Guide slide on NSAIDs and the Kidney: Mechanism of Action and Side Effects)
T cells infiltrate the renal interstitium, sparing the glomeruli and blood vessels
Overproduction of cytokines by T cells causing inflammation,
tissue damage, and cell death, of the renal intersitium
Drug Induced Acute interstitial nephritis (AIN): a type of immune-mediated tubulointerstitial injury
Activated T-cells infiltrate the glomerulus and cause podocyte injury (epithelial cells attached to the glomerular basement membrane)
Membranous nephropathy:
nephrotic syndrome involving autoimmune glomerular basement membrane thickening & complete podocyte effacement (seen on kidney biopsy)
Minimal change disease: nephrotic syndrome caused by autoimmune podocyte effacement (seen on kidney biopsy)
Cytokine mediated activation and
proliferation of immune cells like macrophages and eosinophils
Cytokines travel to hypothalamus,
causing change in the body’s thermal set point
Fever
Podocyte effacement allows for serum proteins to across the glomerulus into the tubular lumen (see Calgary Guide slide on Nephrotic Syndrome for full mechanisms)
Repeated NSAID exposure causing
recurrent unrecognized AIN and damage of the kidney
Chronic interstitial nephritis /analgesic nephropathy
Infiltrating immune cells (predominantly neutrophils) are filtered into/enter the renal tubules, and form clumps (“casts”) within the tubulesà casts are then released into urine
WBC cast on urinalysis
↑ Blood eosinophils
Immune cells infiltrate the
dermis and epidermis of the skin
Rash
Abnormal quantities of protein present in urine
Protein present in the blood is improperly filtered into the filtrate at the glomerulus
Protein- Creatinine
Ratio >3.5mg/mg
Proteinuria >3.5g/d
Hypo- albuminemia
↓ plasma oncotic pressure resulting in fluid extravasation into the interstitium (see Calgary guide slide on Edema for full mechanisms)
Pitting Edema
Legend:
Pathophysiology
Mechanism
Sign/Symptom/Lab Finding
Complications
Published January 13, 2022 on www.thecalgaryguide.com