Urinary albumin to protein ratio: more of the same or making a difference?

Abstract

In this issue, Smith et al. [1] consider whether the simple ratio of urine albumin to total protein (uAPR) provides a measure of low molecular weight (LMW) proteinuria that distinguishes tubular versus glomerular pathology. In a retrospectively studied cohort of 1011 proteinuric patients [protein:creatinine ratio (PCR) >30 mg/mmol], uAPR was correlated with simultaneous findings on urine protein immunofixation electrophoresis (uPEI). A single, blinded observer categorized the electrophoresis pattern as being either tubular (predominantly LMW), glomerular (a dominant albumin band), mixed or overflow (light chain monoclone) proteinuria. The LMW protein b2-microglobulin (b2M) and the tubular enzyme N-acetyl-b-D-glucosaminidase (NAG) were also measured in a subgroup (n ¼ 248) of outpatients and their predictive performance at uPEI classification compared to that of uAPR. Renal biopsy results were available to confirm the diagnostic utility of uAPR for only 68 patients. uAPR gave a reasonable prediction of a ‘tubular’ uPEI proteinuria pattern in ROC curve analysis (AUC 0.84), which was similar to that of b2M and NAG. It also performed better than albuminuria alone in differentiating primary tubular versus glomerular pathology confirmed on biopsy. Clearly, measurement of urine protein leak is central to the detection, diagnosis, prognosis and treatment of kidney disease. Most guidelines currently recommend the measurement of an early morning spot urine for either albumin:creatinine ratio or protein:creatinine ratio. In general, lowlevel albuminuria/proteinuria is considered reflective of vascular or tubulointerstitial renal pathology, while higher levels (>1 g/g � 1 g/24 h) are thought to reflect underlying glomerular pathology. Such interpretation is rather simplistic and frustrating in view of the ready availability of urine for more extensive analysis and interpretation. With the exception of haematology, no other specialty has easy access to a body fluid so closely related to the function of the organ for which it is responsible. Interpretation of raised urine protein level is confounded by the various inter-related factors that influence its excretion (Table 1). These include glomerular factors affecting filtration, tubular factors controlling reabsorption of filtered proteins and vascular influences both at the glomerular and peritubular level. Consequently, the excreted urine protein is seldom the simple result of a well-defined pathology; instead, it mirrors complex glomerular, tubular and vascular interactions. Furthermore, excessively filtered/re-absorbed protein has been implicated for the last 20 years in the pathogenesis of glomerular and tubulointerstitial sclerosis, respectively [2, 3], thus potentially aggravating the very processes that contribute to its leakage. Previous investigations of the clinical implications of urine protein profiles have categorized leaked plasma proteins as low, intermediate or high molecular weight (MW)