Diabetic Kidney Disease (DKD) is the leading cause of end-stage renal disease (ESRD) in Australia. Furthermore, individuals with DKD are at significant risk of cardiovascular (CV) morbidity and mortality, underscoring the importance of early identification, prevention and treatment. It is therefore imperative that patients with diabetes at the greatest risk for a progressive decline in glomerular filtration rate (GFR) are accurately identified so that the management of their risk factors for worsening renal function are optimized. Current clinical risk markers, such as albuminuria, lack predictive accuracy for determining a patient’s risk for a progressive decline in GFR. Furthermore, a significant number of patients with diabetes are now recognized as following a non-albuminuric pathway to renal impairment. Several promising novel serum and urine biomarkers may help to stratify risk for developing progressive DKD in patients with type 2 diabetes. The overall aims of this study are to determine (i) the temporal relationships between changes in novel risk markers and a decline in GFR and (ii) whether novel risk markers improve risk prediction for renal-related events, CV death and all-cause mortality over and above that of traditional risk markers in patients with diabetes. Our preliminary studies suggest that circulating levels of the type 1 tissue necrosis factor receptor (TNFR1) increase as estimated GFR (eGFR) declines independently of albuminuria. Changes in sTNFR1 levels also improved prediction of eGFR decline on top of established risk markers for progression of DKD. Circulating levels of the urokinase plasminogen activator receptor (suPAR) also increase as eGFR declines but whether measuring this biomarker results in an incremental improvement on top of established risk markers for predicting eGFR decline remains to be fully defined. Currently, the potential of uric acid and urinary monocyte chemotactic protein-1 as potential biomarkers for progressive DKD are also being investigated.