Kidney Injury Molecule 1: A potential biomarker of renal injury in the cat

The prevalence of both acute and chronic kidney disease in animals and people is increasing. Increased serum creatinine concentration indicates a decline in renal function but is insensitive for diagnosing acute kidney injury (AKI). As such, there is need to develop sensitive biomarkers of renal injury. At the fore in human medicine is a biomarker of acute renal tubular injury called kidney injury molecule-1 (KIM-1). KIM-1 is a cell membrane glycoprotein with an extracellular domain that is shed from proximal tubular kidney cells and detectable in urine after ischemic and toxic renal injury. KIM-1 was undetectable in normal human urine, but presence in urine correlated with immunohistochemical detection of KIM-1 in injured tubular epithelial cells. For these reasons, KIM-1 was considered a good candidate to investigate as a biomarker of kidney injury in cats. Alignment of KIM-1 sequences from human, rat, dog, and mice indicated a high degree of identity between species and conservation of a cytoplasmic tyrosine motif. Primers based on the conserved regions were used to amplify feline KIM-1 genomic and renal cDNA sequences. PCR assays used to amplify feline KIM-1 revealed the presence of three transcript variants derived by alternative splicing with exon-intron organization similar to KIM-1 orthologous sequences. KIM-1 was detected by IHC in tubules of the cortex and outer stripe of the outer medulla in cats with suspected naturally occurring AKI and cats with experimental unilateral ischemia/reperfusion. The same cells also expressed aquaporin 1, confirming expression of KIM-1 in the proximal convoluted tubules. Further, KIM-1 expression correlated positively with tubular injury scores and vimentin expression in the injured proximal tubules. Available urine immunoassay to rat Kim-1 yielded positive reactions with urine from 11 cats. In conclusion, feline KIM-1 is similar but not identical to human KIM-1. Expression is increased in cats with naturally occurring and experimental kidney injury, and KIM-1 may be detected in urine. KIM-1 is expressed predominantly in cells of the S3 segment of proximal tubules, and appears to persist during dedifferentiation and repair of injured cells. Hence, detection of KIM-1 in urine is a promising indicator of kidney injury in cats.