Proteinuria Round Table

PROTEINURIA ANDRENAL DISEASE

Sponsored by an educational grant from IDEXX Laboratories

A ROUNDTABLE DISCUSSION

Dr. Roberta Relford: Our discussion todayis about kidney disease in dogs and cats.Kidney disease has received a lot of atten-tion in the literature recently, particularlythe role of proteinuria in the detection,characterization, and prognosis of kidneydisease. Because of the importance of pro-teinuria, the American College of VeterinaryInternal Medicine (ACVIM) organized afocus group to produce a consensus state-ment on proteinuria to be published thisspring. The following roundtable discus-sion is important because it addressessome of the confusion that exists aboutproteinuria utilization. The participantsinclude several internationally recognizedexperts as well as members of the ACVIMfocus group. Let’s begin with the current,accepted prevalence of acute and chronickidney disease in dogs and cats.

PrevalenceDr. Sherry Sanderson: According to re-cent literature, one in three elderly cats

and one in five elderly dogs will developsome kind of kidney disease.

Dr. Fred Metzger: Renal disease is cer-tainly a common clinical presentation inprivate practice, but I’m interested to learnhow many cases we currently miss. We’rea little better at picking up acute renal fail-ure than chronic renal failure, but we missa lot of cases because of the way we testfor renal failure.

Dr. Scott Brown: In 1999, Dr. ElizabethLund reported that kidney disease was theNo. 6 reason cats were presented to vet-erinarians—in the top six with gastroin-testinal and dermatologic problems—andNo. 10 in dogs.1

Metzger: That number goes way up whenwe look at the population of older cats.

Brown: Absolutely. One in three seniorcats is a number commonly cited with

chronic kidney failure—at least in referralpractices.2,3

Dr. George Lees: About one in three catsand one in five dogs will develop kidneydisease in their lifetimes. Historically, acuterenal failure surfaces when the animalbecomes ill, and practitioners seldom mis-diagnose it.

The International Renal Interest Society(IRIS) has developed a good staging sys-tem for chronic kidney disease. There arefour stages: I, II, III, and IV, differentiated byplasma or serum creatinine concentra-tions. Late stage III and stage IV (i.e., mod-erately and severely azotemic) animals aretypically symptomatic. The animals we arefuzziest about are in stages I and II (i.e.,nonazotemic or mildly azotemic animals).We need studies to develop a better un-derstanding of the numbers of animals instages I and II and the clinical significanceof their kidney disease. We must guessright now.

Moderator:Roberta Relford, DVM,PhD, DACVP, DACVIM

IDEXX LaboratoriesDallas, Texas

Participants:Scott A. Brown, VMD,PhD, DACVIM

Department of Physiology & PharmacologyCollege of VeterinaryMedicineUniversity of GeorgiaAthens, Ga.

Jonathan Elliott, MA, PhD,Vet MB, Cert SAC, DECVP&T,MRCVS

Department of Veterinary Basic SciencesRoyal Veterinary CollegeLondon, U.K.

Fred Metzger, DVM, DABVP

(canine and feline)Metzger Animal HospitalState College, Pa.

Gregory F. Grauer, DVM,MS, DACVIM

Department of ClinicalSciencesCollege of VeterinaryMedicine Kansas State UniversityManhattan, Kan.

George E. Lees, DVM, MS,DACVIM

Department of SmallAnimal Clinical SciencesCollege of VeterinaryMedicineTexas A&M UniversityCollege Station, Texas

Sherry Sanderson, DVM,PhD, DACVIM, DACVN

Department of Physiology &Pharmacology College of VeterinaryMedicineUniversity of GeorgiaAthens, Ga.

PROTEINURIA AND RENAL DISEASEA ROUNDTABLE DISCUSSION

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Metzger: When our practice instituted asenior care program including diagnostictesting of asymptomatic patients seven oreight years ago, the number of patientsdiagnosed with renal disease increasedsubstantially. I know we could be helping a lot more animals with better testing forrenal disease.

Dr. Jonathan Elliott: In our London prac-tice, we diagnose about 60 new chronickidney disease cases in cats a year. But wehave a high index of suspicion because wehave many senior clients with older cats.About 30% to 40% of these new cases arediagnosed without the owners noticingclinical signs. We’ve detected them withscreening tests rather than waiting to testuntil they present with clinical signs. Someof these cats remain stable and nevershow clinical signs of chronic kidney dis-ease. These are not stage I cats; they’restage II according to the classification sys-tem. About half of them will die because ofanother problem without having shownclinical signs of kidney disease.

Dr. Greg Grauer: A semiepidemiologicMorris Animal Foundation study that polleddog and cat owners about health concernsand causes of pets’ death revealed that forboth species, renal disease was the No. 2natural cause of death.

We’re conducting a longitudinal study at Kansas State—similar to ones beingdone at North Carolina State and ColoradoState—where we monitor staff- and student-owned dogs over a four-year period. We have about a 20% incidence of low-level proteinuria in both species.The bulk of these dogs and cats are per-sistently proteinuric. But that certainlydoesn’t mean that all of those animals aregoing to progress to overt renal failure.

Brown: I liken it to an iceberg. Tradition-ally, in veterinary medicine, we see the tipof the iceberg—those patients with clini-cal signs in late stage III and early stage IVin the IRIS classification system. If youscreen select populations such as seniorcats, as Dr. Elliott suggested, there is noquestion that kidney disease is muchmore common. But we need markers tohelp identify other patients. Proteinuriamay well prove to be a good marker. Urine

screening and critical evaluation of serumcreatinine levels will help in this regard.Rather than simply determining if creati-nine is outside of a broad normal range,sequential serum creatinine determina-tions allow you to follow adult animals soyou can look for trends. And viewing ahigh normal creatinine concentration withsuspicion may cause veterinarians to criti-cally evaluate urinalyses and other ancil-lary tests. We all agree that kidney diseaseis common, but it’s probably much morecommon than we think. Identifying stage I or II animals is a challenge that urine-screening tests facilitate.

Lees: We’re trying to learn more about thebottom of the iceberg. Few studies havebeen performed, and they involve animalsubjects in only the double digits—lessthan 100 in any one study where research-ers have looked microscopically at kidneytissue from seemingly healthy dogs. How-ever, they found that up to 80% of middle-aged or older animals have kidney lesionsand the majority of the lesions wereobserved in the glomeruli.4,5

Brown: The bottom 80% of the icebergcontains many animals that won’t pro-gress to clinically apparent uremia as Dr.Elliott described—but some will. We don’tknow yet how to predict progression.

Metzger: I’m interested in learning moreabout early detection and intervention. This

disease is very emotional for clients andveterinarians. When we diagnose renal fail-ure by detecting azotemia, the patientshave progressed to stages III and IV. Be-cause these are usually older patients,owners and team members are emotional-ly bonded to them.

Prevalence and age groupsRelford: Senior patients, as most of youindicate, have the highest incidence of kid-ney disease, so is there a reason to moni-tor younger animals? Since most patientsare identified when they’re in stage III andlater, this suggests that undetected patho-logic changes were occurring when theywere younger. Is there a way to detectthese patients earlier and alter their out-comes? Additionally, should certain at-riskpatients be monitored?

Brown: In surveys of dogs, there have usu-ally been two peaks of higher prevalence.One occurs at an earlier age and is relatedto congenital or hereditary disease. This isdifferent than what we’ve been talkingabout so far: acquired disease occurringlater in an animal’s life. Hereditary or con-genital kidney disease also progresses andmay be identified by serum and urinescreening tests, but in surveys, it’s seen in dogs about 1 to 3 years of age.

Lees: The principal inheritable disease incats is polycystic kidney disease, in whichrenal failure occurs in middle age. Juvenileonset (i.e., less than 3 years of age) ofchronic renal failure is not common in cats.But some dog breeds have familial renaldiseases that cause juvenile onset renalfailure and are, therefore, at risk. Veterinar-ians caring for those animals should moni-tor them carefully.

Metzger: Mandatory preanesthetic testinghas been a huge wake-up call in our prac-tice. With blood and urine tests, such asblood urea nitrogen (BUN), creatinine, anda complete urinalysis, we’re now diagnos-ing renal failure in pets much earlier. About80% of us perform preanesthetic testing.It might not always be the right testing,but some renal tests are in those profiles.All patients—especially breeds predis-posed to renal disease like Persian cats

SOUND BYTE - DR. METZGER

“When our practice instituteda senior care programincluding diagnostic testingof asymptomatic patientsseven or eight years ago,the number of patients diagnosed with renal diseaseincreased substantially.”

