Microalbuminuria in Cats

Introduction

Microalbuminuria is an important predictor of nephropathy in people with diabetes or hypertension, and early intervention after detection can prevent the progression to renal failure.¹ Microalbuminuria is present in 12% of nondiabetic people and is associated with renal functional abnormalities.² With mounting evidence that microalbuminuria may be an early predictor of renal disease, investigation of this condition in cats is warranted.

Microalbuminuria is defined as the presence of a small amount of albumin (1 to 30 mg/dL) in the urine. Most of the protein in urine is albumin, although exceptions to this include hemoglobinuria, myoglobulinuria, or paraproteinuria from neoplastic conditions such as multiple myeloma.

Testing for Microalbuminuria

Standard urine dipsticks can detect albumin in the urine at levels of 30 mg/dL or higher, and this level is termed overt proteinuria. Microalbuminuria is an albumin concentration beneath the limit of detection of standard dipsticks. Spot measurement of urine protein concentration may not accurately reflect the true amount of albumin lost in the urine, as the concentration varies based on the urine specific gravity. For people, 24-hour protein excretion is the standard method of urinary protein measurement. Because obtaining a complete 24-hour urine sample from animals is difficult, other methods of estimating the 24-hour urine protein loss are often utilized. The urine protein to urine creatinine ratio (UPC) uses the urine creatinine concentration to adjust for urine concentration. A UPC <0.5 has been considered normal, although lower values may be more significant than previously thought.

Albumin levels <30 mg/dL can be measured at some reference laboratories with an enzyme-linked immunosorbent assay (ELISA) using an antibody specific for feline albumin. The same pitfalls in interpretation relative to urine concentration and volume apply for albuminuria as they do for proteinuria. The urine albumin to urine creatinine ratio (UAC) has been used in a fashion similar to the UPC. Dipsticks designed to detect microalbuminuria in people are not reliable for measuring albuminuria in dogs, and to the author’s knowledge, they have not been evaluated in cats.³

A new dipstick test has been developed to measure microalbuminuria in cats.^a This test is based on ELISA technology utilizing a feline albumin antibody. Instead of measuring the urine creatinine to determine a UAC, the urine is diluted to a specific gravity of 1.010 in order to standardize measurements across the spectrum of urine concentrating ability. The test is semi-quantitative and gives negative or low, medium, or high-positive results rather than providing a specific quantification.

The accuracy of this test appears to be good. The sensitivity of the test is 95%, with a specificity of >99%, so there are essentially no false-positive results.^b When cats negative for microalbuminuria were tested by routine dipstick analysis, the majority were positive at trace to 1+ by the standard technique, indicating that there are a lot of false positives with the routine dipstick test.

Causes of Microalbuminuria

Albuminuria can occur from prerenal, renal, or postrenal causes. Causes of prerenal microalbuminuria in people include strenuous exercise, fever, hypothermia, seizures, and venous congestion. In dogs, it has been shown that strenuous exercise does not induce microalbuminuria.⁴ Postrenal causes of microalbuminuria include lower urinary tract infection or inflammation. Hematuria produces a positive result if there is sufficient blood to cause the urine to be grossly pink or red. Cats with feline lower urinary tract disease (FLUTD) syndrome may have a positive test, but not all cats with FLUTD test positive despite active disease.

The source that is most concerning is renal microalbuminuria. Normally only a small amount of albumin is filtered at the glomerulus, and most of that albumin is degraded and reabsorbed by the proximal tubule. Usually only <1 mg/dL of albumin appears in the urine. However, a number of conditions can temporarily or permanently cause an increase in urinary protein excretion by either altering glomerular membrane permeability, inducing glomerular capillary hypertension, or reducing tubular reabsorption. The presence of microalbuminuria in diabetic people is a strong predictor of incipient nephropathy. In people, aggressive glycemic control and treatment of hypertension can stop the progression to overt proteinuria, azotemia, and end-stage renal failure. The same conditions that lead to overt proteinuria and protein-losing nephropathy can cause microalbuminuria in their early stages in dogs.^5–7 Primary protein-losing nephropathy with overt proteinuria, hypoalbuminemia, and other components of the nephrotic syndrome are uncommon in cats, however.

