Chronic kidney disease (CKD) is a major cause of illness in dogs, and it is commonly caused by glomerular diseases that result in proteinuria and a progressive decline in renal function. Despite the importance of glomerular lesions, tubulointerstitial fibrosis identified by histologic evaluation of renal biopsies correlates best with renal function. However, performing a renal biopsy is invasive. Most current non-invasive tests for renal function lack adequate sensitivity and specificity for renal disease. Proteinuria can be both a sensitive and specific marker for renal damage. However, its evaluation in veterinary medicine beyond determination of the magnitude of proteinuria (e.g., urine protein:creatinine ratio (UPC)) is limited. Therefore, in this report, further evaluation of the UPC was performed to aid in the monitoring of renal disease progression and response to treatment. In addition, qualitative evaluation of proteinuria was performed in dogs with progressive CKD in order to identify better non-invasive markers for tubulointerstitial injury. The day-to-day variability of the UPC was determined utilizing data obtained from female dogs that are carriers for X-linked hereditary nephropathy (XLHN). Despite an unchanging magnitude of proteinuria in these dogs, substantial variation in their UPC was observed. Using these results, guidelines were suggested to help assess whether disease progression or treatment leads to a significant change in UPC. Qualitative characterization of proteinuria in dogs with CKD was performed using urine from male dogs affected with XLHN, and results were correlated with clinical and histologic findings concerning renal function and damage. The two discovery proteomic techniques utilized (chromatographic chip array and two-dimensional gel electrophoresis) revealed several proteins that have not previously been implicated as markers for canine CKD, providing a basis for future studies. Specific assays for urinary biomarkers of renal injury were used to serially evaluate renal function in these dogs. All proteins evaluated proved to be sensitive markers for renal damage. However, only retinol binding protein provided clear evidence for renal disease progression. These results will provide the foundation for future studies aimed at monitoring urinary biomarkers in dogs with CKD, which will ultimately help veterinarians better diagnose and monitor proteinuric renal disease.