PROTEINURIA AND RENAL DISEASE

and Wheaton terriers—should be thor-oughly evaluated before anesthesia. Be-fore the advent of preanesthetic testing, Ididn’t think renal disease was present inyoung patients.

Lees: When you start testing young ani-mals before routine spays and neuters, youneed a different frame of reference than inolder animals. A serum creatinine value of1.3 mg/dl in a 5-month-old dog is alarm-ingly abnormal.

Metzger: That’s a great point. Age-specificranges are important too.

Elliott: The average age of diagnosis ofkidney disease in cats is about 12 years.But we do diagnose kidney disease inyounger cats and not just in specificbreeds. We see cats presenting with kid-ney disease at 8, 5, and even 3 years ofage. These cats don’t seem to have a dif-ferent clinical form of the disease thanolder cats—when we examine their kid-ney tissue, they apparently have the sametype of end-stage lesions. The initiatingcause, however, cannot be ascertained atthis late stage.

Relford: That brings us to our next ques-tion. Are there certain kidney disease categories that are more prevalent (e.g.,glomerular vs. tubular)? What categoriesshould veterinarians look for?

Types of kidney diseaseSanderson: Classically, we thought mostrenal failures in dogs involved tubularinterstitial disease, but a histopathologicstudy found that there is a lot moreglomerular disease that we weren’t recog-nizing. Previously, we may have underesti-mated the prevalence of glomerular dis-ease as the underlying cause of renal disease in dogs. A recent study found thatseven of 15 dogs with end-stage renalfailure had glomerular nephritis as theunderlying cause of the renal diseaserather than tubular interstitial disease.6 Anearlier study also showed similar results.7

Lees: One principle of kidney diseasepathology is that it all ends up in the sameplace regardless of its initial cause. Thebulk is interstitial kidney disease. Renal

function correlates best with changes inthe tubulointerstitial compartment in alltypes of kidney disease—whether it startsout as tubular or glomerular disease. Be-cause kidney disease is historically diag-nosed in late stage III and stage IV animalson the basis of clinical signs, clinicians onlyfind the end-stage wreckage and it alwayslooks the same. One of the potential bene-fits of screening seemingly healthy animalsand detecting renal disease early is that itwill not only help our patients, but we’llalso get a better idea of the inciting caus-es. We’ve been handicapped by not lookingfor disease at a time when we could deter-mine the cause.

A wonderful example is the inheritedkidney disease in cocker spaniels. Thiswas the first inherited kidney disease thatveterinarians recognized in dogs beginningin the 1940s. It was described in the vet-erinary literature for about 40 years as arenal cortical hypoplasia. We did electronmicroscopy, found some changes unique tothat disease, and then did studies in dogsby collecting serial biopsies at the begin-ning, middle, and end. We were able tounravel how the disease progresses bylooking at it from the beginning. If you onlylook at the end using light microscopy, asveterinarians did for 50 years, you can tellthey’ve got it, but you can’t tell why.

Common causes of kidney diseaseRelford: What are the common causes of kidney disease? We’ve already talked

about the less common congenital or famil-ial breed predispositions in young pets.

Grauer: Dr. Lees and Dr. Sanderson havealluded to studies that suggest glomerulardisease is associated with end-stage renaldisease in dogs—perhaps to a greaterextent than we once thought. In my opin-ion, however, there aren’t enough longitu-dinal studies (i.e., studies with serial renalbiopsies that would facilitate primary dis-ease process determination) in dogs withspontaneous kidney disease. These typesof studies are invasive and expensive and,therefore, difficult to perform in client-owned animals. Based on the informationwe have today, it does appear that glo-merular disease is an important cause ofend-stage renal disease in dogs. What isthe primary cause in cats?

Elliott: I’d love to be able to take biopsiesof cats when they have normal kidneyfunction and when they have stage II kid-ney disease, but I’d have a hard time con-vincing cat owners to allow me to do that.Glomerular events are going to influencetubular pathology. Proteinuria is an indica-tor of renal pathology or renal disease andis a predictor of survival—proteinuric catswith kidney disease tend to progress morerapidly. We don’t know enough about it atthis stage. We’re diagnosing cats at theend stage and seeing the tubulointerstitialfibrosis that’s resulted from the initial dis-ease process, which is no longer evident.

Lees: The kidneys are composed of fourtypes of structures: vessels, glomeruli,tubules, and interstitium. Let’s discusswhich components are the likely targets forinitial insult. Vascular disease is not com-mon in dogs or cats compared with peo-ple, who have a fair amount of primarycardiovascular disease. The glomeruli arean important target of the initial renal insultin dogs and possibly cats—far greaterthan we’ve appreciated in the past. Evenso, glomeruli are injured secondary to dis-eases in other organ systems most of thetime—the glomeruli are sentinels thatoften indicate problems elsewhere in thebody. There are huge microvascular glo-merular areas available to be injured.

The tubules are the initial target of most diseases that present as acute renal

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SOUND BYTE - DR. LEES

“One of the potential benefitsof screening seeminglyhealthy animals and detectingrenal disease early is that itwill not only help our patients,but we’ll also get a betteridea of the inciting causes.”


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failure; leptospirosis and toxic nephro-pathies are examples. However, diseasesthat initially attack the tubulointerstitiumsometimes do cause chronic renal failure.Pyelonephritis, which occurs when a bac-terial bladder infection works its way up tothe kidneys, is an example.

Metzger: Clients ask, “What caused this?”I often tell clients with older pets that it’sjust age. Maybe that’s true, but maybe it’snot. In Pennsylvania, I’m concerned aboutLyme disease in relation to renal diseasein dogs. But is hypokalemia in cats acause of renal disease or a result? Andwhat about hypercalcemia?

Brown: Clearly, a variety of infectious diseases and cancers lead to immunecomplex formation that potentially causesglomerular inflammation and subsequentdeterioration of renal function. And hyper-calcemia damages the kidney throughmineralization, fibrosis, and other second-ary changes. These two conditions, im-mune complex formation and renal mineralization, are two primary causes of kidney disease.

The link between hypokalemia and kidney disease is quite complex. Chronickidney disease in cats tends to be a potas-sium-losing disease. Even with supplemen-tation, our feline patients are often hypo-kalemic. And there are important conse-quences of hypokalemia, such as muscularweakness. A really interesting question iswhether hypokalemia may be contributingto the deterioration of renal function andblood pressure elevation. Results of somelaboratory studies in rodents and clinicaltrials in people suggest that blood pressureelevation is more likely to occur in associa-tion with low serum potassium levels.

Elliott: We’ve noticed that low potassiumlevels tend to occur in cats with highblood pressure. The potassium remainslow even if you supplement the cats.We’re quite interested in why that’s thecase. It may give us an indication of theendocrine changes that surround hyper-tension. Hypokalemia may be a conse-quence of the disease causing hyperten-sion and, therefore, a marker. Low serumpotassium may actually have some influ-ence on blood-pressure control. We con-

ducted a study where we supplementedpotassium and then looked at the effectson blood pressure in cats with chronickidney disease that weren’t severelyhypertensive. We found no detectableinfluence on blood pressure.

Brown: We conducted a similar laboratorystudy with precise direct measures ofblood pressure and observed only smallblood-pressure reductions with potassiumsupplementation in azotemic cats. I won-der if some therapies, such as salt restric-tion or amlodipine administration, activatethe renin-angiotensin-aldosterone systemin cats, which could enhance urinary lossof potassium.

Elliott: We found that plasma renin activi-ties increase when you decrease bloodpressure with amlodipine treatment. Aldo-sterone production doesn’t change, whichis strange. You’d expect aldosterone to in-crease in those animals. We’re investigat-ing whether there is some dysfunction inaldosterone secretion control in these cats.

Brown: Dr. Lees discussed how the tubu-lointerstitial compartment is commonlyaffected in kidney disease. Basically, anytime there is kidney disease, the lesionsthat correlate best with disease severityare those in the tubulointerstitium—regardless of which compartment thedisease attacks. But in addition, in everykidney disease, there will be significantlesions in the glomerulus that contributeto glomerular dysfunction, decreasedglomerular filtration rate (GFR), andincreased protein loss across theglomerulus. So there are two inevitabili-ties: 1) No matter what happens, theinterstitial compartment is damaged, and2) no matter where the disease origi-nates, all compartments are affected—particularly the glomerulus.

Relford: If one area is affected, then even-tually all four are affected or, at least, thetubulointerstitium is affected. Are thesefair statements?

