Renal diseases are common disorders of felines, considered a leading death cause, and exhibit a diagnostic challenge due to a shortage of early damage markers. The traditional biomarkers [e.g., serum creatinine (sCr) and blood urea nitrogen (BUN)] have low diagnostic sensitivity; thus, acute cases progress to chronic. This study aimed to clarify the clinicopathological, ultrasonographic, and pathological findings of cats affected with renal diseases, and the performance of novel renal biomarkers [symmetric dimethyl arginine (SDMA), kidney injury molecule-1 (KIM-1), Tamm-Horsfall protein (THP), and N-acetyl-β-D-glucosaminidase (NAG)] against the traditional ones. Furthermore, assessing the novel biomarker's role in the follow-up of treated cases. 86 cats were allocated into 4 groups depending on clinical signs, physical examination, sCr concentration, and urine specific gravity (USG) as follows: I. Control negative group (15 apparently healthy cats), II. Control positive group (22 renal diseased cats), III. Pre-azotemic group (31 cats), and IV. Diseased and treated group (18 treated cats). Blood and spot urine samples were collected from all groups. Blood samples for hematological, biochemical, arterial blood gas (ABG) analysis, as well as, SDMA, and KIM-1 concentrations and spot urine samples for routine urinalysis, some biochemical parameters, NAG activity, and THP concentration. Groups II and III showed microcytic hypochromic anemia and significant leukopenia, significant increases in serum concentrations of SDMA, and KIM-1, and activity of urinary NAG; meanwhile, they showed a significant decrease in urinary THP concentration. Group IV after treatment revealed an improvement of all measured parameters except urinary THP concentration. In conclusion, the current study results found out that SDMA, KIM-1, and NAG could serve as efficient biomarkers of early renal injury detection and treatment follow-up.