Urinary parameters predictive of cisplatin-induced acute renal injury in dogs.
A 28-day study was conducted to evaluate changes in urinary cytokine/chemokine expression levels in dogs with renal injury due to administration of cisplatin. Animals (n=17) were administered cisplatin at 0.75 mg/kg/day (i.v.) for five consecutive days. Urine/serum were collected at pre-dosing, 4h post-dosing and on days 2, 3, 4, 8, 10, 14, 16, 18, 21, 23, 25, 28 and unscheduled terminations. Animals were euthanized when serum creatinine (sCr) levels measured at ≥ 1.9 mg/dL, indicating significant loss of renal function (decreased glomerular filtration rate). Relevant clinical observations included lethargy and dehydration. Pre-study sCr levels ranged from 0.6 to 0.8 mg/dL; on days 1 through 4, sCr levels ranged from 0.5 and 1.1mg/dL; and terminal sCr levels ranged from 0.6 and 6.6 mg/dL. Histologically, cisplatin-related renal changes were characterized as proximal tubule dilatation, vacuolization, degeneration, regeneration, and interstitial inflammation. Increased interleukin (IL)-2, IL-8, monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GMCSF) and keratinocyte-derived chemokine (KC) occurred on days 3 through 4. Increased IL-7 occurred on day 4. This study showed for the first time that inflammatory cytokines/chemokines in urine positively identified acute renal tubular injury in dogs at time points earlier than sCr, a traditional marker of nephrotoxicity.
McDuffie
J Eric
JE
Global Preclinical Development, Johnson & Johnson Pharmaceutical Research and Development LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. jmcduffi@its.jnj.com
Sablad
Marciano
M
Ma
JingYing
J
Snook
Sandra
S
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000503:physiopathology / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D016207:Cytokines / Q000097:blood / Q000652:urine; D004285:Dogs; D005919:Glomerular Filtration Rate; D008297:Male
D000970:Antineoplastic Agents; D016207:Cytokines; D002945:Cisplatin