Brown: The two compartments that weknow are affected eventually in every kid-ney disease case are the tubulointerstitiumand the glomerulus in both dogs and cats.

Relford: And even though we may notknow what initiated the disease, we needto learn what is causing it to progress. Thiscan only be done with early detection andmonitoring with treatment.

Grauer: Nephrolithiasis, ureterolithiasis,ascending infections, hyperphosphatemia,acidosis, hypertension, and proteinuria areall potentially treatable causes of continuedrenal function deterioration once failurehas been diagnosed.

Elliott: With the exception of nephrolithiasisand ureterolithiasis in cats, we generallyview those conditions as complicationsrather than initiating causes. We couldargue whether hypertension comes first,but many of those conditions are a conse-quence of later kidney disease stages.

Brown: I agree with your list, Dr. Grauer.Most of them occur as part of the milieu ofwhat happens in kidney disease. Uremicsyndrome is a term that is commonly used.Hypertension is potentially one kidney dis-ease complication that may also be acause of kidney disease. But we knowremarkably less than we should about thecauses. If one in three geriatric cats haschronic kidney disease, we had better findways of detecting it earlier and figuring outwhat the primary causes are.

Clinical signsRelford: What are the common clinicalsigns that veterinarians should be lookingfor in the different stages of kidney dis-ease? And what about animals that showno clinical signs?

Grauer: It’s easy to diagnose overt stage IIIor IV renal failure, that is, azotemia or ure-mia with persistent urine concentrationdeficits. We need to focus on diagnosingpatients earlier when there may be no clin-ical signs, beginning with annual or semi-annual physical exams for mature and sen-ior pets. Dr. Lees has wonderful data thatshow you can have significant declines inrenal excretory function, and yet still havecreatinine levels well within the normallimits simply because that normal range isso wide. Plus you have compensation oc-curring with nephron loss. Looking at thetrends even within that normal range, you


can see greater than a 50% reduction inexcretory function. You may also see trendsin urine specific gravity, creatinine, phos-phorus, packed cell volume, proteinuria, orbody weight over time.

Lees: Of the four stages, stages I and IIare, by definition, absent of clinical signs.So if by clinical signs, we mean somethingthe client or veterinarian would observeand report—we are limiting ourselves todiagnosing late stage III and stage IV dis-ease. The disease is insidious, so the signsare insidious. Changes in urinary habits(including frequency and amounts), waterconsumption, appetite, and body conditionare a few signs. Weight loss can be hard topin down; it’s a fairly early, subtle sign. Theexception would be the acutely ill animal—whether it’s a decompensation of chronicrenal failure or acute renal failure crisis.

Grauer: But when you put it all togetherover time and start to see declines in urinespecific gravity, increases in proteinuriaand creatinine concentration, and declinesin body weight, it should make you take acloser look.

Metzger: It sounds like an easy question:What are the clinical signs? But it’s compli-cated. I think the “ain’t doing right” animalis a perfect candidate for chronic renal fail-ure. Cat owners might not notice polyuria-polydipsia (PU-PD), anorexia, and lethargy,for example. You would think it would beeasy to tell if an animal is drinking and uri-nating more or eating less. If there aremultiple animals living in the same home,it’s not that easy unless you are looking forit. That’s why I’m so interested in seniorcare programs and testing animals beforethey are clinical.

Elliott: Cats don’t show clinical signs untilthe latter stages of many different dis-eases. So screening is important. Retro-spectively, the owners will often say, “Well,yes, I noticed that.”

Lees: It’s partly what you are looking for—a product of your index of suspicion. Someclients are astute judges of their animals’well-being; others never notice. So, yes,it’s crucial to have tools available so that once the light bulb goes on in your

head, there are steps you can take to evaluate patients.

Brown: I agree. By definition, there are nouremic signs in stages I and II. By uremicsigns, I mean such things as vomiting,lethargy, weakness, and anorexia associ-ated with marked azotemia as seen in lateIRIS stage III or stage IV. But there is fur-ther complexity as there are two othersets of clinical signs that can occur—albeit less frequently. First, there are disease-specific signs. For example, if the animal has pyelonephritis, it may notbe uremic, but it may have renal painobserved by owners or veterinarians asreluctance to handling or inappetence.Here, clearly, urinalysis is the key to dis-ease identification.

The other type of early preuremic clini-cal sign is hypertension. Animals withstage I or stage II chronic kidney diseasemight exhibit systemic hypertension. Inthese animals, retinal abnormalities orother sequelae of systemic hypertensionmight appear before the uremic signs.Because hypertension increases proteintraffic across the glomerulus, many ofthese animals will be proteinuric. Here,urinalyses, blood pressure measurements,and ophthalmic exams are the key to dis-ease identification.

Lees: How do we define a clinical sign? Idon’t hear a heart murmur until I use astethoscope, but to me, it’s a clinical sign.The same might be said for screening uri-nalyses for proteinuria. If we define clinicalsigns to include abnormalities that we candetect using tools—stethoscopes, bloodpressure cuffs, urinalyses—then we endup with a different set of signs.

Diagnostic testsRelford: If veterinarians suspect kidneydisease, what are some diagnostic teststhey should consider?

Lees: There is nothing more importantthan a complete urinalysis. Urinalysis isthe beginning and the fulcrum aroundwhich everything else should hinge—there should never be a clinical investiga-tion involving screening tests, such ascomplete blood counts (CBCs) or chem-istry profiles, without a urinalysis as well.

Brown: We’re trying to identify animalswith early kidney disease. Late stage IIIand stage IV animals are relatively easy todiagnose if they have severe azotemia inthe face of a low urine specific gravity. Butthe only thing on the serum chemistrypanel that is going to be helpful in thoseearly patients is the serum creatininedetermination. Here, either a high normalserum creatinine or a serum creatinine thathas been inching up within the normalrange is helpful. In IRIS stage II, a slightlyelevated serum creatinine is helpful aswell. Historical studies in both dogs andcats show that in order for creatinine toincrease out of the normal range, three outof every four nephrons in the kidneys mustbe destroyed, so we’re talking about se-vere disease at that stage. As a profession,we should begin to look at serial creatininelevels, measure them routinely, and com-pare current to previous values in seniorpatients. A high normal value should makea veterinarian suspicious even if earliervalues aren’t available. But generally, youwon’t see any obvious abnormalities on theCBC and serum chemistry panel in stage Iand stage II.

Elliott: Body condition score is importantwhen you’re interpreting creatinine be-cause the animal’s muscle mass will makea big difference. We see a lot of old skinnycats that have normal creatinine levels. It’squite abnormal if the creatinine level is atthe top end of the reference range.

Grauer: The urinalysis is a must if you’regoing to interpret the serum chemistry pro-file. I think serial serum chemistry and uri-nalysis assessments are absolutely critical.

Sanderson: Pretreatment urine samplesare ideal. They ensure you’re not inter-preting therapy’s effects on top of every-thing else.

Lees: Additionally, it’s important to interpretthe various laboratory test results in light ofone another and the patient’s status. Clin-ical judgment is what the client pays you tobring to the table. Do the numbers makesense in the context of this patient?

Sanderson: If you’re looking for glomeru-lar disease, you may not see any changes

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on the initial blood work. You may bemissing glomerular disease if you don’tlook at the urine.

Lees: Historically, veterinarians have notalways been good at getting a clean urinespecimen. Somehow it’s easier to do avenipuncture than it is to get a urine sam-ple. If you’re not doing a urinalysis, you’remissing the single biggest window into the problem.

Brown: One of our faculty members atthe University of Georgia always refers tourine as liquid gold, meaning it’s critical toevaluate the urine if we want to identifythese patients in the early stages. Even in the absence of a creatinine change, a low specific gravity should raise a veteri-narian’s index of suspicion. With the dip-stick evaluation, you’re looking for pro-teinuria and other abnormalities that mayindicate kidney disease. You must evalu-ate the sediment in order to identify uri-nary tract infections (UTIs) or ongoingrenal damage.

Lees: Let’s not forget that in these samepatients, lower urinary tract disease isfairly common as well. Twenty percent ofdogs, female dogs particularly, will havebacterial UTIs. Stone disease is fairlycommon. So a complete urinalysis thatallows you to examine the sediment forpus, blood, and so on is screening for notonly kidney disease but other commonurinary tract diseases that are importantto the animal’s health as well. We’vealready talked about ascending infectionsand urolithiasis damaging the kidneys.But again, these are the tip of the icebergof a larger set of diseases that you willnot find regularly unless you look.

