Download 6.2.4 Kidney The function of the kidney is to filter waste products and

6.2.4 Kidney
The function of the kidney is to filter waste products and toxins out of the blood whileconserving essential substances
such as glucose, amino acids, and ions such as sodium.Anatomically, the kidney is a complex arrangement of vascular
endothelial cells and tubularepithelial cells, the blood vessels and tubules being intertwined. The functional unit of the
kidneyis the nephron (Fig. 6.8). Although all nephrons have their glomeruli and primary vascularelements in the
cortex, the position of the nephron within the kidney does vary in that it may liecompletely within the cortex (cortical
nephron) or the glomerulus may be located at the cortexmedullaboundary (juxtamedullary nephron). The environment
both inside and outside thenephron varies along its length, and this influences the types of toxic effect produced
bynephrotoxic agents. The kidney is a target organ for toxicity for the following reasons:1. Renal blood flow. The
blood passing through the mammalian kidney represents 25%of the cardiac output, despite the fact that the kidney only
represents about 1% of thebody mass. Therefore, the exposure of kidney tissue to foreign compounds in
thebloodstream, especially the cortex, which receives more blood than the medulla, isrelatively high.2. The
concentrating ability of the kidney. After glomerular filtration, many substancesare reabsorbed from the tubular fluid.
Thus, 98% to 99% of the water and sodium arereabsorbed. Hence, the concentration of foreign substances in the
tubular lumen isconsiderably higher than that in the blood, and the tubular fluid/blood ratio mayreach values of 500:1.
For example, some sulfonamides when given in high dosesmay cause renal tubular necrosis as a result of the
crystallization of less soluble,acetylated metabolites in the lumen of the tubule due to the increased concentrationin the
tubular fluid and pH-dependent solubility (chap. 4, Table 1). Similarly, oxalatecrystals may occur in the renal tubules
after ingestion of toxic amounts of ethyleneglycol (see chap. 7). Foreign substances may also be reabsorbed from the
tubular fluidalong with water and endogenous compounds. In this case, the tubular cells maycontain relatively high
concentrations of the foreign compound. The countercurrentexchange of small molecules may lead to very high
concentrations of compounds inthe interstitial fluid of the renal medulla. An example of a compound, which
isnephrotoxic as a result of uptake from the tubular fluid, is the aminoglycosideantibiotic gentamycin. This drug is
excreted into the tubular fluid by glomerularfiltration, but binds to anionic phospholipids on the brush border of the
proximaltubular cells. The resulting complex is absorbed into the cell by phagocytosis, isstored in secondary
lysosomes, and hence accumulates in the proximal tubular cells.Gentamycin causes a variety of biochemical
derangements in the cell, and theFigure 6.8 Schematic representation of a mammaliannephron.202 Chapter 6 lysosomes are
destabilized such that their enzymes are released with resulting degradation of cellular components.
3. Active transport of compounds by the tubular cells. Compounds that are activelytransported from the blood into the
tubular fluid may accumulate in the proximaltubular cells, especially at concentrations where saturation of the
transport systemoccurs. Again, concentrations to which tubular cells are exposed may be very muchhigher than in the
bloodstream. An example of this is the drug cephaloridine, whichcauses proximal tubular damage as discussed in more
detail in chapter 7.4. Metabolic activation. Although the kidney does not contain as much cytochromesP-450 as the
liver, there is sufficient activity to be responsible for metabolic activation,and other oxidative enzymes such as those of
the prostaglandin synthetase systemare also present. Such metabolic activation may underlie the renal toxicity
ofchloroform and paracetamol (see chap. 7). Other enzymes such as C-S lyase and GSHtransferase may also be
involved in the activation of compounds such ashexachlorobutadiene (see chap. 7). In some cases, hepatic metabolism
may beinvolved followed by transport to the kidney and subsequent toxicity.It is clear that the tissues of the kidney are
often exposed to higher concentrations ofpotentially toxic compounds than most other tissues. The toxic effects caused
may be due to avariety of mechanisms ranging from the simple irritant effects of sulfonamides and oxalatecrystals to
the enzyme inhibition and tubular damage proposed to underlie aspirin-inducedmedullary lesions. It has been
suggested that the latter is due to inhibition of prostaglandinsynthesis by aspirin, giving rise to vasoconstriction of the
vasa recta (Fig. 6.8), and hencereduction of blood flow and ischemic damage to the kidney. The proximal tubule, and
hencethe cortex, is the most common site of damage from foreign compounds, whereas the medullais less commonly
damaged and the collecting ducts only rarely. The glomerulus may bedamaged by nephrotoxins such as the
aminoglycosides, although these compounds alsodamage the proximal tubule. The proximal convoluted tubule is
damaged by chromium,whereas other metals such as mercury (see chap. 7) damage the straight portion (pars
recta).The pars recta section of the proximal tubule contains the highest concentration of cytochromesP-450, and this is
one reason for its particular susceptibility to toxic injury. Another is theparticular capacity for secretion of organic
compounds. Hence, cephaloridine damages thissection (see chap. 7). The loop of Henle is particularly susceptible to
damage from analgesics,such as aspirin and phenacetin, fluoride, and 2-bromoethylamine, which damage the thinlimb
and collecting ducts. This is manifested as papillary necrosis, following damage to therenal papillae. The distal
convoluted tubule is less commonly a target, although cisplatin, theanticancer drug, damages this portion of the
kidney. Interestingly, the trans isomer does notcause kidney damage at the same doses as the cis isomer. Amphoterecin
causes damage toboth proximal and distal tubules. It is a surface-active compound, which is believed to act bybinding
to membrane phospholipids, causing the cells to become leaky.The kidney has a marked ability to compensate for
tissue damage and loss, andconsequently, unless it is evaluated immediately, nephrotoxic effects may not be
recognized.Similarly, chronic toxicity may not be detected because of this compensatory ability.Detection of Kidney
DamageThere are a variety of ways in which kidney damage can be detected ranging from simplequalitative tests to
more complex biochemical assays.Simple tests include urine volume, pH, and specific gravity measurement;
kidneyweight/body weight ratio; and detection of the presence of protein or cells in the urine.Clearly, overt
pathological damage can be detected by light or electron microscopy, butthis requires sacrifice of the animal. Damage
can also be detected by measurement of a variety ofurinary constituents. Thus, damage to tubular cells results in the
leakage of enzymes such asg-glutamyltransferase and N-acetylglucosaminidase into the tubular fluid, and therefore
thesecan be detected and quantitated in the urine. Also, such damage will be reflected in altered renaltubular function,
leading to the excretion of glucose and amino acids. Measurement of urea orcreatinine in the plasma will also indicate
renal dysfunction if these are raised. The morecommon measurement is urea or blood urea nitrogen (BUN).
Measurement of urea orToxic Responses to Foreign Compounds 203creatinine in the urine and plasma allows the renal
clearance of these endogenous compoundsto be determined, and this will also indicate renal dysfunction. However,
clearance of thepolysaccharide inulin is a better indicator of glomerular filtration as it is less affected by otherfactors
such as protein metabolism.Different types of damage will cause different urinary profiles for endogenouscompounds
as has been investigated using high-resolution proton nuclear magnetic resonance(NMR) of urine to generate urinary
metabolite data patterns (see “Bibliography”).