PRINCIPLES OF TOXICOLOGY

6.1 BASIC KIDNEY STRUCTURES AND FUNCTIONS 133
If tubular reabsorption of substances is compromised, then less water is reabsorbed. The result is
diuresis (increased urine flow) and polyuria (excess urine production). Toxic agents can cause polyuria
by affecting active solute reabsorption.
Tubular Secretion Active transport of certain organic compounds into the tubular fluid also occurs
in the proximal tubule. There are two separate active secretory systems in the proximal tubule: one for
anionic (negatively charged) organic chemical species, and a similar but separate system for cationic
(positively charged) organic chemical species. The organic anion secretory system is the better studied.
Organic cations such as tetramethyl ammonium are actively secreted, but this system is not as well
studied as the organic anion secretory system. The two secretory systems also have unique competitors
and inhibitors. Penicillin and probenecid are actively secreted by the organic anion secretory system.
As a consequence, they inhibit the excretion of PAH (p-amminohippuric acid) and each other. In fact,
probenicid has been used to prolong the half-life of penicillin in the blood since probenicid inhibits
secretion of penicillin into the proximal tubules and its subsequent excretion in the urine. These organic
anions do not inhibit secretion of organic cations or compete with them for secretion. The reverse is
also true. The result is that substances reabsorbed from the tubule will have a clearance significantly
less than the glomerular filtration rate (approximately 125 mL/min), while those secreted into the
tubules will have a clearance greater than the glomerular filtration rate in the adult human.
The Loop of Henle After the glomerular filtrate has passed the proximal tubule in the nephron, it
moves into the loop of Henle. A nephron with a glomerulus in the outer portion of the renal cortex has
a short loop of Henle, whereas a nephron with a glomerulus close to the border between the cortex and
medulla (juxtamedullary nephrons) has a long loop of Henle extending into the medulla and papilla
(Figures 6.2 and 6.3). Approximately 15 percent of the nephrons in humans are juxtamedullary. As the
tubule descends into the medulla there is an increase in osmolality of the interstitial fluid. In the
descending limb the tubular fluid becomes hypertonic (high in salt) as water leaves the tubule to
maintain isoosmolality with the hypertonic interstitial fluid. However, in the thick segment of the
ascending portion of the loop of Henle the tubule becomes impermeable to water, and sodium is actively
transported out of the tubule with a decrease in the osmolality of the filtrate and an increase in the
osmolality of the interstitial fluid. The sodium transport in the ascending limb is necessary for
maintenance of the interstitial fluid concentration gradient. An additional 5 percent of the glomerular
filtrate fluid is reabsorbed in the loop of Henle, making a total of 80 percent of the total water reabsorbed
at this point.
Urine Formation Once the tubular fluid enters the distal convoluted tubule and collecting duct, it is
hypotonic (low salt concentration) in comparison to blood plasma because of the active transport of
sodium out of the tubule at the loop of Henle. In the presence of vasopressin, the antidiuretic hormone,
the collecting duct becomes permeable to water, and the water moves from the tubular fluid in order
to maintain isoosmolality. However, in the absence of vasopressin, the collecting duct is impermeable
to water, which results in excretion of a large volume of hypotonic urine. Normally, another 19 percent
of the original glomerular filtrate fluid is reabsorbed in the last portion of the nephron, so that a total
of 99 percent of the fluid filtered at the glomerulus is reabsorbed—only 1 percent of the fluid entering
the nephron is excreted in the urine. Thus, the normal flow of urine is only about 1 mL/min, while in
the absence of vasopressin it can be increased to 16 mL/min. The kidney’s ability to concentrate urine
is determined by the measurement of urine osmolality. Urine osmolality can vary between 50 and 1400
mOsm/L. Certain nephrotoxicants compromise the kidney’s ability to concentrate the urine. These
changes occur early after the exposure to the nephrotoxicant and frequently foreshadow graver
consequences.
The excretion of urea, a metabolic breakdown product of protein, is a special case. Urea passively
diffuses out of the glomerular filtrate of the tubules as fluid volume decreases. At low urine flow, more
urea has the opportunity to leave the tubule. Under these conditions only 10–20 percent of the urea is
excreted. At conditions where the urine flow is high, the urea has less time to diffuse through