A number of years ago, we did studieson UTI. For an 18-month period, we care-fully evaluated all the dogs that we diag-nosed with UTIs in our teaching hospital.Exactly half (19 out of 38 patients) haduncomplicated bacterial UTIs that wereinitially detected only by urinalysis(asymptomatic UTIs).

Elliott: In my experience, it’s almost 100%in cats. We don’t see lower urinary tractsigns when they have poor concentratingability and bacterial infections. Those pa-

tients are not showing the increased fre-quency or dysuria.

Sanderson: It’s unfortunate that somepeople think that cats don’t get UTIs.Young, healthy cats are not at great risk,but add renal failure to the equation and afair number of them do get concurrentUTIs. You cannot always rely on the urinal-ysis to diagnose UTIs; there may not be a significant inflammatory response. Ifyou’re trying to rule out an infection, thegold standard is actually the culture.

Lees: Especially when there is concurrentrenal failure.

Relford: Your minimum database shouldinclude a CBC, serum chemistry panel,and a complete urinalysis with specificgravity, dipstick chemistry analysis, and asediment examination. If you suspectrenal disease, there should be a culture.

Metzger: I think we’d all agree that cysto-centesis is the way to go, but it can be aproblem in practice. If a practice owns anultrasound machine, it’s a wonderful wayto use it. At our practice, we’ll do an ultra-sound urine collection for a minimum of$38. You can almost always get a cysto-centesis if you have an ultrasound. Youcan also do a quick screen of the bladderand kidneys for urolithiasis, neoplasia,and other abnormalities.

Elliott: Another practical point: If you advisethe owner not to feed the cat in the morn-

ing, you have a much better chance of get-ting a urine sample because cats often uri-nate after they’ve eaten. We’re able to getsamples from about 75% of the cats thathave fasted and haven’t urinated in theirboxes on the way to the clinic. Detecting afull bladder on palpation suggests that thecat is polyuric; a urine specific gravity willhelp with the interpretation, particularly ifthe patient fasted overnight. If it has asmall bladder and the owners confirm ithas not urinated that morning, thenchances are it’s not polyuric.

ProteinuriaRelford: What are some ways of evaluatingproteinuria?

Grauer: I think we’d all agree that protein-uria, with some caveats (i.e., kidney local-ization and persistence), is a sign of kidneydisease. The standard assessment of pro-tein in the urine, the dipstick, is unfortu-nately not a reliable or sensitive test. It’snonspecific in cats—in other words, thereis a high percentage of false-positiveresults. Thorough analyses for proteinuriashould combine the standard dipstickanalysis with additional testing.

Relford: What are some recommendationsfor additional proteinuria testing?

Grauer: In academic settings, the sulfosali-cylic acid turbidimetric test is a good test,but it hasn’t caught on with practitioners.

Lees: The sulfosalicylic acid test is a good,simple test. It’s a lot easier than severalother procedures veterinarians learn to doand become adept at.

We’ve gone from no laboratory testingwithin recent memory to some laboratorytesting. Generations of veterinarians wereraised on doing a urinalysis with a dipstick.The protein pad on the dipstick will oftenchange color in moderately to highly con-centrated urine from dogs or cats evenwhen there is no protein. These false-positive reactions occur because of the pHand concentration of the urine and the lim-ited buffer capacity of the reagent teststrip. So we have a whole generation ofveterinarians finding trace and 1+ positivecolor changes in animals that they knewwere perfectly normal. They thought it was

SOUND BYTE - DR. BROWN

“One of our faculty membersat the University of Georgiaalways refers to urine as liquid gold, meaning it’s critical to evaluate the urineif we want to identify thesepatients in the early stages.”


protein and said to themselves, “A little bitof proteinuria is normal in cats and dogs.”The truth: The level of proteinuria thatwould cause the dipstick to turn color isnever normal if it’s a true positive. We’vedesensitized ourselves while learning to dolab tests. We only think about it being pro-teinuria if it is 4+, which means we needto change our frame of reference.

Grauer: So a positive dipstick should befollowed up with a confirmatory test?

Lees: Yes.

Grauer: If you’re interested in detecting alow level of protein in the urine, the dipstickis not sensitive enough. We’re going to geta lot of false positives, but we may also seesome false negatives with a low proteinurialevel. The sulfosalicylic acid, urine microal-bumin assay, and urine protein–creatinineratio tests are much more sensitive thanthe dipstick at detecting these lower con-centrations of protein in the urine.

Relford: What about quantitation with theurine protein–creatinine ratio?

Elliott: The standard dipstick tests for pro-tein are of little help when screening caturine because there are so many falsepositives. There are two possible ap-proaches: 1) run a urine protein–creatinineratio test initially and forget the screeningtest or 2) screen with the microalbumin-uria test (if this is negative, you can beconfident the urine protein–creatinine ratiowill be so low that it’s not worth quantify-ing). Any positive on the microalbuminuriatest should be followed up by a urine pro-tein-creatinine ratio test in my opinion.Either of these two approaches is appro-priate provided the urine sediment hasbeen carefully examined for signs of activeinflammation. In our experience, if themicroalbuminuria assay is negative in acat, then the urine protein–creatinine ratiois likely less than 0.2.

Grauer: What is the clinical significance oflow-level proteinuria? And what do clini-cians do with that information?

Lees: That low level of proteinuria alonesignifies that the animal is in the bottom

part of the iceberg—a small, abnormalamount of proteinuria that shouldn’t bethere. We don’t know the proportion ofthose animals that will ultimately be diag-nosed with end-stage renal disease. If wethink they’re at risk, we need serial evalu-ations to detect trends in a timely man-ner—if the protein amount rises, the kindsof protein change, or the creatinine beginsto creep up. Ideally we notice when thecreatinine goes from 1.2 to 1.5 mg/dl—not when it leaps from 2.5 to 4 mg/dl.

Elliott: It’s going to be difficult to educatepractitioners because there will be animalswith transient proteinuria that test positive.The next time you test them, the proteinlevel is below the threshold and they testnegative. It should be interpreted as tran-sient proteinuria in those instances, notfalse-positives.

Grauer: It was abnormal at the time buttransient proteinuria is probably associatedwith little consequence. Persistence is thekey to pathology.

LocalizationRelford: Once you’ve determined that pro-teinuria exists, it’s important to determinethe source or location of the protein—whether it’s prerenal, renal, or postrenal inorigin. How should veterinarians localizethe source of the proteinuria?

Lees: There is no urine test that sayswhere the protein originated. You rely onclinical judgment and other information tomake a reasonable assessment of the like-ly source of the protein. Healthy kidneysproduce urine that contains negligibleamounts of protein. Protein often enters the

urine in its course through the excretorypathway through blood or exudation fromthe walls of the urinary tract. Sometimes,depending on how the sample is collected,protein is added later. We call that post-renal proteinuria—either urinary or extra-urinary. The key finding in this situation isusually the coincident presence of redblood cells and positive dipstick reactionsfor blood or white blood cells, which is why it’s crucial to examine the sediment.Studies that use the commercially availabledipsticks with leukocyte esterase assayshave shown them to be unreliable in dogsand cats. So you must examine the urinesediment microscopically for the presenceof red or white blood cells—or both. If theyare present, the proteinuria is explained bythe primary hemorrhagic or inflammatorydisease process and becomes an inciden-tal finding. Determine whether there is aninfection—do a culture. Do a survey forstones or, in an older animal, determine ifthe proteinuria is associated with a urinarytract tumor.

Grauer: With postrenal proteinuria, therewould be no need to do a microalbumin-uria assay, a urine protein–creatinine ratio,or a sulfosalicylic acid test.

Brown: We’re using the same nomencla-ture for protein in the urine that we use forazotemia, which is prerenal, renal, andpostrenal. Prerenal refers to extraurinarycauses, such as Bence Jones proteinuria ofmultiple myeloma. Postrenal refers to con-ditions of the lower urinary tract. With renaland postrenal being the most common,veterinarians should perform the set ofevaluations exactly as you proposed anytime proteinuria is identified. Is it prerenal,renal, or postrenal? It’s critical becauseeach is addressed in a completely differentmanner diagnostically and therapeutically.

Elliott: How you’ve collected the urinesamples matters as well. If you collectedsamples by cystocentesis, then you’veruled out one part of the urinary tract—the urethra—as a source of additionalprotein. You may iatrogenically causehematuria by taking a sample by cysto-centesis, but the studies suggest it’s notsufficient to cause significant proteinuriaon the urine protein–creatinine ratio test.

