Background: Our laboratory previously demonstrated that heparanase (HPSE), an enzyme that cleaves heparan sulfate, upregulates growth factors and their receptors, resulting in enhanced multiple myeloma (MM) growth, chemoresistance, and metastasis. Targeting HPSE therapeutically decreases chemoresistance and relapse. Renal dysfunction is a major problem in MM patients with nearly 50% having renal dysfunction at diagnosis of which 19% are advanced, and 8% require dialysis. There is no specific therapy for myeloma associated renal dysfunction highlighting the need to identify novel mechanisms that lead to the development of targeted therapies. This is the first study to investigate the association between HPSE activity and renal dysfunction in MM patients by utilizing high-sensitivity biomarkers.Methods: Human Kidney 2 (HK-2) cells were treated with HPSE. Necrosis and apoptosis were assessed by flow cytometry. Cell lysates were examined for expression of kidney injury biomarkers by western blotting. HK-2 clusters were co-cultured with MM-spheroids with low or high HPSE. SCID mice were injected with 3 million luciferase-positive myeloma cells with low or high level of HPSE. Kidneys were harvested after 3 weeks and processed for studies. HPSE activity and biomarkers using multiplex magnetic bead ELISA were assessed in peripheral blood from a MM patient with serum creatinine 1.2 mg/dL and a healthy control donor. Results: HPSE induced HK-2 cell necrosis and apoptosis. HPSE induced significant expression by HK-2 cells of KIM-1, NGAL and IGFBP-7. Co-culturing HK-2 organoids with MM-spheroids expressing high HPSE compromised HK-2 organoids survival over 7 days. Damage to HK-2 cells was prevented by HPSE inhibitors Roneparstat or OGT-2115. Kidney tissues from mice harboring HPSE-high myeloma tumors expressed more KIM-1 and NGAL than those harboring HPSE-low myeloma tumors. HPSE activity was 6-fold higher and kidney injury biomarkers were many fold (range 2 – 84) higher in the plasma of a MM patient than in plasma from healthy control. Conclusions: HPSE causes kidney cellular injury which can be detected early by the measurement of high sensitivity biomarkers and can be prevented by treatment with HPSE inhibitors, Roneparstat and OGT-2115. Further studies are ongoing to investigate the association between HPSE activity and renal dysfunction in a larger cohort of MM patients which have been accrued as a part of the UAB-Integrative Molecular And Genetic Epidemiology (IMAGE) Study of Myeloma.