NSAIDs and the Kidney: Mechanism of Action and Side Effects
Authors: Kyle Moxham Mehul Gupta Reviewers: Emily Wildman Yan Yu* Adam Bass* *MD at time of publication
Concurrent use of angiotensin- converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB)
AECi and ARBs act to ↓ renin- angiotensin-aldosterone system (RAAS) activation
Reduced angiotensin (AT) 2 activity at its receptors on efferent arteriole of the nephron
Net vasodilation of efferent arterioles ↓ in glomerular pressure
↓ blood perfusing kidney tissueà↑ hypoxemia & renal ischemia
Pre-existing ↓effective arterial blood volume (EABV) from
dehydration, GI loss, diuretics, CKD, CHF, cirrhosis, etc.
Decreased EABV triggers endogenous renal autoregulation, resulting in norepinephrine (NE) mediated vasoconstriction of afferent arteriole of the nephron
Net ↓ in renal blood flow and ↓ in glomerular pressure
↓ volume of blood filtered by the glomeruli per unit time
Non-steroidal anti-inflammatory drugs (NSAIDs)
Inhibition of Cyclooxygenase COX-1 (expressed in kidney) and COX-2 (expressed in kidney and sites of inflammation)
↓ Renal prostaglandin (PG) synthesis: local hormones involved in renal homeostasis
NSAID induced nephrotoxicity:
associated with chronic usage independent of dosage
(see Calgary Guide slide on NSAIDs and the Kidney: NSAID induced nephrotoxicity)
↓ intrarenal PG reduces inhibitory effects of PG over ADH in cortical colleting duct (CCD) of the kidneyà↓ antagonism on ADH activity
↑ ADH activity causes insertion of more
aquaporins (water channels) in the collecting duct of renal tubules
Net ↑ in volume of water reabsorbed into the blood
↓ vasodilatory effect of PG at the afferent arteriole of the nephron
↓ Glomerular filtration rate (GFR)
↓ PG signalling results in ↓ renin secretion at juxtaglomerular apparatus
Low renin levelsà↓ conversion of angiotensinogen into its AT1 form and, by extension, ACE mediated conversion of AT1 to AT2
↓ ACE 2 signalling leads to ↓ levels of aldosterone in the serum
↓ Na+ and K+ channel insertion on apical surface and ↓ Na/K ATPase activity on basolateral surface of principal cells
↓ K+ excretion into urine, and ↓ Na+ reabsorption
back into the blood, at the late DCT and collecting duct of the kidney
Pre-renal Acute Kidney Injury (AKI): kidney injury due to renal hypoperfusion
Prolonged and/or severe ischemia causes cell death and aggregation of tubular epithelial cells of the kidney with subsequent inability to reabsorb luminal Na+
Renal dehydration predisposes
precipitation of uromodulin protein
Renal tubules mold uromodulin into cylindrical structures known as “casts”. Casts that contain only uromodulin protein are known as “hyaline casts”
Hyaline cast seen on urinalysis
Hypoperfusion of the kidney activates the renin- angiotensin- aldosterone system (RAAS)
↑ amount of sodium (Na) reabsorbed from the filtrate (less Na excreted)
Fractional excretion of Na <1% Papillary necrosis: ureteral passage of sloughed ischemic tissue causing ureteral obstruction Acute tubular necrosis: a type of kidney injury causing damage to the tubules Hypertension Post-renal AKI: a type of kidney injury due to obstruction of the urinary tract Distal distal obstruction of the urinary tract causes fluid to accumulate within the kidneysàenlarging the kidneys Renal Ultrasound shows hydronephrosis (enlarged kidneys) Damaged tubule epithelial cells slough into the tubular lumen Epithelial cell breakdown in the tubular lumen releases uromodulin & other proteins, which aggregate into “casts” (cylindrical imprints of the renal tubule). The varied protein content of these casts result in them having a coarse, granular appearance Damaged tubular epithelial cells are unable to properly reabsorb sodium ↓ amount of sodium (Na) reabsorbed from filtrate into the blood (more Na excreted) Fractional excretion of Na >2%
True excess of free water relative to Na+ in the blood
Excess free water ↑ venous hydrostatic pressure (see Calgary Guide slide on edema for full mechanisms)
Pitting Edema
Hyperkalemia
Hyponatremia
Coarse granular casts seen on urinalysis
Legend:
Pathophysiology
Mechanism
Sign/Symptom/Lab Finding
Complications
Published January 29, 2022 on www.thecalgaryguide.com