8

SOUND BYTE - DR. GRAUER

“If you’re interested in de-tecting a low level of proteinin the urine, the dipstick isnot sensitive enough.”


9

* Active sediment = cells, casts, and bacteria

** Monitor = recheck to determine trends. Recheck should include renal panel (albumin, BUN, calcium, creatinine, phosphorus, and total protein),urine protein–creatinine ratio, CBC, and electrolytes.

Investigate = determine underlying cause, if any. Consider ancillary testing asneeded (radiology, ultrasonography, blood pressure evaluation, infectious diseasetesting, endocrine testing, and autoimmune panel).Treat = consider the following treatment options when appropriate: dietarychanges, ACE inhibitor therapy, phosphate binders, and fluid therapy.

Prerenal

CBC, serum chemistryprofile, urinalysis

(examine urine sediment and specific gravity)

Active sediment *PollakiuriaAzotemia

Active sediment PollakiuriaAzotemia

Active sedimentPollakiuriaAzotemia

History and physical exam

Renal PostrenalIf prerenal ruled out If postrenal ruled out

HemoglobinuriaMyoglobinuriaBence Jones proteinuria (myeloma)

Urine protein–creatinine ratio Urinary tract infectionStonesTumors

<0.5canine and feline

Withinreference

range

Azotemia

>0.5 to <1.0canine and feline

Monitor

>1.0 to <2.0canine and feline

Monitor and investigate

>2.0canine and feline

Monitor, investigate,and treat

Within reference range Monitor, investigate, and treat **

Azotemia

Investigateazotemia

Kidney disease withproteinuria

Repeat urine protein–creatinineratio in two weeks

Investigate forpotential causes ofimmune-mediatedglomerulonephritis

or interstitial nephritis

Work up forproteinuria

UrineProtein–CreatinineRatio DiagnosticProtocol

>0.5 canine>0.4 feline

<0.5 canine<0.4 feline


So if it appears on the dipstick as micro-scopic hematuria but you can’t see urinediscoloration, then it’s unlikely to alter theurine protein–creatinine result. The situa-tion is different with acute or chronic uri-nary tract inflammation, which results inprotein exudation and white blood cells inthe sediment. Urine microscopy is impor-tant in these cases. If you have exudation,the white cell content will exceed the redcell content. If you just nicked a blood ves-sel while taking the sample, then you’llhave many more red cells.

Grauer: Renal proteinuria caused by in-flammatory diseases of the kidney isanother example of proteinuria typicallyassociated with active sediment wherequantitation of the protein is not indicated.Examples of kidney tissue inflammationthat can result in renal proteinuria includepyelonephritis and renal urolithiasis. Pro-teinuria associated with kidney inflamma-tion is classically associated with an activesediment, whereas glomerular and tubularproteinuria are typically associated withinactive sediments.

PersistenceRelford: So if a patient has proteinuria,the first step is to determine if it’s fromthe lower urinary tract or from the kid-neys. If it’s from the kidneys, the next stepis to determine if the proteinuria is per-sistent. How should veterinarians deter-mine persistence? What would be theirdiagnostic plan?

Lees: Persistence means that you find itrepeatedly. When you take a snapshot of atrain on a track, you can’t tell whether it’sgoing 100 miles per hour or has beenparked there for years. You need severaldifferent observations with some sense oftime in between to know whether thingsare changing or staying the same.

Relford: When should the animal be retest-ed? In six months? Six weeks?

Lees: It depends on the clinical context.The standard would be about two to fourweeks in apparently healthy animals. Ifyou’re dealing with a sick animal, the timeframe may need to be pushed up a little. Ifyou get a positive protein and think it might

be transient, you want to learn if it’s re-peatable. Somewhere within two to fourweeks would be a good recommendation.

Lees: If I see it twice, then there is some-thing to worry about, and I’m going to con-tinue evaluating this patient.

Elliott: It would be similar to how weapproach a cat with marginally high bloodpressure. I would want to see it in twoweeks to see if its blood pressure is stillabove our threshold.

Monitoring, investigation,and interventionRelford: So we’ve localized the proteinuriato the kidney and identified that it’s persis-tent. Let’s discuss the ACVIM consensusstatement and guidelines for monitoring,investigating, and intervention.

Lees: “Monitor, investigate, and inter-vene” became our mantra while workingon the consensus statement. Monitoringmeans doing the same tests over andover again (i.e., serial evaluations to lookfor worrisome trends over time). Investi-gate means performing additional tests,which are usually focused on discoveringa potentially treatable underlying cause.Intervene means treat with medication,diet, exercise, or other lifestyle changes.

So let’s say we’ve determined that thepatient has persistent renal proteinuria.The key is magnitude, and we especiallywant to know about changes in magni-tude over time. For microalbuminuria, wecan use the semiquantitative amounts(i.e., low, medium, and high positives)indicated by the commercially availablepoint-of-care test. However, we mainlyuse serial urine protein–creatinine ratiosto evaluate proteinuria magnitude be-cause they are useful for measuring anylevel of proteinuria. We want to monitorthe proteinuria and the patient. Withregard to renal function, we want to moni-tor the serum creatinine concentration.But don’t lose sight of the patient and any changes in weight or body condition.The three key questions to answer re-garding monitoring are: How is the urineprotein–creatinine ratio doing? How is the serum creatinine doing? How is thepatient doing?

Grauer: What change in the urine protein–creatinine ratio do you consider significantvs. just day-to-day variability?

Lees: We’re analyzing data on that subject.We have dogs with clinically stable glomer-ular proteinuria that are in stage I (i.e., theyaren’t azotemic). We’ve done daily urineprotein–creatinine ratios for three to fiveconsecutive days in these dogs and lookedat how much the values varied from day today. It takes at least a 30% change in theurine protein–creatinine ratio for the differ-ence to exceed ordinary day-to-day varia-tion. If a urine protein–creatinine ratio is 3,then 3.2 a week or two later, the animal’slevel of proteinuria probably hasn’tchanged. But if it increases to 5 or 6, italmost certainly reflects a meaningfulchange. It’s the same principle if it de-creases. If it decreases from 3 to 2.5, it’sborderline, but if it decreases from 3 to 2or less, it’s likely a genuine change. Thisalso applies when using proteinuria magni-tude changes as treatment response indi-cators to guide further treatment decisions.

Elliott: You’re dealing with lower level pro-teinuria in cats—urine protein–creatinineratios of about 0.4 to 1 in most proteinuriccats. We’d classify nonproteinuric cats asthose with ratios of less than 0.2. Urineprotein–creatinine ratios between 0.2 and0.4 could reflect normal variability. Theratio would need to double in a cat beforewe’d say it’s a significant change.

Lees: Another consideration that’s receivedlittle attention in veterinary medicine—theurine protein–creatinine ratio is influencedby not only the protein in the urine but bythe creatinine in the urine. If less creatinineis produced in the body, the urine creati-nine will decrease. You’re dividing the pro-tein by a smaller number and, therefore,getting a higher ratio. I think that’s whyurine protein–creatinine ratios are oftenhigh in puppies even though there is notmuch protein in the urine; puppies don’thave as much creatinine in their urine.

Grauer: The key to monitoring is lookingfor trends over time.

Lees: Yes. It’s the serial evaluation of cru-cial variables over time. Monitoring can tell

10


11

you to investigate immediately because thetrend is worsening.

Monitoring frequencyRelford: Before moving to investigation,let’s discuss monitoring frequency. How of-ten should you monitor patients’ conditions?

Grauer: If your screening test was negativeand you’re dealing with a mature animalwith no hereditary risk for disease, I’d rec-ommend annual or semiannual monitoring.

Lees: That’s the frequency for screeningapparently healthy animals. How frequentlyshould patients with persistent renal pro-teinuria be monitored?

Grauer: The magnitude of the positive re-sult and the patient’s condition will drivehow zealous you need to be.

Brown: Dr. Grauer, let’s say you have anonazotemic animal with persistent renalproteinuria. How frequently would youwant to measure serial serum creatininelevels and to reevaluate the urine protein–creatinine ratio?

Grauer: Again, I think it depends on themagnitude. If the magnitude causes me tointervene, I’d reassess that patient month-ly. If the magnitude doesn’t require inter-vention but I want to see if it’s persistent,I’d also reassess monthly.

Lees: A monthly interval is a good recom-mendation to begin monitoring. If youreassess after a month and it hasn’tchanged, it’s reasonable to extend therecheck intervals. For example, you coulddouble the recheck interval with everygood recheck. Rather than imposing oneschedule, I’m guided by what I learn. Someanimals are reasonably stable for extendedperiods of time; then, without any outwardmanifestation, they abruptly change. Butyou’ve done the best you can by monitor-ing them carefully.

