Both afferent and efferent arterioles control glomerular capillary pressure and glomerular plasma flow rate
The glomerulus is a complex, specialized capillary bed composed primarily of endothelial cells
The glomerulus is characterized by an attenuated and fenestrated cytoplasm and visceral epithelial cells such as cell body (podocyte), trabeculae and pedicles (foot processes), glomerular basement membrane (GBM)
Three discrete segments of the Proximal Tubule
S1 - pars convolute
S2 - transition between pars convolute and pars recta
S3 - pars recta
The proximal tubule is the workhorse of the nephron, as it reabsorbs 60-80% of solute and water filtered at the glomerulus
The proximal tubule also reabsorbs virtually all the filtered low MW proteins by specific endocytotic protein reabsorption processes
Approximately 25% of the filtered Na and K and 20% of the filtered water are reabsorbed by the segments of the Loop of Henle
Tubular fluid entering the thin descending limb - iso-osmotic to the renal interstitium
Water is freely permeable, and solutes (electrolytes and urea)
Thin ascending limb - impermeable to water, electrolytes are reabsorbed by the active Na/K/2Cl cotransport mechanism (Na, K, ATPase)
The early distal tubule reabsorbs most of the remaining impermeable to water
The late distal tubule, cortical collecting tubule, and medullary collecting duct perform the final regulation and fine-tuning of urinary volume and composition
Acute kidney injury (AKI) is characterized by an abrupt decline in GFR with resulting azotemia
AKI describes the entire spectrum of the disease and is defined as a complex disorder that comprises multiple causative factors with clinical manifestations ranging from minimal elevation in serum creatinine to anuric renal failure
Postrenal factors - ureteral or bladder obstruction
Intrarenal factors - glomerulonephritis, tubular cell injury, death and loss resulting in back leak
Mechanisms of Chemically-induced AKI
Prerenal
Diuretics
Angiotensin receptor antagonists
Angiotensin-converting enzyme inhibitors
Antihypertensive agents
Mechanisms of Chemically-induced AKI
Vasoconstriction
NSAIDS
Radiocontrast agents
Cyclosporine
Tacrolimus
Amphoterin B
Mechanisms of Chemically-induced AKI
Crystalluria
Sulfonamides
Methotrexate
Acyclovir
Triamterene
Ethylene glycol
Protease inhibitors
Mechanisms of Chemically-induced AKI
Tubular Toxicity
Aminoglycosides
Cisplatin
Vancomycin
Pentamidine
Radiocontrast agents
Heavy metals
Haloalkane- and Haloalkene - cysteine conjugates
Mechanisms of Chemically-induced AKI
Endothelial Injury
Cyclosporine
Mitomycin C
Tacrolimus
Cocaine
Conjugated estrogens
Quinine
Mechanisms of Chemically-induced AKI
Glomerulopathy
Gold
Penicillamine
NSAIDS
Mechanisms of Chemically-induced AKI
Interstitial Nephritis
Antibiotics
NSAIDS
Diuretics
Chronic Kidney Disease (CKD) is the progressive deterioration of the renal function due to long-term exposure to various chemicals such as analgesics, lithium, and cyclosporine
In CKD, alterations are maladaptive, and focal glomerulosclerosis eventually develops, which may lead to tubular atrophy and interstitial fibrosis
NSAIDs
Prostaglandin synthesis suppressor --> decreased renal blood flow --> AKI
ACEi
Blocks vasoconstriction --> precipitous decline in filtration pressure + AKI
Many nephrotoxicants have their primary effects on discrete segments or regions of the nephron
Site-selective injury
Can be attributed to the following:
site-specific differences in blood flow
transport and accumulation of chemicals
physicochemical properties of the epithelium
reactivity of cellular/molecular targets
balance of bioactivation/detoxification reactions
cellular energetics
regenerative/repair mechanisms
The glomerulus is the initial site of chemical exposure within the nephron
Cyclosporine, Amphotericin B, and Gentamcin
Impairs glomerular ultrafiltration without significant loss of structural integrity and decrease GFR
Amphotericin B
Decreases GFR by renal vasoconstriction and decreases glomerular capillary ultrafiltration coefficient (Kf)
Gentamicin
Interacts with anionic sites on the endothelial cells which leads to decreased GFR and decreased Kf
Cyclosporine
Renal vasoconstriction and vascular damage, injurious to the glomerular endothelial cell
The proximal tubule is the most common site of toxicant-induced renal injury
The proximal tubule has a leaky epithelium, favoring the flux of compounds into proximal tubular cells