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Proceeding of the NAVC North American Veterinary Conference

Jan. 8-12, 2005, Orlando, Florida

Reprinted in the IVIS website with the permission of the NAVC http://www.ivis.org/

Published in IVIS with the permission of the NAVC

The North American Veterinary Conference 2005 Proceedings

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THE PRACTITIONERS APPROACH TO PROTEINURIA

George E. Lees, DVM, MS, DACVIM Texas A&M University College Station, TX Frederick L. Metzger, DVM, DABVP Metzger Animal Hospital State College, PA Urine obtained from healthy dogs or cats with healthy kidneys typically contains a small amount of protein, but proteinuria generally means detection of an excess of protein in the urine. Several methods are utilized to detect proteinuria in dogs and cats including: (1) semiquantitative tests in a conventional urinalysis, (2) determination of urine protein:creatinine ratio (UPC), and (3) assay of urine albumin concentration. Each method has its place in veterinary practice but none of the methods entirely replaces the others, and they can be used in a complementary fashion. Many conditions can result in proteinuria without having associated renal disease. This type of proteinuria has been classified as functional renal proteinuria (as opposed to pathological renal proteinuria). The hallmark of such functional proteinuria is that it is mild and transient, but pathological proteinuria generally is persistent, unless the renal lesions that are responsible for it actually resolve. Thus, to avoid undue concern about proteinuria that might be functional, it is important to distinguish between transient proteinuria and persistent proteinuria, especially when the magnitude of proteinuria is not large. The only way to know whether proteinuria is transient or persistent, of course, is to wait an appropriate interval and repeat the test. There is no well-established length of time to wait before retesting, and the appropriate interval may vary with circumstances; however, our suggestion is to consider proteinuria that can be demonstrated repeatedly over a period of a month (eg, 2 tests one month apart) or more to be defined as being persistent. Moreover, this principle applies regardless of the method(s) employed to detect the proteinuria. That is, persistent proteinuria should be considered a sign of renal disease (once the possibility of it having a prerenal or postrenal origin has been excluded properly), even if the magnitude of proteinuria (or albuminuria) is small. The reagent pad (dipstick) colorimetric test and the sulfosalicylic acid (SSA) turbidimetric test are two types of semiquantitative tests routinely used for urine protein determination. For technical reasons related to how dipstick colorimetric tests work, they often indicate a weak positive reaction (trace to 1+) in moderately to well concentrated and/or alkaline canine and feline urine samples even when proteinuria is not present. Such erroneous dipstick reactions occur because the buffer capacity of the reagent strip often is insufficient for the urine of dogs and cats, which frequently have urine that is more concentrated than the urine of humans for which the test strips were originally developed.1 Misleading dipstick colorimetric tests for protein can be distinguished from positive reactions that actually are indicative of proteinuria by performing a SSA turbidimetric test on supernatant urine from the same specimen.2 Thus, it is best to focus mainly on the SSA turbidimetric test result when interpreting a routine urinalysis. Consideration should be given to the urine specific gravity when interpreting the
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results of semiquantitative tests for proteinuria; however, there is no reliable way to interpret semiquantitative test results in conjunction with urine specific gravity values to confidently ascertain the amount of protein being lost in the urine. Thus, the next step when a semiquantitative test, especially the SSA turbidimetric test, gives a positive result is to determine the UPC regardless of the urine specific gravity value. The UPC cutoff most widely used in dogs and cats to differentiate values thought to be indicative of proteinuria from those that are not is 1.0 (ie, UPC values 1.0 considered abnormal). However, numerous reports of UPC values determined in healthy young adult dogs and cats indicate that such animals typically have UPC < 0.5. Thus, some have recommended interpreting UPC values < 0.5 as normal, those that are 0.5 but 1.0 as questionable, and values > 1.0 considered abnormal.1,3 Interpretation of UPC values is a prototypical example of the need to select an appropriate cutoff value for the way the test result is being used. In dogs, the cutoff must be as high as 2.0 to be confident that no dog is incorrectly labeled as proteinuric, especially if puppies less than 4 months of age are being evaluated. Dogs with UPC 2.0 are certain to be abnormal (ie, the cutoff giving near 100% specificity). Regardless of age, however, healthy dogs do not have UPC values that are persistently 0.5. Therefore, UPC 0.5 is the more appropriate cutoff to use when screening for proteinuria in apparently healthy dogs, and the important issue that is questionable about UPC values between 0.5 and 1.0 (or 2.0) is whether or not the proteinuria will prove to be persistent. Similarly, the most appropriate UPC cutoff value to use for cats should not be higher than 0.5. Emerging evidence from recent studies of cats with CKD suggests that even relatively small UPC increases (ie, into the 0.5 1.0 range) are consequential because they are associated with greater risk of more rapid disease progression.4 Evaluation of the UPC is the next most logical step for patients with a positive semiquantitative test for protein in a complete urinalysis that does not reflect concomitant urinary hemorrhage or inflammation,. Usually the UPC will confirm existence of proteinuria and provide an index of the magnitude of proteinuria for comparison with subsequent values as monitoring continues. If the positive semiquantitative test is not an indication of actual proteinuria (eg, as might be the case with a weak positive reaction in a highly concentrated urine sample), the UPC value will be less than 0.5. For animals that unequivocally have renal proteinuria (eg, dogs with a UPC 2.0 that is otherwise unexplained), testing to detect albuminuria is not worthwhile. For animals with UPC values in the questionable range; however, testing for albuminuria may be helpful. Additionally, testing for albuminuria is the logical next step to screen seemingly healthy animals (ie, those with negative semiquantitative tests or UPC values < 0.5) for evidence of renal disease. In our judgment, however, it is not justifiable to routinely screen all seemingly healthy animals for albuminuria. Seemingly healthy animals that should be screened for albuminuria are those with an increased risk of having renal disease either because of their age or some other factor (eg, a breed-associated predisposition).5 Assays have been developed to measure the concentration of albumin in the urine of dogs and cats using speciesspecific antibody-mediated methods.6,7 These assays have been calibrated to work optimally for measuring low concentrations of albuminuria that usually would escape 550
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Small Animal Nephrology - Urology detection by conventional semiquantitative tests (eg, dipstick colorimetric tests). As with the concentration of all urine proteins used in the UPC ratio, the concentration of urine albumin must be adjusted in some way for differences in urine volume and concentration to permit comparison of values within and among individuals. Although it is possible to calculate a urine albumin-to-creatinine ratio (mg albumin/g creatinine) for this purpose, the manufacturer of the commercially-available tests has chosen to adjust (ie, normalize) concentrations of urine albumin to a specific gravity of 1.010. When normalized in this way, the concentration of albumin in the urine (nUAlb) of normal dogs and cats is < 1 mg/dL. Microalbuminuria refers to a particular kind and degree of proteinuria; that is, an abnormal amount of albumin in a urine specimen that would likely test negative for protein if evaluated by other, more conventional, testing methods. Because the lower limit of urine protein detection by dipstick colorimetric tests is approximately 30 mg/dL, the concentration of albumin in the urine of dogs and cats that is defined as microalbuminuria is nUAlb 1.0 and < 30 mg/dL. Greater concentrations (ie, nUAlb 30 mg/dL) also are abnormal, but the micro- prefix no longer applies; that is, nUAlb 30 mg/dL defines albuminuria in much the same way that UPC 0.5 defines proteinuria. However, as discussed above, it is not proteinuria (or albuminuria), per se, that is a reliable indicator of renal disease; it is persistent proteinuria or albuminuria (including microalbuminuria) that is otherwise unexplained by prerenal or postrenal abnormalities that carries this implication. Thus, screening for early renal disease by testing for proteinuria requires both repetitive urine tests to demonstrate that the proteinuria is persistent and adequate ancillary testing to exclude non-renal sources of the excess proteins found in the urine.5 Microalbuminuria, albuminuria or proteinuria that is of renal origin usually indicates the existence of altered permselectivity of the glomerular filtration barrier, but renal tubular abnormalities also can be at least partially responsible (ie, due to inability of the renal tubules to reabsorb proteins that are normally filtered). The mechanisms that alter glomerular permselectivity in dogs and cats generally are set into motion initially by non-renal disease processes. Discovery of an underlying infectious, inflammatory, metabolic or neoplastic condition, especially if the condition is potentially treatable, likely is the single most beneficial outcome that may arise from detection of proteinuria. For this reason, detection of microalbuminuria, albuminuria or proteinuria should prompt an assiduous search for such an underlying condition. Blood pressure also should be evaluated, and hypertension should be treated appropriately if it is present. Management dilemmas arise, however, when the search for underlying conditions proves unproductive, especially when the magnitude of albuminuria proteinuria or albuminuria is small and renal function, based on other indices (eg, urine specific gravity and serum creatinine concentration), remains normal. Because it is likely that some, and possibly many, animals of this type have mild non-progressive renal disease for which treatment is unnecessary, it seems most prudent to carefully monitor such patients unless or they show some worsening trend (eg, an increasing magnitude of proteinuria, diminishing urine concentrating ability, or increasing serum creatinine concentration). In our judgment, the key task is to be sufficiently vigilant to detect such indications of progressing renal injury in a timely manner, if they occur. 551
