Background: Diabetic nephropathy is a serious complication of both type 1 and type 2 diabetes. It's also called diabetic kidney disease (DKD). In the United States, about 1 in 3 people with diabetes have diabetic nephropathy. This necessitates identifying better biomarkers that diagnose diabetic nephropathy. The study aimed to evaluate tumor necrosis factor α (TNFα) and type IV collagen as potential biomarkers for the detection of diabetic nephropathy and its progression in patients with type 2 diabetes. Materials and Methods: A total of 88 subjects were included in this cross-sectional study. Patients were classified into three ‎major groups; diabetics with DKD group (n=50), diabetics without DKD group (n=28), and healthy control group (n=10). TNFα and type IV collagen levels were measured in all subjects. The diagnostic value of single and combined TNFα and type IV collagen was assessed by the area under the receiver operating characteristic (AUC). Results: For discrimination between diabetics with DKD from healthy individuals, the most efficient marker was TNF-α (AUC= 0.81, 70% sensitivity, and 70% specificity. For discriminant between DM patients with DKD from DM patients without DKD, the most efficient marker was type IV collagen (AUC= 0.77, 69% sensitivity, and 73% specificity. Interestingly, we developed a new index for differentiating between DM and DM-DKD based on two blood markers (TNF-α and type IV collagen). The AUC of the developed index was 0.93; 0.79 for discriminated DM with DKD from DM without DKD. The AUC of the developed index was 0.90 for discriminated early DKD from healthy individuals. Also, The AUC of the developed index was 0.83 for discrimination early from late DKD among DM patients.
 Conclusions:  TNFα and type IV collagen may be potentially useful for early detection and to discriminate diabetics with DKD from DM without DKD.