protein uria

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Proceeding of the NAVC

North American Veterinary ConferenceJan. 8-12, 2005, Orlando, Florida

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The North American Veterinary Conference 2005 Proceedings

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THE PRACTITIONERS APPROACH TO

PROTEINURIA

George E. Lees, DVM, MS, DACVIMTexas A&M University

College Station, TX

Frederick L. Metzger, DVM, DABVPMetzger Animal Hospital

State College, PA

Urine obtained from healthy dogs or cats with healthykidneys typically contains a small amount of protein, butproteinuria generally means detection of an excess ofprotein in the urine. Several methods are utilized to detectproteinuria in dogs and cats including: (1) semiquantitativetests in a conventional urinalysis, (2) determination of urineprotein:creatinine ratio (UPC), and (3) assay of urine albuminconcentration. Each method has its place in veterinarypractice 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 havingassociated renal disease. This type of proteinuria has been

classified as functional renal proteinuria (as opposed topathological renal proteinuria). The hallmark of suchfunctional proteinuria is that it is mild and transient, butpathological proteinuria generally is persistent, unless therenal lesions that are responsible for it actually resolve. Thus,to avoid undue concern about proteinuria that might befunctional, it is important to distinguish between transientproteinuria and persistent proteinuria, especially when themagnitude of proteinuria is not large. The only way to knowwhether proteinuria is transient or persistent, of course, is towait an appropriate interval and repeat the test. There is nowell-established length of time to wait before retesting, andthe 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 beingpersistent. Moreover, this principle applies regardless of themethod(s) employed to detect the proteinuria. That is,persistent proteinuria should be considered a sign of renaldisease (once the possibility of it having a prerenal orpostrenal origin has been excluded properly), even if themagnitude of proteinuria (or albuminuria) is small.

The reagent pad (dipstick) colorimetric test and thesulfosalicylic acid (SSA) turbidimetric test are two types ofsemiquantitative tests routinely used for urine proteindetermination. For technical reasons related to how dipstickcolorimetric tests work, they often indicate a weak positivereaction (trace to 1+) in moderately to well concentrated

and/or alkaline canine and feline urine samples even whenproteinuria is not present. Such erroneous dipstick reactionsoccur because the buffer capacity of the reagent strip often isinsufficient for the urine of dogs and cats, which frequentlyhave urine that is more concentrated than the urine ofhumans for which the test strips were originally developed. P

1P

Misleading dipstick colorimetric tests for protein can bedistinguished from positive reactions that actually areindicative of proteinuria by performing a SSA turbidimetrictest on supernatant urine from the same specimen. P

2PThus, it

is best to focus mainly on the SSA turbidimetric test resultwhen interpreting a routine urinalysis. Consideration shouldbe given to the urine specific gravity when interpreting the

results of semiquantitative tests for proteinuria; howeverthere is no reliable way to interpret semiquantitative tesresults in conjunction with urine specific gravity values toconfidently ascertain the amount of protein being lost in theurine. Thus, the next step when a semiquantitative testespecially the SSA turbidimetric test, gives a positive result isto determine the UPC regardless of the urine specific gravityvalue.

The UPC cutoff most widely used in dogs and cats to

differentiate values thought to be indicative of proteinuriafrom those that are not is 1.0 (ie, UPC values 1.0considered abnormal). However, numerous reports of UPCvalues determined in healthy young adult dogs and catsindicate that such animals typically have UPC < 0.5. Thussome have recommended interpreting UPC values < 0.5 asnormal, those that are 0.5 but 1.0 as questionable, andvalues > 1.0 considered abnormal. P

1,3P Interpretation of UPC

values is a prototypical example of the need to select anappropriate cutoff value for the way the test result is beingused. In dogs, the cutoff must be as high as 2.0 to beconfident that no dog is incorrectly labeled as proteinuricespecially if puppies less than 4 months of age are beingevaluated. Dogs with UPC 2.0 are certain to be abnorma

(ie, the cutoff giving near 100% specificity). Regardless oage, however, healthy dogs do not have UPC values that arepersistently 0.5. Therefore, UPC 0.5 is the moreappropriate cutoff to use when screening for proteinuria inapparently healthy dogs, and the important issue that isquestionable about UPC values between 0.5 and 1.0 (o2.0) is whether or not the proteinuria will prove to bepersistent. Similarly, the most appropriate UPC cutoff valueto use for cats should not be higher than 0.5. Emergingevidence from recent studies of cats with CKD suggests thateven relatively small UPC increases (ie, into the 0.5 1.0range) are consequential because they are associated withgreater risk of more rapid disease progression. P