Elliott: That is one of the issues we’re trying to address in longitudinal studies:What can we use to predict those abruptdecreases in kidney function? Or jumps inplasma creatinine concentration or weightloss, which we see in about two-thirds of

the cats that progress? About one-third ofthese animals show a nice linear progres-sion. Our initial studies suggest that urineprotein behaves the same as the plasmacreatinine concentration—jumping tohigher values when the plasma creatinineconcentration jumps. I was quite hopefulthat the proteinuria preceded and predict-ed those jumps in plasma creatinine butthis does not appear to be the case.

The degree of proteinuria when theanimal is first diagnosed with renal dis-ease is helpful in predicting survival time,according to our studies. It’s a gradation;the lower the protein level in the urine,the longer the cat is going to survive.That’s fine in a population study, but notvery useful in the individual patient.Veterinarians want the cut-off point—when should they start worrying aboutproteinuria? We say it’s linear across thewhole range and the lower it is, the bet-ter the cat’s prognosis. We need to moni-tor it along with the parameters you’dnormally monitor in the azotemic animal.

Lees: Monitoring also happens duringtherapy—to monitor how the patient isdoing and to evaluate treatment efficacy.You can use a blood pressure analogy. Ifyou have high blood pressure, you givemedicine to lower it, but you still need tocheck to see whether it went down. If youdidn’t reach your target, you change the

dose or add other drugs. With renal dis-ease, once the patient’s magnitude of pro-teinuria is in, or progresses to, the treat-able range, monitoring intervals should bedictated by your need to assess responseto treatment.

Grauer: I like the idea of the monthly ap-proach that doubles if the patient is stable.When you first detect and confirm abnor-mal proteinuria but you don’t know if it’stransient or persistent, would you wait amonth to reevaluate?

Lees: No, I’d wait two weeks in thatinstance.

Brown: We seem to agree that two to fourweeks is a good recheck interval for patients with proteinuria. One month isadvisable for the otherwise healthy pa-tient with persistent renal proteinuria. Iwould prefer not to go beyond the six-month interval if it’s a senior pet. I thinkwe, as veterinarians, tend to wait too longin the face of stability and the lack of clin-ical abnormalities.

Elliott: You need to consider what intervalis acceptable to owners and doctors. Petowners are not paying for the rechecksinvolved in the research we’re doing inthe United Kingdom. Even so, rechecksevery six weeks, in our experience, seemacceptable. If I take blood samples morefrequently, many owners with cats thatappear outwardly stable will question it.

Metzger: One of the possible pitfalls oftesting is whether you can use a freecatch sample. Is that an acceptable sam-ple for the urine protein–creatinine ratioor microalbuminuria test? Often when Itell owners that I need another sample,they’ll say they’d prefer to drop the sam-ple off.

Grauer: Several studies have examinedmultiple collection techniques. As long as we rule out proteinuria caused by a postrenal component or an inflamma-tory renal component with a sedimentexam, sure.

Metzger: Great, I think you’d see excellentcompliance then.

SOUND BYTE - DR. ELLIOTT

“The degree of proteinuriawhen the animal is firstdiagnosed with renal diseaseis helpful in predicting sur-vival time, according to ourstudies. It’s a gradation; thelower the protein level in theurine, the longer the cat isgoing to survive.”


Lees: Voided samples are fine if they’recollected properly. We routinely use mid-stream, voided samples for proteinuriaassessment in our male research dogs.Catching a clean midstream sample in a small cup is easy with these Labrador-sized dogs. It’s much harder to get goodmidstream samples from females. Weroutinely use cystocentesis to obtain urine samples from the female dogs we study.

Grauer: Are you suggesting that a mid-stream, voided sample obviates the needfor a sediment exam?

Lees: No, not at all. Proteinuria should beassessed in the context of a complete uri-nalysis, but catching a clean midstreamsample during voiding can be satisfactory.Even if the genitalia harbor some secre-tions or debris, contamination should benegligible after the first washout.

Investigation Relford: We’ve discussed performing several diagnostic tests to determine thatthe patient has renal proteinuria, but let’sexpand on the ACVIM recommendations for investigation.

Lees: Basically, the idea is to do newtests. “Tests” can even mean new physi-cal exams and thorough history reviews.Examine pets like you’ve never seen thembefore to make sure you’re not missinganything. Ask a colleague to look at thepatient. Learn what drugs are beingadministered—not just medication you’veprescribed, but health foods, nutraceuti-cals, or other supplements. Get them offunnecessary or harmful drugs. Becauseso much of the kidney disease that occursin dogs and cats is secondary to otherphenomena, we’re really looking for someunderlying disease that might affect thekidneys, such as active periodontal dis-ease or inflammatory bowel disease.Exhaustive searches can be daunting.

The other crucial issue is whether youshould investigate the kidney disease di-rectly with testing. Minimally invasiveultrasound evaluations and radiographsanswer questions about the kidney’s size,the presence of stones, and so on. As weprogress, one of the key issues will be

the role of renal biopsies (i.e., examiningrenal tissue to diagnose the cause of theprimary renal lesions). Renal biopsies areonly as good as the people performingthem. Good pathologic evaluation of kid-ney tissue requires expertise. In humanmedicine, renal biopsies are evaluated bynephropathologists—pathologists whospecialize in renal disease. At some point,veterinary medicine will bring that levelof expertise to renal biopsies.

I liken it to dermatopathology. It usedto be that we’d do a skin biopsy, send itin, and they’d say, “It’s dermatitis.” Butnow we know that if you look in the rightplace in the right way with the rightapproach, you see things that are indeeduseful. Now people do skin biopsies cor-rectly and helpful information comesback from dermatopathology services.

Today, with renal disease, we’re in that “it’s dermatitis” phase. One of ourchallenges is to investigate kidney dis-ease in a way that’s productive for thepatient and the client. It’s coming, but nothere yet. One of the reasons we performkidney biopsies less often is because thebiopsy reports would say kidney disease,but they rarely taught us anything. Withearly diagnosis, the view through thepathologic window into kidney disease is more interesting and useful. We stillneed to examine biopsies in more sophis-ticated and helpful ways. But we possessthe ability to evaluate the patient as awhole and to find underlying, treatablesystemic diseases—whether they are

inflammatory, infectious, noninfectious,or degenerative.

Relford: So the investigation phase in-volves two areas. One phase constitutesidentifying the underlying cause of thekidney disease—whether it’s the initialcause or the cause of the current kidneyfunction deterioration. The second phaseinvolves the kidney function evaluation.Are there some special conditions you’dlook for in cats?

Elliott: Hyperthyroidism is common in catsand is occasionally problematic to diag-nose. Hyperthyroidism causes proteinuriaat levels we can detect with microalbumin-uria tests but also at levels significantlygreater than urine protein–creatinine ratiothresholds. We often see urine protein–creatinine ratios between 0.5 and 1 in catswith hyperthyroidism. You should rule thatout with your initial screen. But occasional-ly, you see cats with hyperthyroidism andnormal T

4concentrations initially that you

diagnose as hyperthyroid when you retest.Hypertension is also an issue in cats.

The higher the blood pressure, the morelikely the cat is to have significant protein-uria. Blood pressure measurement issomething I’d recommend in the initialevaluations of aging nonazotemic protein-uric cats.

Proteinuria will actually resolve as youtreat the hyperthyroidism in most cases.We’ve done prospective studies involvinghyperthyroid cats with proteinuria andexamined their response to treatment.Whether they become azotemic or not, theproteinuria decreases with hyperthyroidismtreatment. We’d classify hyperthyroidism asa risk factor for hyperfiltration and potentialkidney damage.

InterventionRelford: Let’s now shift our discussion tointervention. Dr. Brown, what interventionsshould the veterinarian consider with pro-teinuric patients?

Brown: We’re somewhat limited in termsof intervention, but there are some thera-pies that we know are antiproteinuric.Veterinarians may ask themselves,“Should proteinuria be treated? Is thatthe target of therapy?”

12

SOUND BYTE - DR. RELFORD

“The investigation phaseinvolves two areas. Onephase constitutes identifyingthe underlying cause of thekidney disease. The secondphase involves kidney func-tion evaluation.”


