Why albumin to creatinine ratio should replace protein to creatinine ratio: it is not just about nephrologists

Abstract

Accurate identification of proteinuria is essential to the diagnosis and management of patients with kidney disease, as stated by Methven and MacGregor. We can further agree that collection of 24 h urine samples is not necessary to measure protein loss and that reagent strip devices are generally unsuitable for proteinuria detection. However, these authors conclude that the urinary albumin to creatinine ratio (ACR) is less sensitive than urinary total protein to creatinine ratio (PCR) at predicting proteinuria and patient-relevant outcomes, fails to detect a significant minority of proteinuric patients and is more costly. We present an alternative view that although urinary albumin assays are marginally more expensive, they offer a more accurate and reliable test for proteinuria, especially at the low levels seen in the early stages of chronic kidney disease (CKD), the prognostic importance of which is becoming increasingly apparent. Further, urinary total protein assays are subject to interference which may give a false-positive indication of proteinuria potentially resulting in overinvestigation and unnecessary patient anxiety. If proteinuria in this context is defined as urinary loss of ‘total protein’, as historically it has been, then it is inevitable that ACR will appear worse at predicting proteinuria than PCR, since both PCR and urinary total protein loss are based on the same total protein measurement. But this presupposes that total protein loss should be the metric by which we judge the degree of kidney damage and glomerular permeability. The association between kidney disease and proteinuria goes back at least as far as the early 19th century, when Bright first described albuminous nephritis. It was not until the 1960s that sensitive assays capable of specifically measuring urinary albumin became available. For much of the intervening period, and beyond, the so-called total protein methods have been used to estimate urinary protein concentration albeit that, somewhat unknowingly, albumin has always been the main protein that has been measured. Although Bright and others were able to recognize the critical importance of albumin in this context, it is not surprising that (total) ‘proteinuria’ has subsequently remained embedded in clinical nephrology practice as the sine qua non. But laboratory diagnostics does not stand still: increasing evidence suggests that albumin measurement is both a technically superior test and a better marker of kidney damage. Methven et al. state that ACR is less sensitive than PCR at predicting proteinuria. As noted above, this analysis was biased in favour of PCR, and in any case is not the key question. Let us ask instead: what is the best test at detecting a clinically significant increase in urinary protein loss? Urinary albumin measurement provides a more specific and sensitive measure of changes in glomerular permeability than total protein. Albuminuria is the earliest marker of glomerular diseases, including diabetic glomerulosclerosis, where it generally appears before the reduction in glomerular filtration rate (GFR). Albumin is the predominant protein in the vast majority of proteinuric kidney diseases: generally proteinuria reflects albuminuria. In health, relatively small amounts of albumin (less than 30mg/ 24 h) are lost in the urine.* Because total protein assays are imprecise and insensitive at low concentrations,