Toxic Response of The Kidney

Toxic Response of the kidney
• The functional integrity of the

mammalian kidney is vital to
total body homeostasis,
because of its role in the
excretion of metabolic wastes,
synthesis and release of the
hormones renin and
erythropoietin, and the
regulation of extracellular fluid
volume, electrolyte
composition, and acid–base
balance.
Functional anatomy
• three anatomical areas:

1) cortex - receives 90% blood flow
2) medulla - 6 to 10%
3) papilla - 1 to 2%
• Nephron - functional unit of the
kidney
Three portions:
1) vascular element
2) glomerulus
3) tubular element
Renal Vasculature and Glomerulus
• The renal artery
branches into
afferent arterioles
that supply the
glomerulus. Blood
then leaves the
glomerular capillaries
via efferent arterioles.
• the glomerulus is a complex,
specialized capillary bed that
filters a portion of the blood
into an unltrafiltrate that
passes into the tubular portion
of the nephron.
• Although the glomerular
capillary wall permits a high
rate of fluid filtration,it
provides a significant barrier to
the transglomerular passage of
macromolecules.
Proximal Tubule
• The proximal tubule consists of three discrete segments: the S1 (pars
convulota) , S2 (transition between pars convulota and pas recta) , S3
(pars recta) segment.
• it reabsorbs approximately 60 to 80 percent of solute and water
filtered at the glomerulus mostly by numerus transpost systems
capable of driving concentration transport of many metabolic
substrates.
Loop of Henle
• Approximately 25% of the filtered Na+ and K+ and 20% of the filtered
water are reabsorbed.
• the tubular fluid entering the thin descending limb is iso-osmotic to
the renal interstitium; water is freely permeable and solutes, such as
electrolytes and urea, may enter from the interstitium.
• In contrast, the thin ascending limb is relatively impermeable to water
and urea, and Na+ and Cl- are reabsorbed by passive diffusion. The
thick ascending limb is impermeable to water, and electrolytes are
reabsorbed by the active Na+/K+/2Cl- cotransport mchanism, with
the energy provided by the Na+, K+ -ATPase.
Distal Tubule and Collecting Duct
• The distal convoluted tubule and collecting duct is the final site of
reabsorption in the nephron. Unlike the other components of the
nephron, its permeability to water is variable depending on a
hormone stimulus to enable the complex regulation of blood
osmolarity, volume, pressure, and pH.
• The collecting duct is similar in function to the distal convoluted
tubule and generally responds the same way to the same hormone
stimuli. It is, however, different in terms of histology. The osmolarity
of fluid through the distal tubule and collecting duct is highly variable
depending on hormone stimulus.
PATHOPHYSIOLOGIC RESPONSES OF THE KIDNEY:
• Acute Kidney Injury

One of the most common manifestations of nephrotoxic damage is
acute renal failure (ARF), characterized by an abrupt decline in GFR
with resulting azotemia, or a buildup of nitrogenous wastes in the
blood.
• Acute Kidney Injury 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.
Pre-renal Acute Failure
• are the physiologic response that leads to
decreased kidney function.
Causes: used of drug such as Cyclosporine, ACE
inhibitors, Amphotericin B, NSAIDs.
Intrinsic Acute Renal Failure
•the decrement in GFR is directly
proportional to kidney damage.
example: Acute tubular Necrosis (ATN)
Causes: hypotension, obsteric (birth-related)
complications, obstructive jaundice, sepsis;
used of drugs such as Aminoglycosides,
Amphotericin B, and Cisplatin.
Acute Interstitial Nephritis
• is rapidly developing inflammation that occurs within the interstitium
which results in reduced GFR and renal flow.
causes:
Mainly due to antibiotics and NSAIDS such as Ibuprofen, Cephtholin,
Cimetidine, Cyclosporine,Methicillin and Penicillins.
Post-renal ARF
• is caused by an acute obstruction that affects the normal flow of
urine out of both kidneys. The blockage causes pressure to build in all
of the renal nephrons.
causes:
drugs that cause Post-Renal ARF are Acyclovir, Methotrexate, Indinavir
and Sulfadiazine.
• Adaptation Following Toxic Insult
The kidney has a remarkable ability to compensate for

a loss in renal functional mass. Following a unilateral
nephrectomy, GFR of the remnant kidney increases in
single-nephron GFR are accompanied by proportionate
increases in proximal tubular water and solute
reabsorption; glomerulotubular balance is therefore
maintained and overall renal function appears normal
by standard clinical tests
Chronic Renal Failure
• Progressive deterioration of renal function may occur with long-term
exposure to various chemicals.
• Following nephron loss, adaptive increases in glomerular pressures
and flows increase the single-nephron GFR of remnant viable
nephrons, which serve to maintain whole kidney GFR
causes: diabetes, high blood pressure and drug such as Cyclosporine,
Analgesic abuse, cisplatin, Nitrosureas.
SPECIFIC NEPHROTOXICANTS
• Heavy Metals
Mercury – the kidneys are the primary target organs of accumulation of
Hg², and the S3 segment of the proximal tubule is the initial site of
toxicity.
Cadmium – cadmium has half-life of greater than 10 years in humans
and thus accumulates in the body over time.
• Chemically Induced α2ᴜ- Globulin Nephropathy
A diverse group of chemicals, including unleaded gasoline, D-limonene,
1,4-dichlorobenzene, decalin, tetrachloroethylene, and lindane, causes
α2ᴜ- globulin nephropathy or hyaline droplet nephropathy in male rats.
• Halogenated hydrocarbons
Chloroform – the primary cellular target of chloroform is the proximal
tubule, with no primary damage to the glomerulus or the distal tubule.
Tetraflouroethylene- is conjugated with glutathione in the liver, and the

GSH conjugate is secreted into the bile and small intestine where it is
degraded to the cysteine S-conjugate (TFEC), reabsorbed, and
transported to the kidney.
Bromobenzene – biotransformation of bromobenzene and other
halogenated benzenes is critical for thei nephrotoxicity.
• Mycotoxins are products of molds and fungi and are commonly found
on corn and corn products. Fumonisins β1 and β2 are common
mycotoxins that have been known to produce nephrotoxicity in rats
and rabbits.
Therapeutic Agents:
Acetaminophen
NSAIDs
Aminoglycosides
Amphotericin B
Cyclosporine
Cisplatin

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Toxic Response of the kidney

• The functional integrity of the

• three anatomical areas:

• Acute Kidney Injury

The kidney has a remarkable ability to compensate for

Tetraflouroethylene- is conjugated with glutathione in the liver, and the

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