<b><i>Introduction:</i></b> Kidney biopsies (KBs) are performed in patients with type 2 diabetes (T2D) to diagnose non-diabetic or hypertensive kidney disease (NDHKD) potentially requiring specific management compared to diabetic and or hypertensive nephropathy (absence of NDHKD). Indications for KB are based on the presence of atypical features compared to the typical course of diabetic nephropathy. In this study, we assessed the association of different patterns of atypical features, or KB indications, with NDHKD. <b><i>Methods:</i></b> Native KBs performed in patients with T2D were analyzed. Data were collected from the patients’ records. KB indications were determined according to the presence of different atypical features considered sequentially: (1) presence of any feature suggesting NDHKD which is not among the following ones, (2) recent onset of nephrotic syndrome, (3) low or rapidly declining estimated glomerular filtration rate (eGFR), (4) rapid increase in proteinuria, (5) short duration of diabetes, (6) presence of hematuria, or (7) normal retinal examination. <b><i>Results:</i></b> Among the 463 KBs analyzed, NDHKD was diagnosed in 40% of the total population and 54, 40, 24, and 7% of the KBs performed for indications 1–4 respectively. Conversely, no patient who underwent KB for indications 5–7 displayed NDHKD. Logistic regression analyses identified eGFR<sub>CKD-EPI</sub> >15 mL/min/1.73 m<sup>2</sup>, urinary protein-to-Cr ratio <0.3 g/mmol, hematuria, HbA1c <7%, and diabetes duration <5 years as predictors of NDHKD, independently from the indication group. <b><i>Conclusion:</i></b> NDHKD is frequent in T2D. Despite the association of hematuria with NDHKD, our results suggest that presence of hematuria and absence of DR are insufficient to indicate KB in the absence of concurrent atypical features. Conversely, rapid progression of proteinuria and rapid deterioration of eGFR are major signals of NDHKD.