Tetracycline, especially outdated products, may affect the renal medulla and induce

interstitial nephritis. Amphotericin-B induces renal toxicity in a majority of the

patients, affecting various renal structures.
Methoxyurane, an anesthetic, is known to be nephrotoxic in humans and
certain animals, producinghigh-output renal failure. This chemical was shown to
be biotransformed to inorganic uoride and oxalate. Experimental data suggest
that the F
-
acts on several parts of the nephron to reduce the reabsorption of water.
First, it interferes with the capability of the proximal tubules to reabsorb water.
Second, methoxyurane inhibits the enzymes involved in the transport of ions at
the ascending limb of the loop of Henle, thus reducing the interstitial osmolarity,
thereby decreasing water reabsorption. This chemical also damages the collecting
tubules, rendering them insensitive to ADH (Mazze, 1976).
Analgesic mixtures containing aspirin and phenacetin, a derivative of
acetaminophen, produce chronic renal failure, with adverse effects located predominantly
in the medulla, that is, loop of Henle, vasa recta, interstitial cells, and
collecting tubules (Schnellmann, 1998). The effects might be a result of vasoconstriction
of the vasa recta (the blood vessels surrounding the loop of Henle) due to
an inhibition of the synthesis of vasodilator prostaglandin (Nanra, 1974). Cisplatin
affects many parts of the tubules in patients taking this chemotherapeutic agent
(Tanaka et al., 1986). Cyclosporin produces acute thrombotic microangiopathy
and chronic nephropathy with interstitial brosis (Racusen and Solez, 1988).
Other types of toxicity include renal carcinogenicity of DMN (dimethylnitrosamine),
and tubular blockade induced by the metabolites of sulfapyridine
(acetylsulfapyridine) and glycols (oxalic acid). Penicillins and sulfonamides were
reported to produce inammatory interstitial nephritis in humans. An immunologic
mechanism was suggested as responsible for this toxicity (Appel and Neu,
1977). High concentrations of calcium may lead to calcication in the kidney and
subsequent renal failure (Hwang et al., 2003).
TESTING PROCEDURE
Functional and morphologic examinations of the kidney are routinely carried out
as an integral part of short-term and long-term toxicity studies. The types of
examinations involved are described in chapter 6 and are further elaborated here.
In studies designed specically for nephrotoxicity, dogs, rabbits, and rats
are the commonly used animals. Examinations of kidney functions may be done
in a number of ways.
Urinalysis
Proteinuria
Because of the size of their molecules, only a very small amount of proteins of low
molecular weight pass through the glomerular lter. The low-molecular-weight
proteins are readily reabsorbed by the proximal tubules. The occurrence of large
amounts of such protein in the urine is thus an indication of a loss of tubular
reabsorptive function, as in cadmium poisoning (Diamond et al., 2003). On the
other hand, excretion of high-molecular-weight protein indicates a loss of integrity
of glomeruli. It is to be noted that normal rat urine may contain some protein. A
critical comparison of the treated animals with the controls is therefore important.
Glycosuria
Glucose in the glomerular ltrate is completely reabsorbed in the tubules, provi-
ded the amount of glucose to be reabsorbed does not exceed thetransport maximum
(Tm). Glycosuria in the absence of hyperglycemia thus indicates tubular
dysfunction.
Urine Volume and Osmolarity
These two values are usually inversely related and are useful indicators of renal
function in aconcentration test, wherein water is withheld from the animal, and
also in adilution test, wherein a large amount of water is given to the animal.
The osmolarity can be estimated from the specic gravity, but the freezing point
of urine provides a more accurate measurement. A toxicant may produce highoutput
renal failure as noted above. On the other hand, it may cause oliguria or
even anuria, resulting from tubular injury, with concomitant interstitial edema and
intraluminal sediment or debris, which blocks urine ow.
Acidifying Capacity
This can be assessed from urine pH, titratable acids, and NH
4
+
. This capacity is
reduced when there is distal tubular dysfunction.
Enzymes
Enzymes such as maltase and acid phosphatase in urine may indicate destruction
of proximal tubules. Urine alkaline phosphatase, on the other hand, may be renal
or hepatic in origin. Plummer (1981) suggested that the urinary enzymes not only
are useful indicators of renal damage but also indicate the subcellular site of origin.
For example, alkaline phosphatase is located in endoplasmic reticulum, glutamate
dehydrogenase in mitochondria, and lactate dehydrogenase in cytoplasm. In general,
urinary enzymes are more useful measures in acute nephrotoxic conditions.
Blood Analysis
Blood Urea Nitrogen (BUN)
Blood urea nitrogen is derived from normal metabolism of protein and is excreted
in the urine. Elevated BUN usually indicates glomerular damage. However, its
level can also be affected by poor nutrition and hepatotoxicity, which are common
effects of many toxicants.
Creatinine
Creatinine is a metabolite of creatine and is excreted completely in the urine via
glomerular ltration. An elevation of its level in the blood is thus an indication of
impaired kidney function. Furthermore, data on its level in blood and its amounts
in urine can be used to estimate the glomerular ltration rate. One drawback with
this procedure is the fact that some creatinine is secreted by the tubules.
Special Tests
Glomerular Filtration Rate (GFR)
The glomerular ltration rate can be more accurately determined by the clearance
of inulin, a polysaccharide. It is diffused into the glomerular ltrate and is neither
reabsorbed nor secreted by the tubules. Reduced GFR indicates impairment of
glomerular ltration.
Renal Clearance
This is the volume of plasma that is completely cleared of a substance in a unit of
time. The renal clearance ofp-aminohippuric acid (PAH) exceeds that of inulin
because it is not only ltered through the glomeruli but also secreted by the
tubules. A reduction of PAH elimination without a concomitant decrease of GFR
indicates tubular dysfunction. PAH is nearly completely (up to 90%) removed
from the blood in one passage. The rate of its clearance is therefore useful in
determining the effective renal plasma ow (ERPF). The renal blood ow can also
be determined by the use of radiolabeled microspheres or an electromagnetic ow
meter.
PSP Excretion Test
The rate of excretion of phenolsulfonphthalein (PSP) is related to renal blood ow.
It is, therefore, often used in the assessment of renal function. However, a reduced
secretion rate can also result from cardiovascular diseases.
NATURE OF TOXICITY
The kidney has a remarkable compensatory capability. Even after appreciable
changes in renal functions and morphology, the kidney may compensate and
regain normal functions. Therefore, it is important to perform tests at repeated and
appropriate time intervals.
Nephrotoxicants can exert adverse effects on various parts of the kidney,
resulting in alterations of different functions. A variety of tests should therefore
be performed. The most sensitive and reliable tests appear to vary depending on
the nature of the nephrotoxicants as well as the experimental conditions (e.g.,
animal species, duration of exposure). Kluwe (1981) concluded from his studies
that in vitro accumulation of organic ions (e.g., PAH, TEA), urinary concentrating
ability, and kidney weight were the most sensitive and consistent indicators of
nephrotoxicity. Standard urinalysis, serum analyses, qualitative enzymuria, and
histopathologic changes were less sensitive and less consistent. It was observed
that urine osmolarity was the most sensitive indicator of the nephrotoxicity of a
platinum complex, whereas GFR and ERPF were affected only later and at higher
doses.
In assessing the renal effects of a toxicant, extrarenal factors that might
affect the blood volume or blood pressure should be taken into account, since they
may indirectly impair renal functions. Furthermore, kidney diseases, such as those
associated with aging, may be prevalent and should also be considered.