Background: Previously we found that kidney tissue and urinary exosomes from patients of diabetic kidney disease (presenting with microalbuminuria) showed high levels of ceruloplasmin (CP). Because CP is an acute phase protein of kidney origin, it could be an early marker of many other kidney diseases. To investigate this hypothesis we first measured urine exosomal and kidney expression of CP in non-diabetic kidney disease patients (membranous nephropathy, focal segmental glomerulosclerosis, lupus nephritis and IgA nephropathy) followed by a longitudinal study in rat passive Heymann nephritis (PHN), a model of human membranous nephropathy. Methods: Urinary exosomes were isolated from urine of chronic kidney disease patients (and rats) by differential centrifugation. The exosomal extracts were used for measuring CP using ELISA. Kidney expression of CP was evaluated by immune-staining biopsy tissues. Similar techniques were applied in rat PHN model to analyze urine exosomal and kidney CP. Rat PHN was produced by injection of anti-gp600 antiserum prepared previously. Results: Ceruloplasmin level was found to be >10-20 times higher in CKD patient samples compared to control subjects. Consistent with the high CP levels in exosomes, we found high immune-reactive CP localized in tubules and collecting ducts of biopsies of CKD patients. In the PHN model urinary exosomal CP level was significantly higher prior to the onset of proteinuria. Early rise of urine exosomal CP, which preceded proteinuria, correlated with high immunoreactive CP found in rat kidneys at this time. Conclusion: We propose that increase of urine exosomal CP is a signal for underlying kidney disease occurring prior to proteinuria, making it a potential urinary biomarker to diagnose early kidney disease of many different etiologies.
Krishnamurthy P Gudehithlu, Peter Hart, Amit Joshi, Ignacio Garcia-Gomez, David J Cimbaluk, George Dunea, Jose A L Arruda and Ashok K Singh
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