Page 299 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

266 SECTION | II Organ Toxicity

VetBooks.ir Distal Nephron/Renal Papillary Injury broilers, OTA causes renal edema and renal tubular
necrosis (Huff et al., 1975). OTA is teratogenic, muta-
Toxic injury to the distal nephron is relatively uncommon,
genic and carcinogenic, and it induces renal tumors in rat
and injury to this area generally manifests as decreased
models (Haschek et al., 2002).
urine concentration ability or defects in acid secretion.
Injury to the renal papilla is most commonly seen with
chronic consumption of nonsteroidal antiinflammatory Citrinin
drugs (NSAIDs), although the use of NSAIDs in hypovo- Citrinin is produced by toxic strains of several
lemic animals or in conjunction with other nephrotoxi- Penicillium, Aspergillus and Monascus spp. (Bennett and
cants (e.g., aminoglycoside antibiotics) has also been Klich, 2003), and has been associated with rice, wheat,
associated with the development of renal papillary necro- oats, rye, corn, barley, vegetarian foods colored with red
sis (Talcott, 2006). Monascus pigments, and naturally fermented sausages
from Italy. Citrinin is often found in association with
OTA and is less toxic than OTA (Kitabatake et al., 1993).
NEPHROTOXIC AGENTS Dogs receiving citrinin at dosages of 80 micromoles/kg
intravenously or 10 mg/kg orally developed proteinuria,
Mycotoxins
glucosuria, and ultrastructural changes in the epithelium
Ochratoxins of the S 2 segment, thick ascending limb, distal convoluted
tubule and collecting ducts (Kitchen et al., 1977; Krejci
Ochratoxins are produced by various species of the fungi
et al., 1996). Dogs given oral 10 mg/kg citrinin twice at
Aspergillus and Penicillium and are produced on a variety
24 h intervals developed similar lesions and developed
of cereal grains, cottonseed, nuts, dried beans and coffee
glucosuria, proteinuria, and granular casts in the urine;
beans (Haschek et al., 2002). Ochratoxin A (OTA) is the
glucosuria was the earliest abnormality noted and per-
most common and most toxic of the ochratoxins that have
sisted for 5 days, as did proteinuria (Kogika et al., 1993).
been identified to date. The coproduction of penicillic
Cylindruria persisted from days 1 to 15, and renal values
acid by Penicillium ochraeus or citrinin by Aspergillus
(BUN, creatinine) were elevated from days 2 to 5.
spp. or Penicillium spp. greatly enhances the toxicity of
Clinical signs in dogs administered 10 mg/kg citrinin per
OTA (Haschek et al., 2002; Kumar et al., 2007). OTA is
day for 14 days included anorexia, retching, tenesmus,
thought to be the causative factor in endemic Balkan
weight loss, prostration, and death. Citrinin is teratogenic,
nephropathy of humans (Maxie and Newman, 2007).
embryotoxic, and a putative carcinogen.
Ochratoxin toxicosis has been reported in a variety of ani-
mal species including swine, ducklings, horses, chickens,
rabbits, turkeys, dogs and fish (Kitchen et al., 1977; Drugs
Haschek et al., 2002; Kumar et al., 2007; El-Sayed et al.,
2009). Cattle are thought to be resistant due to degrada- Aminoglycoside Antibiotics
tion of ochratoxins within the rumen, although prerumi- Aminoglycoside antibiotics exert their nephrotoxic effects
nant calves are susceptible (Haschek et al., 2002). In through induction of apoptosis and necrosis within the
domestic animals, ochratoxicosis is most commonly renal tubular epithelial cells of the proximal convoluted
reported in pigs and chickens as a subchronic to chronic tubule as well as the distal tubules and collecting ducts
disease affecting growth and production (Maxie and (Lopez-Novoa et al., 2011). Within these cells, aminogly-
Newman, 2007; Sakthivelan and Sudhakar Rao, 2010). cosides internalized though endocytosis accumulate in
Pigs are considered to be the most sensitive species, with lysosomes, Golgi apparatus and endoplasmic reticulum.
chronic toxicosis occurring following ingestion of diets As the aminoglycoside concentration increases beyond a
containing 0.2 4 ppm OTA, while broiler chickens threshold level, the endosomal membranes become dis-
develop toxicosis at 2 ppm OTA (Haschek et al., 2002). rupted and the drug leaks into the cytosol where it acti-
The renal lesions in pigs consist of proximal tubular vates the intrinsic apoptotic pathway, increases
degeneration and atrophy with interstitial fibrosis and production of reactive oxygen intermediates, and interacts
infiltration by mononuclear cells. Cystic dilatation of with mitochondria to interrupt the respiratory chain.
degenerated tubules occurs, which can lend a pitted, Interaction with endoplasmic reticulum and Golgi appara-
irregular appearance to the renal capsule; glomerular hya- tus results in dysfunction of protein synthesis and packag-
linization may occur in severe cases. In acute cases, peri- ing. In sublethally affected cells, aminoglycosides
renal edema may occur (Maxie and Newman, 2007). interfere with cell membrane transporter systems, altering
Additional lesions of OTA toxicosis in pigs include mul- tubular reabsorption and threatening epithelial cell viabil-
tifocal necrotizing enteritis, fatty degeneration of the ity. Cellular necrosis and apoptosis result in the accumu-
liver and lymphoid necrosis (Szczech et al., 1973). In lation of cellular residues in the tubular lumen, causing