Hypertension is associated with microalbuminuria in people. In a surgically induced model of chronic renal failure (CRF) in cats, albuminuria was correlated with an increase in blood pressure.⁸ In a naturally occurring feline renal failure study, the albumin:creatinine ratio was positively correlated with blood pressure and with creatinine.⁹

Microalbuminuria may also occur as a consequence of diseases not primarily involving the kidney. Inflammatory diseases in humans that are associated with microalbuminuria include inflammatory bowel disease, neoplasia, systemic sclerosis, sickle cell anemia, ankylosing spondylitis, acute stroke, acute pancreatitis, and myocardial infarction.¹⁰¹¹ Critically ill people have a 69% prevalence of microalbuminuria, and the presence of microalbuminuria is a predictor of mortality.¹¹ The microalbuminuria in this instance is a marker of disease severity, not the cause of the mortality. Microalbuminuria is also a predictor of mortality secondary to cardiovascular disease. Studies in dogs with lymphosarcoma or osteosarcoma have shown increased microalbuminuria, although microalbuminuria did not decrease with reduced tumor burden.¹² Diseases in the cat that have been associated with microalbuminuria include dental disease, cholangiohepatitis, inflammatory bowel disease, immune-mediated diseases, feline infectious peritonitis, feline immunodeficiency virus infection, feline leukemia virus infection, heartworm disease, ehrlichiosis, diabetes mellitus, hypertension, hyperthyroidism, and neoplasia.^b

Prevalence and Significance of Microalbuminuria in Cats

In a study of over 600 healthy cats, about 14% had microalbuminuria, with the prevalence increasing with age [Figure 1].^c In a study of 345 cats with a variety of medical conditions, the overall incidence of microalbuminuria was almost 43%.^c The prevalence in the older age groups was similar to that of the healthy cats, but there was a marked increase in the prevalence of microalbuminuria in the younger cats that were ill [Figure 2].^c

Not all cats that develop microalbuminuria progress to renal failure. In nondiabetic people, microalbuminuria has been associated with an initial period of hyperfiltration, which is not present at higher levels of microalbuminuria or macroalbuminuria.² This finding led to the speculation that the affected humans with hyperfiltration (the microalbuminuria group) would eventually progress to renal functional impairment (the macroalbuminuria group), although the cross-sectional study design prevented the authors from reaching a firm conclusion. Because microalbuminuria can be caused by a variety of different events that secondarily damage the kidney, a thorough search for the underlying cause is indicated, with the hope that treatment of the cause may result in regression of the microalbuminuria. In approximately 50% of microalbuminuric cats and dogs, an underlying cause cannot be found.^c

The significance of microalbuminuria in cats is unclear. Furthermore, there is only limited information available on the predictive value of proteinuria in general. In a study of cats with naturally occurring CRF, the urine albumin:creatinine ratio was correlated with survival time. Median survival time of cats with a protein:creatinine ratio >0.43 was 281 days versus 766 days for those with a lower UPC.¹³

Angiotensin converting enzyme (ACE) inhibitors reduce proteinuria by decreasing the glomerular capillary hydrostatic pressure and by potentially inducing changes in the mesangial cells. In one study, the ACE inhibitor, benazepril, also decreased glomerular blood pressure and hypertrophy in a surgical model of CRF in cats.¹⁴ In a randomized placebo-controlled study of cats with naturally occurring CRF, cats treated with benazepril had a lower posttreatment UPC than placebo-treated cats, and this effect was more dramatic in cats with a higher initial UPC.¹⁵ In the placebo group, the initial UPC correlated with survival time, and in a subgroup of cats with a UPC >1.0 (i.e., overt proteinuria), benazepril conferred a survival advantage. It is important to note that the subgroup with a UPC >1.0 was a small group of cats and that there was not a statistically significant difference in overall survival of the cats treated with benazepril. Because microalbuminuric animals may have a UPC <0.5, it is difficult to draw conclusions about the significance of microalbuminuria in predicting survival.

Recommendations

Easy testing for microalbuminuria in cats has only recently become available, and information about microalbuminuria is rapidly accruing. It is difficult to make firm recommendations about testing protocols for microalbuminuria until results of longitudinal studies become available. In canine breeds predisposed to hereditary glomerulonephritis, testing of young dogs may help to identify affected individuals, but hereditary glomerulonephritis has not been described in cats except for amyloidosis in Abyssinians.

Because the prevalence of microalbuminuria increases with age, routine testing of older cats is rational. If microalbuminuria is detected, general diagnostics (e.g., biochemical panel, complete blood count, complete urinalysis, blood pressure measurement, serum thyroid levels) to search for causes of microalbuminuria are warranted. If an underlying condition is discovered, treatment should be instituted and the microalbuminuria followed to determine effectiveness of therapy. If no underlying cause is found and the microalbuminuria persists, the trend in measurements should be followed over time. The long-term effects of stable microalbuminuria are unknown, but it intuitively makes sense to avoid potential damage to the kidneys (i.e., aggressive fluid therapy prior to and during anesthesia, judicious use of nephrotoxic drugs) in any cat that is persistently positive. Because an increasing level of microalbuminuria predicts progression to overt proteinuria in dogs, further diagnostic testing (e.g., radiography, ultrasonography, serology) in cats with an increasing microalbuminuria level should be considered. At this point in time, evidence is insufficient to recommend routine use of ACE inhibitors in cats unless overt proteinuria develops.

Conclusion

Microalbuminuria is an important indicator of early renal damage. Further evaluation of microalbuminuria will hopefully better determine which animals to test and when to test them, as well as determine which animal is most likely to benefit from interventive therapy.