13

Mild renal proteinuria, sometimes calledmicroalbuminuria, has been studied exten-sively in rodents and people. In people, it’sclearly a marker for two diseases. The firstis early stage kidney disease. The secondis cardiovascular disease where mild renalproteinuria seems to be an indicator ofgeneralized endothelial or vascular dys-function with myocardial infarction orstroke as potential sequelae. Based on asubstantial amount of data, even mild renalproteinuria is a target for therapy in people.The identification of proteinuria and thera-pies that reduce proteinuria are valued.

Lees: The worst outcomes in people withchronic renal disease often are not end-stage renal failure but fatal cardiovascularevents. In people, kidney disease and pro-teinuria are risk factors for serious cardio-vascular disease.

Brown: One reason for excitement is thatproteinuria may be a marker that allows usto assess the efficacy of renal failure treat-ments. Drs. Elliott and Syme reported thatthe magnitude of proteinuria is a predictorof mortality in cats8 and a recent Universityof Minnesota study suggests that the level ofproteinuria (measured by the urine protein–creatinine ratio) predicts mortality as well.9

Lees: That’s the level of proteinuria at thetime of renal failure diagnosis.

Brown: Correct. And we have antiprotein-uric therapies that seem beneficial. Theseare interventions that can lower the magni-tude of renal proteinuria. The most com-mon are dietary protein restriction, dietaryfish oil supplementation, and interventionsthat interfere with the renin-angiotensin-aldosterone system. In veterinary medicine,that latter group includes angiotensin-converting enzyme (ACE) inhibitors, suchas benazepril or enalapril. In terms of reno-protection, the interventions that are sup-ported by studies are ACE inhibitors anddietary fish oil supplementation. In dogs,for example, there is evidence that ACEinhibitors decrease proteinuria and renallesion magnitude concurrently.10 In addi-tion, a multicenter trial that Dr. Grauer ledindicated that ACE inhibitors are antipro-teinuric and potentially beneficial in spon-taneous glomerular disease.11

Fish oil supplementation is also antipro-teinuric and renoprotective in dogs,12 butthere is no evidence yet of fish oil’s bene-fits in chronic kidney disease. Ongoingclinical trials in which Dr. Sanderson isinvolved are evaluating the potential bene-fits of long-term fish oil supplementation indogs with spontaneous chronic kidney dis-ease. There is reason for excitement.

Lees: I’m a “work in stages” sort of a per-son. My first impulse is to fix underlyingconcurrent conditions—whether it’s perio-dontal disease, skin problems, cancer, or in-fectious disease—and then reevaluate anddecide whether to add in additional thera-pies (e.g., renoprotective diets or drugs).

Elliott: So we wouldn’t put our hyperthy-roid cats on ACE inhibitors. We’d treat thehyperthyroidism.

Lees: The interventions we’ve talked aboutdecrease proteinuria and injury to the kid-neys. I’ll use the term renoprotective. Eachof these diet-related therapies—whetherit’s adjusting fish oil, fatty acid, or proteincontent—affect the patient and the kid-neys beyond the proteinuria. ACE inhib-itors have an antiproteinuric effect as wellas a number of other beneficial effects onthe kidney.

Brown: Everybody has their own way ofapproaching these patients, but in summa-ry, there are three different types of avail-able therapy. I’d call the first, and the mostimportant, disease-specific therapy. If a cathas hyperthyroidism, you treat the hyper-thyroidism. If a dog has pyelonephritis, youtreat the pyelonephritis. We may not findthe problem, but we certainly will not find itif we don’t look for it. If we’re fortunateenough to find the disease, it becomes themost important therapy to institute.

The second is renoprotective therapy(i.e., therapy designed to prevent chronickidney disease progression). For example,this could be ACE inhibitors, dietary pro-tein restriction, and fish oil supplementa-tion in dogs. This approach is generallyeffective because it influences multiplemechanisms in several renal diseases—proteinuric and nonproteinuric.

The third category is symptomatic ther-apy. Here we may be alleviating signs of

uremia. Systemic hypertension, for exam-ple, is one sign of chronic kidney diseasethat needs to be managed in stages I to IV.Symptomatic therapy is not for stage IIIand IV animals only.

The role of dietRelford: In talking about intervention, diethas come up several times. Dr. Sanderson,can you comment on nutrition in regard torenal disease and proteinuria?

Sanderson: Diet is still one of our maintreatments for renal disease. There is a lotof confusion right now surrounding dietand its role in slowing the progression ofrenal failure in animals. I get calls frompractitioners who think that we don’t usespecial diets to treat renal failure anymore.That is not true. In renal failure models,phosphorus restriction has been shown toslow disease progression. Omega-3 fattyacids in diets have beneficial effects thatrelate to metabolites. The omega-6 fattyacids produce more inflammation thanomega-3 fatty acids. When changing pro-tein levels, we may not be changing theoutcome of renal failure itself, but we’rehoping to lessen some of the extrarenalsigns. Protein restriction is still indicated inthese cases. When animal protein is meta-bolized, it creates acid metabolites thatneed to be excreted by kidneys that arealready having difficulties regulating theanimal’s acid base status. But you don’twant to go to the other extreme and cre-ate protein malnutrition by severely re-stricting protein. We try to have a balance.

Most renal diets will include B vitaminsupplementation because of the loss ofwater-soluble vitamins. The potassiumlevel in the feline renal diets is higher thanin maintenance diets. And if you add cer-tain kinds of fiber into the diets, you cancreate alternative routes for urea excretion.Normally, the kidneys would excrete urea.But if you add fiber sources in the colon,the bacteria will metabolize them and useurea as a source of nitrogen—lesseningsome of the urea that is ultimately excret-ed by the kidneys.

Another consideration is canned vs. drydiets. It’s beneficial for cats and dogs toeat canned diets because they’re 60% to70% water, and cats, especially, are notbig drinkers. But some clients may not be


able to afford canned food. So addingadditional water to diets will also be help-ful. There are a lot of therapeutic optionsavailable. The five main pet food compa-nies all make renal diets now.

Grauer: Although it may be difficult to fer-ret out the actual influences of the variousdiet manipulations, research shows thatappropriate dietary therapy in naturallyoccurring disease can significantly affectpatient longevity.

Sanderson: I definitely agree. Maintenancediets were compared with renal failure dietsin the research you mentioned.13 But was itphosphorus restriction, phosphorus andprotein restriction, omega-3 fatty acid sup-plementation, or a combination of variablesin the renal diet that were beneficial andincreased patient longevity? There is a lotwe need to learn. There haven’t been manystudies in patients with naturally occurringrenal disease—the gold standard. I hopethat in the years to come we’ll acquire moreinformation to help clarify these issues.

Lees: The more protein you feed to a pro-teinuric subject, the more protein appearsin the urine. Studies in people and rodentsshow it has a direct effect on the permse-lectivity of the glomerular filtration barrier.The diet’s protein can cause the damagedglomerulus to be even more permeable toprotein. Such studies have not been re-peated in dogs or cats. But there is a phys-iologic rationale for limiting protein andadding ACE inhibitors on top of protein re-striction in proteinuric patients. I wouldn’topt for drugs instead of diet. I would changethe diet, then add in drugs as needed.

Grauer: Dr. Elliott, did you study the additionof a phosphate binder in your research?

Elliott: The goal was to control parathyroidhormone secretion in the group that wouldaccept phosphorus restriction. It was anuncontrolled study.14

Grauer: But you saw almost a threefoldincrease in lifespan, did you not?

Elliott: Yes, the difference was quite staggering. But as I mentioned, it was anuncontrolled study; the cats were self-

selecting. The cats that wouldn’t eat the diet at the beginning were fed stan-dard maintenance diets. But there wereno significant differences between anything we measured at entry (e.g.,plasma creatinine, phosphorus, potassi-um, packed cell volume, urine specificgravity, and body weight) between thetwo groups.

Brown: It was important and very wellconducted. The results of that study aswell as Jacob’s study13 imply that dietaryintervention can have a powerful influ-ence in cats and dogs with chronic kid-ney disease. But the right diet in stage Imay be different from the right diet instage IV.

In dogs, which nutrients are more im-portant? The data are much stronger forfish oil supplementation and phosphorusrestriction than protein reduction in slow-ing progression from stage II and stage III.I think we all agree protein restriction isessential in reducing uremia in stage IV.Dr. Elliott, in what stage of kidney diseasewere your cats when you found benefitsto restricting phosphorus and controllingparathyroid hormone secretion?

Elliott: They were in late stage II and earlystage III. There was an effect in both stages.

Lees: We all recognize the importance ofcontrolling serum phosphorus through di-etary phosphorus restriction with intestinalphosphate binders as needed. And the re-stricted dietary protein in renal diets is ra-tional even if it has no other effect than allowing us to limit dietary phosphorus forstage II and III patients, which we know is crucial.