4P

Evaluation of the UPC is the next most logical step for

patients with a positive semiquantitative test for protein in acomplete urinalysis that does not reflect concomitant urinaryhemorrhage or inflammation,. Usually the UPC will confirmexistence of proteinuria and provide an index of themagnitude of proteinuria for comparison with subsequenvalues as monitoring continues. If the positivesemiquantitative test is not an indication of actual proteinuria(eg, as might be the case with a weak positive reaction in ahighly concentrated urine sample), the UPC value will be lessthan 0.5. For animals that unequivocally have renaproteinuria (eg, dogs with a UPC 2.0 that is otherwiseunexplained), testing to detect albuminuria is not worthwhileFor animals with UPC values in the questionable rangehowever, testing for albuminuria may be helpful. Additionally

testing for albuminuria is the logical next step to screenseemingly healthy animals (ie, those with negativesemiquantitative tests or UPC values < 0.5) for evidence ofrenal disease. In our judgment, however, it is not justifiable toroutinely screen all seemingly healthy animals foalbuminuria. Seemingly healthy animals that should bescreened for albuminuria are those with an increased risk ofhaving renal disease either because of their age or someother factor (eg, a breed-associated predisposition). P

5P

Assays have been developed to measure the concentrationof albumin in the urine of dogs and cats using species-specific antibody-mediated methods.

P

6,7P These assays have

been calibrated to work optimally for measuring lowconcentrations of albuminuria that usually would escape

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Small Animal Nephrology - Urology

551

detection by conventional semiquantitative tests (eg, dipstickcolorimetric tests). As with the concentration of all urineproteins used in the UPC ratio, the concentration of urinealbumin must be adjusted in some way for differences inurine volume and concentration to permit comparison ofvalues within and among individuals. Although it is possibleto calculate a urine albumin-to-creatinine ratio (mg albumin/gcreatinine) for this purpose, the manufacturer of thecommercially-available tests has chosen to adjust (ie,

normalize) concentrations of urine albumin to a specificgravity of 1.010. When normalized in this way, theconcentration of albumin in the urine (nUAlb) of normal dogsand cats is < 1 mg/dL.

Microalbuminuria refers to a particular kind and degree ofproteinuria; that is, an abnormal amount of albumin in a urinespecimen that would likely test negative for protein ifevaluated by other, more conventional, testing methods.Because the lower limit of urine protein detection by dipstickcolorimetric tests is approximately 30 mg/dL, theconcentration of albumin in the urine of dogs and cats that isdefined as microalbuminuria is nUAlb 1.0 and < 30 mg/dL.Greater concentrations (ie, nUAlb 30 mg/dL) also areabnormal, but the micro- prefix no longer applies; that is,

nUAlb

30 mg/dL defines albuminuria in much the same waythat UPC 0.5 defines proteinuria. However, as discussedabove, it is not proteinuria (or albuminuria), per se, that is areliable indicator of renal disease; it is persistent proteinuriaor albuminuria (including microalbuminuria) that is otherwiseunexplained by prerenal or postrenal abnormalities thatcarries this implication. Thus, screening for early renaldisease by testing for proteinuria requires both repetitiveurine tests to demonstrate that the proteinuria is persistentand adequate ancillary testing to exclude non-renal sourcesof the excess proteins found in the urine. P

5P

Microalbuminuria, albuminuria or proteinuria that is of renalorigin usually indicates the existence of alteredpermselectivity of the glomerular filtration barrier, but renal

tubular abnormalities also can be at least partiallyresponsible (ie, due to inability of the renal tubules toreabsorb proteins that are normally filtered). Themechanisms that alter glomerular permselectivity in dogs andcats generally are set into motion initially by non-renaldisease processes. Discovery of an underlying infectious,inflammatory, metabolic or neoplastic condition, especially ifthe condition is potentially treatable, likely is the single mostbeneficial outcome that may arise from detection ofproteinuria. For this reason, detection of microalbuminuria,albuminuria or proteinuria should prompt an assiduoussearch for such an underlying condition. Blood pressure alsoshould be evaluated, and hypertension should be treatedappropriately if it is present. Management dilemmas arise,

however, when the search for underlying conditions provesunproductive, especially when the magnitude of albuminuriaproteinuria or albuminuria is small and renal function, basedon other indices (eg, urine specific gravity and serumcreatinine concentration), remains normal. Because it is likelythat some, and possibly many, animals of this type have mildnon-progressive renal disease for which treatment isunnecessary, it seems most prudent to carefully monitor suchpatients unless or they show some worsening trend (eg, anincreasing magnitude of proteinuria, diminishing urineconcentrating ability, or increasing serum creatinineconcentration). In our judgment, the key task is to besufficiently vigilant to detect such indications of progressingrenal injury in a timely manner, if they occur.

