Nephrotoxicity
Introduction
Recall that the primary function of the kidney is to 1) excrete wastes,
2) conserve water and electrolytes, and 3) synthesise erythropoietin,
vitamin D, renin, prostaglandins, kinins and participate in other biochemical
pathways including metabolism. Toxic injury to the kidney may interfere
with any of these functions.
Also recall that the functional unit of the kidney, the nephron, is
divided into several sections, each with a specific function, such as the
glomerulus (where initial filtration takes place), the proximal convoluted
tubule (where active reabsorption occurs), the loop of Henle (water conservation
via the countercurrent mechanisms), and the distal convoluted tubule
and collecting tubule (aldosterone-dependent Na conservation and ADH-dependent
water conservation).
Also, recall that the cortex (outer layer) of the kidney receives a
large blood supply, owing to the afferent/efferent arteriolar network that
provides for filtration and the peritubular capillary network (vasa
recta) providing the reabsorptive pathway for conservation of water
and electrolytes and that the medulla (inner layer) is the site of urine
concentration by the loop of Henle, where great osmotic pressures may be
generated.
Cellular responses to toxic insult may be functional in nature, for example
1) minor alterations in transport, 2) polyuria (increased urine output),
or 3) oliguria or anuria (little or no urine output, respectively).
Each of these may be reversible if preventative measures are employed,
however chronic exposure may lead to irreversible kidney damage.
Specific areas of toxic effects within the kidney include damage to
the glomerulus (where filtration may decrease), vascular toxicity such
as vasoconstriction (which would decrease renal blood flow and also decrease
filtration and/or venous outflow), the loop of Henle (which is especially
sensitive to analgesics, due to the role that prostaglandins play in the
loop), or the tubules (changes in permeability thereby altering reabsorption
and/or secretion or blocking urine flow).
The kidney is extremely susceptible to toxic insult. Factors that
increase the risk of nephrotoxicity, relative to other organs, include
1) high degree of blood flow presented to the kidneys, 2) the large number
of mitochondria present in the kidney (necessary for energy dependent-metabolic
processes and -transport), and 3) the large concentration of toxicant that
is presented to the kidney (as a primary sight of elimination).
Nephrotoxicity may assessed by a number of different parameters that
examine
1) urine characteristics such as
osmolarity
pH
relative concentration of
glucose
proteins
electrolytes
creatinine clearance
volume
2) blood such as
blood urea nitrogen
creatinine
electrolytes.
Since the kidneys are bilateral, there does exist some compensatory mechanism
for dealing with toxic injury. If the toxicity is limited to or less
in one kidney, the un-harmed kidney may hypertrophy and re-coup at least
some of the function lost by the damaged organ. This selective
toxicity may or may not occur and is often a matter of pure chance with
regards to most nephrotoxins.
Some specific nephrotoxins include
Heavy metals -- which bind to cellular proteins and are reabsorbed
into the PCT, where the metal directly damages the cell, leading to necrosis
(often through disruption of lysosomal membranes thus allowing autolysis
or self-destruction of the cell). The detritus of the cell
will slough off, "plugging" or occluding the tubular lumen, thus preventing
the passage of the forming urine.
Some specific heavy metals that are nephrotoxic include
Mercury -- all forms (elemental or Hg, inorganic mercury such as HgCl2
which damages the blood vessels of the kidney, and organic mercury
such as methylmercury, MeHg or HgCH3, which damages both the
blood vessels and renal cells causing necrosis)
Platinum -- especially the anti-neoplastic cisplatin -- Pt(NH3)2Cl2
-- which damages the PCT, DCT, and collecting ducts (some believe the damage
is not due to the platinum but rather from the chloride radical that
is formed during metabolism)
Cadmium, which damages the PCT.
All of the heavy metals may produce proteinuria and glucosuria as signs
of nephrotoxicity.
Halogenated Hydrocarbons which damage the PCT.
Chloroform, CHCl3 (which may be formed from carbon tetrachloride
in the liver) undergoes hepatic metabolism to phosgene, COCl2,
which was used as a nerve gas in the Great War, is a classic example of
a nephrotoxin, producing acute renal damage, renal hypertrophy, swelling
and necrosis of renal tubular epithelium, and fatty degeneration of
the kidney (similar to that seen in the liver).
Other halogenated hydrocarbons that are nephrotoxic include hexachlorobutadiene
and bromobenzene (through its metabolite hydroxybromoquinone).
Analgesics (aspirin, the NSAIDs, and phenacetin) are classic examples of
drugs that are nephrotoxic. Their specific nephrotoxicity is probably
related to the decreased synthesis of prostaglandins that is their mechanism
of action. (Recall that the loop of Henle is a site of PG synthesis
and at least some of the function of the nephron is mediated by PG).
These agents especially affect the PCT and CT of the nephron.
Anaesthetics, especially methoxyflurane, will produce a high output
(polyuric) renal failure that may be mediated by oxalate metabolites.
Aminoglycoside antibiotics (such as gentamicin, tobramycin, amikacin,
neomycin) are also classic nephrotoxins (10% of all acute renal failure
is due to aminoglycoside toxicity!). These agents damage the glomerulus,
PCT, and may also produce cellular necrosis by interacting with intracellular
endoplasmic reticula and lysosomes. Aminoglycosides are cationic
(RECALL that Bowman's capsule surrounding the glomerulus is anionic and
prevents the filtration of anionic proteins such as albumin) and as such
may neutralise and disrupt the epithelium of Bowman's capsule and the brush
border of the PCT, thus disrupting the filtration and reabsorption of each,
respectively.
END MATERIAL FOR TEST ONE
Go To Next Topic (CNS/Behavioural Toxicity)