Elliott: Some cats with kidney failure areable to regulate their phosphorus concen-trations with a standard maintenance diet.The goal should be to keep the serumphosphorus concentration at the lower end of the reference range.

Metzger: I begin with phosphorus restric-tion or a phosphate binder (aluminumhydroxide) before they are hyperphospha-temic. A lot of clinicians wait until patientsare azotemic with phosphorus at 16 mg/dlbefore starting phosphorus restriction.

Sanderson: There are advantages to intro-ducing renal diets during the early renalfailure stages. If animals have uremiccrises and you put the food in front ofthem, it’s probably the last thing they wantto see again. But if they’re still feeling goodwhen the diet is introduced, they may bemore likely to eat it on a long-term basis.

Elliott: We occasionally see cats becomehypercalcemic with phosphorus restriction.They don’t seem to do as well clinically. Itreverses when we add more phosphorus totheir diets. Not all treatments suit all ani-mals with kidney disease—diets need tobe tailored to the individual animal’s needs.

Metzger: How about the nonclinical, non-azotemic animal with persistent protein-uria? If I have a senior patient with per-sistent proteinuria, should I initiate a renal diet?

Sanderson: Yes, there are some indica-tions for renal diets in the nonazotemicproteinuric patient. If you have a choicebetween early-stage renal diets, whichtend to have a little more protein, andadvanced-stage diets, go with the early-stage diet in the beginning. The benefitsare the omega-3 fatty acids and the pro-tein itself. You want to keep up with whatthey’re losing, but you don’t want to givethem so much that more and more proteinis leaked into the kidneys and causesdamage. Mild dietary protein restriction iswarranted in those cases. Renal diets areindicated in both chronic renal failure andglomerular disease.

Grauer: We’re trying to expand our thera-peutic window for proteinuria and renal

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SOUND BYTE - DR. SANDERSON

“There are advantages tointroducing renal diets during the early renal failurestages.”


15

disease, but here is the conundrum: Wedon’t have prospective controlled random-ized clinical trial data showing we can influence the outcome of nonazotemic pro-teinuric disease in its early stages with anytype of treatment. There was a multicenterclinical trial with enalapril showing that thedrug decreased proteinuria and systolicblood pressure and prevented serum crea-tinine increases, but the study involvedspontaneous disease in nonazotemic pro-teinuric dogs with urine protein–creatinineratios of 3 or more to begin with.

Lees: But they did receive a renal diet aspart of their treatment.

Grauer: Yes, in addition to the enalapriland low-dose aspirin.

Metzger: What forms do omega-3 fattyacids come in?

Brown: We tend to think of fish oil as aprimary source of omega-3 polyunsaturat-ed fatty acids but there are other sources.Omega-3 fatty acids are often incorporat-ed into renal diets for cats and dogs,though I’m not aware of evidence thatshows their benefits in cats. Clients canbuy capsules at pet stores, health foodstores, or grocery stores.

Metzger: What would be the dose, even ifit were anecdotal?

Brown: It has been proposed that a 1-ggel cap of concentrated omega-3 polyun-saturated fatty acids be added per 250kcal of diet. That’s probably as close aswe can come to a dose. One problem isthat each commercial diet has differentlevels and types of polyunsaturated fattyacids and the ideal dosage is thus hard to predict.

ConclusionLees: So which patients do we treat? Ifit’s stable, low-level proteinuria, such as a

urine protein–creatinine ratio of less than2 in a dog that has good renal functionotherwise, I’m not going to intervene.I’ll watch it. If it’s higher—say a 4 to 6urine protein–creatinine ratio, or a 2 that’srisen to a 4—I make the decision to treat.Even if the serum creatinine is fine andthe dog looks fine, I’ll recommend a renaldiet and see how it affects the urine pro-tein–creatinine ratio. Then, I’ll carefullyadd enalapril or benazepril in stages andincrease the dose until I get the effect I want.

Brown: The ACVIM proteinuria consensuspanel recommendations are consistentwith our discussions here today. If theurine protein–creatinine ratio is persist-ently abnormal and the protein is renal inorigin but less than 1 in stable, nonazo-temic animals, the panel recommendsmonitoring. If it’s between 1 and 2, weinvestigate the kidneys and the patient todetermine potential causes. A ratio above2 means we should monitor and investi-gate but it’s now appropriate to intervene.That leaves a large group of animals tomonitor, so we’ll need to convince clientsto comply.

With a nonazotemic patient with aurine protein–creatinine ratio that exceeds2, intervention could include fish oil sup-plementation, dietary protein restriction,and ACE inhibitors. We don’t have evi-dence that suggests that fatty acids, spe-cial diets, or ACE inhibitors are routinelyneeded for animals with lower urine protein–creatinine ratios, such as 0.6 or0.7—the panel would recommend moni-toring these nonazotemic patients.

Grauer: With this exception: If you see a urine protein–creatinine ratio of 0.6 inan animal with a concurrent underlyingdisease, you should treat the underlyingdisease.

Relford: We hope you’ve found the discus-sion on kidney disease, proteinuria, and

the ACVIM’s recommendations for moni-toring, investigation, and intervention use-ful. The consensus panel’s full recommen-dations will be published in the May/June2005 issue of the Journal of VeterinaryInternal Medicine.

References1. Lund E, Armstrong P, Kirk C, et al. Health status

and population characteristics of dogs and cats exam-ined at private veterinary practices in the United States.J Am Vet Med Assoc 1999;214:1336-1342.

2. Polzin DJ, Osborne CA, Adams LG, et al. Medicalmanagement of feline chronic renal failure. In: Kirk RW,Bonagura JD, eds. Current Veterinary Therapy XI. Phila-delphia, Pa: WB Saunders Co, 1992:848-853.

3. Krawiec D, Gelberg H. Chronic renal disease incats. In: Kirk RW, ed. Current Veterinary Therapy X.Philadelphia, Pa: WB Saunders Co, 1989:1170-1173.

4. Rouse BT, Lewis RJ. Canine glomerulonephritis:prevalence in dogs submitted at random for euthana-sia. Can J Comp Med 1975;39:365-370.

5. Short RP, Lobetti RG, Nesbit JW. Renal pathologyin working dogs in the South African National DefenceForce. J S Afr Vet Assoc 1999;70:158-160.

6. Mathews KA, Holmberg DL, Miller CW. Kidneytransplantation in dogs with naturally occurring end-stage renal disease. J Am Anim Hosp Assoc 2000;36:294-301.

7. MacDougall DF, Cook T, Steward AP, et al. Caninechronic renal disease: Prevalence and types of glomer-ulonephritis in the dog. Kidney Int 1986;29:1144-1151.

8. Syme HM, Elliott J. Relation of survival time andurinary protein excretion in cats with renal failureand/or hypertension. J Vet Int Med 2003;17:405A.

9. Jacob F, Polzin DJ, Osborne CA, et al. Evaluationof the association between initial proteinuria and mor-bidity rate or death in dogs with naturally occurringchronic renal failure. J Am Vet Med Assoc 2005;226:393-400.

10. Brown SA, Finco DR, Brown CA, et al. Evaluationof the effects of inhibition of angiotensin-convertingenzyme with enalapril in dogs with induced chronicrenal insufficiency. Am J Vet Res 2003;64:321-327.

11. Grauer G, Greco D, Gretzy D, et al. Effects ofenalapril treatment versus placebo as a treatment forcanine idiopathic glomerulonephritis. J Vet Intern Med2000;14:526-533.

12. Brown SA, Brown CA, Crowell WA, et al. Effectsof dietary polyunsaturated fatty acid supplementation inearly renal insufficiency in dogs. J Lab Clin Med2000;135:275-286.

13. Jacob F, Polzin DJ, Osborne CA, et al. Clinicalevaluation of dietary modification for treatment of spon-taneous chronic renal failure in dogs. J Am Vet MedAssoc 2002;220:1163-1170.

14. Elliott J, Rawlings JM, Markwell PJ, et al.Survival of cats with naturally occurring chronic renalfailure: effect of dietary management. J Small AnimPract 2000;41:235-242.

Cover art by Kip Carter.The views in this publication represent those of the participants and do not necessarily reflect those of IDEXX Laboratories or the publisher.

© 2005 Advanstar Communications Inc. All rights reserved. Published by Advanstar Veterinary Healthcare Communications,Lenexa, Kan. Printed in the United States of America.

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Proteinuria Round Table