Kidney

• Principal Roles of the Kidney

  • excretion of metabolic wastes
  • regulation of extracellular fluids
  • electrolyte composition
  • acid-base balance
• Three demarcated anatomical areas of the kidney

  • Cortex (90%) - biggest
  • Medulla (6-10%)
  • Papilla (1-2%)
• Functional Units of the Kidneys

  • Nephron
  • Vascular element
  • Glomerulus
  • Tubular element
• Renal artery supplies blood to the glomerulus
• Pathway of blood from the Renal Artery to Glomerulus

  Interlobar - arcuate - interlobular arteries - afferent arterioles
• 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
• Any decline in GFR is complex and may result from

  • Prerenal factors - renal vasoconstriction, intravascular volume depletion, insufficient caloric output
  • 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

  1. Diuretics
  2. Angiotensin receptor antagonists
  3. Angiotensin-converting enzyme inhibitors
  4. Antihypertensive agents
• Mechanisms of Chemically-induced AKI

  Vasoconstriction

  1. NSAIDS
  2. Radiocontrast agents
  3. Cyclosporine
  4. Tacrolimus
  5. Amphoterin B
• Mechanisms of Chemically-induced AKI

  Crystalluria

  1. Sulfonamides
  2. Methotrexate
  3. Acyclovir
  4. Triamterene
  5. Ethylene glycol
  6. Protease inhibitors
• Mechanisms of Chemically-induced AKI

  Tubular Toxicity

  1. Aminoglycosides
  2. Cisplatin
  3. Vancomycin
  4. Pentamidine
  5. Radiocontrast agents
  6. Heavy metals
  7. Haloalkane- and Haloalkene - cysteine conjugates
• Mechanisms of Chemically-induced AKI


  Endothelial Injury

  1. Cyclosporine
  2. Mitomycin C
  3. Tacrolimus
  4. Cocaine
  5. Conjugated estrogens
  6. Quinine
• Mechanisms of Chemically-induced AKI

  Glomerulopathy

  1. Gold
  2. Penicillamine
  3. NSAIDS
• Mechanisms of Chemically-induced AKI

  Interstitial Nephritis

  1. Antibiotics
  2. NSAIDS
  3. 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