Andrew H. Sparkes, BvetMed, PhD, DECVIM, MRCVS; Ellie J. Mardell, MA, VetMB, CertSAM, MRCVS
Urine produced by a healthy kidney contains little protein, as these molecules are largely retained at the level of the glomerulus due to their size and/or charge. Small proteins or amino acids that do pass through the normal glomerulus are mostly reabsorbed by renal tubules, or degraded by tubular epithelial cells. Persistently increased proteinuria is an abnormal finding, and in the absence of lower urinary tract disease may reflect either altered glomerular permeability, reduced tubular re-absorption; increased secretion of proteins from tubular epithelial cells or, less commonly, overflow from the circulation if there is raised serum levels of low-molecular weight proteins). Alterations in glomerular permeability may occur in primary glomerular disease (amyloidosis, immune-mediated glomerulonephritis, hereditary glomerulonephropathies) or as a result of glomerular capillary hypertension, or endothelial cell dysfunction.
Proteinuria (in the absence of lower urinary tract disease) is therefore usually a marker of renal damage or dysfunction (glomerular or tubular), although this may result from either primary or secondary renal disease. In human beings, most cases of renal failure occur secondary to diabetes mellitus or essential hypertension, and there is considerable interest in the potential role of proteinuria as a cause, as well as an indicator, of progressive renal damage. Proteinuria may be measured quantitatively over 24 hours, or more simply by a random urine protein to creatinine (UPC) ratio (the two showing a close correlation in both humans and cats). However, evidence in humans suggests that early increases in albuminuria (microalbuminuria, MA) reflect glomerular damage undetectable by the traditional UPC ratio, and may serve as both a negative prognostic marker and also potentially contribute to renal damage in cases of renal failure, although MA may also be found in conditions affecting glomerular function other than renal failure. In man, MA is defined as an albumin to creatinine ratio (expressed as mg albumin/g creatinine) in the range 30-300, which equates to urinary albumin loss of 20-200 µg/min. Smaller losses are within normal ranges and greater losses are detectable by the UPC ratio (overt proteinuria). Monitoring for MA is encouraged in patients at risk of renal disease in order to allow early therapeutic intervention.
In the veterinary field, significant renal-origin proteinuria has been demonstrated in association with a variety of underlying conditions in dogs, and there is evidence to suggest that in cases of canine chronic renal failure, proteinuria is a negative prognostic indicator, with a number of recent studies also evaluating MA in dogs. In the cat, a UPC ratio >0.4-0.5 is accepted as abnormal proteinuria. Proteinuria has been shown to occur in cats with immune-mediated glomerulonephritis, multiple myeloma, acute renal failure, chronic renal failure, hyperthyroidism acute pancreatitis, drug reactions and hypertension. There is also preliminary evidence that higher levels of proteinuria correlate with reduced survival times in cats with or without renal failure.
Much less is known about the occurrence and significance of MA in the cat though. A commercial semi-quantitative ELISA-based test for the measurement of feline MA is available, but normal urine albumin concentrations have not been well established for feline patients. One brief report suggests that healthy cats may have an age-related increase in urinary albumin concentrations, and that cats with a wide range of medical conditions may also have elevated MA measurements. However, the fact that tubulointerstitial disease (rather than glomerular disease) tends to dominate in feline renal failure raises important doubts over any assumptions that the interpretation of MA in cats will necessarily be the same as in humans.
In this study, proteinuria was assessed in 100 randomly selected sick cats and 22 healthy cats by means of the urine protein:creatinine ratio, a traditional urine 'dipstick' and a commercial ELISA-based dipstick designed to detect microalbuminuria (MA) semi-quantitatively. In addition the repeatability and reproducibility of the MA test was assessed by comparing results of five replicate tests of 26 urine samples, interpreted by two different readers. Discrepancies existed in the replicate test results in 23% and 27% of the samples examined by reader 1 and 2 respectively, and on several occasions this discrepancy was between whether the sample was 'positive' or 'negative' for MA. The inter-reader agreement was good (κ=0.75), but again discrepancies were noted and part of the reason for these problems appeared to be the necessity for subjective interpretation of colour changes when reading test results. Proteinuria was significantly (P<0.014) more prevalent in the sick than the healthy cats with 36% and 9% respectively having detectable MA, 34% and 5% respectively having a UPC ratio >0.5, and 84% and 9% respectively having positive urine protein dipstick analysis. There was a moderate significant correlation between UPC ratio and MA concentrations (rs=0.68, P<0.0001). While 13/87 cats with a UPC ratio <0.5 had positive MA results, 10/84 cats with negative MA results had a UPC ratio >0.5, and none of these had evidence of lower urinary tract disease. This study confirmed that MA and proteinuria are commonly seen in cats with a variety of diseases, but they are not necessarily both elevated, and the UPC ratio can be elevated with negative MA results. Furthermore, some repeatability problems were demonstrated with the semi-quantitative MA test. These findings demonstrate that the semi-quantitative MA test should not be relied on as the sole determinant of proteinuria.