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For proteinuric animals that require treatment, the therapeutic goals are to reduce the magnitude of proteinuria and to slow the rate of renal disease progression. The main therapeutic interventions to consider for such animals are dietary modifications and administration of an angiotensin converting-enzyme inhibitor (ACEi). Unfortunately, there currently is a paucity of solid evidence about the actual effects of such interventions on proteinuria and disease progression in dogs and cats with spontaneous proteinuric nephropathies, especially those with mild proteinuria and renal function that is otherwise normal. Consequently, the development of evidence-based therapeutic recommendations for dogs and cats with proteinuria currently is work in progress. Nevertheless, both clinical studies in humans and experimental studies using rodents have indicated that therapeutic interventions that reduce proteinuria also slow the progression of renal disease. Therapeutic protocals include blood pressure control, dietary salt restriction, dietary protein restriction, and ACEi therapy. In nephrotic rats and humans, augmenting dietary protein intake causes increased urinary albumin losses by altering glomerular permselectivity and may lead to paradoxical decreases in albumin pools despite direct effects of dietary protein that increase albumin gene transcription and albumin synthesis. Conversely, restricting dietary protein reduces proteinuria, which can lead to improved serum albumin concentrations despite the reduction of albumin synthesis that also occurs. Consequently, the goal of dietary therapy for nephrotic patients is to minimize proteinuria without compromising nutritional status. In a recent study, Burkholder, et al, found that diet had a large effect on the magnitude of proteinuria in heterozygous female dogs with Xlinked hereditary nephropathy (XLHN).8 These dogs had glomerular proteinuria but their renal function was otherwise unremarkable (ie, they had good urine concentrating ability and midrange normal plasma creatinine concentrations). However, the study also showed that a restriction of protein intake that is too severe can lead to loss of body weight and decreased plasma protein concentrations. Commercially available diets formulated for dogs and cats with renal disease generally are moderately restricted in protein content and contain restricted amounts of sodium. These diets are reasonable to feed to animals with proteinuria, but effects of such diets on the magnitude of proteinuria and rate of disease progression have not been evaluated by controlled trials in dogs or cats with proteinuric nephropathies. Grauer, et al, showed that treatment of dogs with idiopathic glomerulonephritis for 6 months with enalapril plus standard therapy that included a diet change affecting multiple nutrients including protein and minerals reduced proteinuria and systolic blood pressure and improved outcome during treatment compared with standard therapy alone.9 Enalapril therapy also reduced proteinuria without altering systemic blood pressure and slowed renal disease progression in male dogs with XLHN.10 Based on these limited data, ACEi drug administration appears to be of potential benefit in animals with proteinuria as it is humans, but much more data are needed to properly establish: (1) which animals are appropriate candidates for such treatment, and (2) the safety and efficacy of ACEi administration in those animals. In any event, it probably will be important to administer ACEi therapy with appropriate monitoring, partly to detect adverse effects (i.e., excessive reduction of GFR) but also to evaluate response to therapy (i.e., satisfactory reduction of UPC) because titration of the drug dose may be necessary.
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The North American Veterinary Conference 2005 Proceedings
REFERENCES 1. Osborne CA, Stevens JB. Urinalysis: A Clinical Guide to Compassionate Patient Care. Shawnee Mission, KS: Bayer Corp., Agricultural Division, Animal Health, 1999. 2. Moore FM, Brum SL, Brown L. Urine protein determination in dogs and cats: comparison of dipstick and sulfasalicylic acid procedures. Vet Clin Pathol 1991;20:95-97. 3. Center SA, Wilkinson E, Smith CA, Erb H, Lewis RM. 24Hour urine protein/creatinine ratio in dogs with proteinlosing nephropathies. J Am Vet Med Assoc 1985;187:820-824. 4. Syme HM, Elliott J. Relation of survival time and urinary protein excretion in cats with renal failure and/or hypertension (abstract). J Vet Intern Med 2003;17:405. 5. Lees GE. Early diagnosis of renal disease and renal failure. Vet Clin North Am Small Anim Pract 2004; 34:867-885.

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Syme HM, Elliott J. Development and validation of an enzyme linked immunosorbent assay for the measurement of albumin in feline urine (abstract). J Vet Intern Med 2000;14:52. 7. Pressler BM, Vaden SL, Jensen WA, Simpson D. Detection of canine microalbuminuria using semiquantitative test strips designed for use with human urine. Vet Clin Pathol 2002;31:56-60. 8. Burkholder WJ, Lees GE, LeBlanc AK, et al. Diet modulates proteinuira in heterozygous female dogs with X-linked hereditary nephropathy. J Vet Intern Med 2004;18:165-175. 9. Grauer GF, Greco DS, Getzy DM, et al. Effects of enalapril versus placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 2000;14:526-533. 10. Grodecki KM, Gains MJ, Baumal R, et al. Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin converting enzyme (ACE) inhibitor. J Comp Pathol 1997;117:209-225.

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