For proteinuric animals that require treatment, thetherapeutic goals are to reduce the magnitude of proteinuriaand to slow the rate of renal disease progression. The maintherapeutic interventions to consider for such animals aredietary modifications and administration of an angiotensinconverting-enzyme inhibitor (ACEi). Unfortunately, therecurrently is a paucity of solid evidence about the actuaeffects of such interventions on proteinuria and diseaseprogression in dogs and cats with spontaneous proteinuric

nephropathies, especially those with mild proteinuria andrenal function that is otherwise normal. Consequently, thedevelopment of evidence-based therapeuticrecommendations for dogs and cats with proteinuria currentlyis work in progress. Nevertheless, both clinical studies inhumans and experimental studies using rodents haveindicated that therapeutic interventions that reduceproteinuria also slow the progression of renal diseaseTherapeutic protocals include blood pressure control, dietarysalt restriction, dietary protein restriction, and ACEi therapy.

In nephrotic rats and humans, augmenting dietary proteinintake causes increased urinary albumin losses by alteringglomerular permselectivity and may lead to paradoxicadecreases in albumin pools despite direct effects of dietary

protein that increase albumin gene transcription and albuminsynthesis. Conversely, restricting dietary protein reducesproteinuria, which can lead to improved serum albuminconcentrations despite the reduction of albumin synthesisthat also occurs. Consequently, the goal of dietary therapy fornephrotic patients is to minimize proteinuria withoucompromising nutritional status. In a recent studyBurkholder, et al, found that diet had a large effect on themagnitude of proteinuria in heterozygous female dogs with Xlinked hereditary nephropathy (XLHN). P

8P These dogs had

glomerular proteinuria but their renal function was otherwiseunremarkable (ie, they had good urine concentrating abilityand 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 anddecreased plasma protein concentrations. Commerciallyavailable diets formulated for dogs and cats with renadisease generally are moderately restricted in protein contenand contain restricted amounts of sodium. These diets arereasonable to feed to animals with proteinuria, but effects ofsuch diets on the magnitude of proteinuria and rate odisease progression have not been evaluated by controlledtrials in dogs or cats with proteinuric nephropathies.

Grauer, et al, showed that treatment of dogs with idiopathicglomerulonephritis for 6 months with enalapril plus standardtherapy that included a diet change affecting multiplenutrients including protein and minerals reduced proteinuriaand systolic blood pressure and improved outcome during

treatment compared with standard therapy alone.P

9P

Enalapritherapy also reduced proteinuria without altering systemicblood pressure and slowed renal disease progression in maledogs with XLHN.

P

10P Based on these limited data, ACEi drug

administration appears to be of potential benefit in animalswith proteinuria as it is humans, but much more data areneeded to properly establish: (1) which animals areappropriate candidates for such treatment, and (2) the safetyand efficacy of ACEi administration in those animals. In anyevent, it probably will be important to administer ACEtherapy with appropriate monitoring, partly to detect adverseeffects (i.e., excessive reduction of GFR) but also to evaluateresponse to therapy (i.e., satisfactory reduction of UPCbecause titration of the drug dose may be necessary.


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REFERENCES

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3. Center SA, Wilkinson E, Smith CA, Erb H, Lewis RM. 24-

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4. Syme HM, Elliott J. Relation of survival time and urinaryprotein excretion in cats with renal failure and/orhypertension (abstract). J Vet Intern Med 2003;17:405.

5. Lees GE. Early diagnosis of renal disease and renalfailure. Vet Clin North Am Small Anim Pract 2004;34:867-885.

6. Syme HM, Elliott J. Development and validation of anenzyme linked immunosorbent assay for themeasurement of albumin in feline urine (abstract). J VeIntern Med 2000;14:52.

7. Pressler BM, Vaden SL, Jensen WA, Simpson DDetection of canine microalbuminuria usingsemiquantitative test strips designed for use with humanurine. Vet Clin Pathol 2002;31:56-60.

8. Burkholder WJ, Lees GE, LeBlanc AK, et al. Die

modulates proteinuira in heterozygous female dogs withX-linked hereditary nephropathy. J Vet Intern Med2004;18:165-175.

9. Grauer GF, Greco DS, Getzy DM, et al. Effects oenalapril versus placebo as a treatment for canineidiopathic glomerulonephritis. J Vet Intern Med2000;14:526-533.

10. Grodecki KM, Gains MJ, Baumal R, et al. Treatment oX-linked hereditary nephritis in Samoyed dogs withangiotensin converting enzyme (ACE) inhibitor. J CompPathol 1997;117:209-225.


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