RVC OPEN ACCESS REPOSITORY – COPYRIGHT NOTICE

This is the peer-reviewed, manuscript version of the following article:

Vaden, S. L. and Elliott, J. (2016) 'Management of Proteinuria in Dogs and Cats with Chronic
Kidney Disease', Veterinary Clinics of North America: Small Animal Practice, 46(6), 1115-1130.

The final version is available online: http://dx.doi.org/10.1016/j.cvsm.2016.06.009.

© 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
http://creativecommons.org/licenses/by-nc-nd/4.0/.
The full details of the published version of the article are as follows:

TITLE: Management of Proteinuria in Dogs and Cats with Chronic Kidney Disease
AUTHORS: Shelly L. Vaden and Jonathan Elliott
JOURNAL TITLE: Veterinary Clinics of North America: Small Animal Practice
PUBLISHER: Elsevier
PUBLICATION DATE: November 2016
DOI: 10.1016/j.cvsm.2016.06.009
ARTICLE TITLE

Management of Proteinuria in Dogs and Cats with Chronic Kidney Disease

AUTHOR NAMES AND DEGREES

Shelly L. Vaden, DVM, PhD, DACVIM

Jonathan Elliott MA Vet MB PhD Cert SAC Dip ECVPT MRCVS

AUTHOR AFFILIATIONS

Professor of Internal Medicine

Department of Clinical Sciences

College of Veterinary Medicine

North Carolina State University

Raleigh, NC

Professor of Veterinary Clinical Pharmacology

Department of Comparative Biomedical Sciences

Royal Veterinary College, University of London

London UK

AUTHOR CONTACT INFORMATION

1052 William Moore Drive

Raleigh, NC 27607

slvaden@ncsu.edu

1
Royal Veterinary College

Royal College Street

London NW1 0TU

UK

jelliot@rvc.ac.uk

CORRESPONDING AUTHOR

Shelly Vaden

DISCLOSURE STATEMENT

Vaden: I have acted as a paid consultant for Heska Corporation and Idexx LTD. I receive

research grant funding from Morris Animal Foundation and the American Kennel Club

Canine Health Foundation.

Elliot: I have acted as a paid consultant for Bayer Animal Health, Boehringer Ingelheim,

Elanco Animal Health, Idexx Ltd, CEVA Animal Health, Orion Inc, Nextvet Ltd., Waltham

Centre for Pet Nutrition. I receive research grant funding from CEVA Animal Health, Elanco

Animal Health, Zoetis Animal Health, Royal Canin Ltd. and Waltham Centre for Pet

Nutrition. I am a member of the International Renal Interest Society, which receives

financial support from Elanco Animal Health.

KEY WORDS

Urine protein: creatinine ratio, proteinuria, hypertension, angiotensin, aldosterone,

glomerular, chronic kidney disease

KEY POINTS

2
In dogs and cats proteinuria is a negative prognostic for chronic kidney disease and is

associated with degree of functional impairment as well as the risk of a uremic crisis,

progressive worsening of azotemia or death.

Normal dogs and most normal cats should have a urine protein:creatinine ratio that is <0.4

and <0.2, respectively; persistent proteinuria above this magnitude warrants attention.

Administration of angiotensin converting enzyme inhibitors and/or angiotensin receptor

blockers is considered a standard of care in dogs and cats with renal proteinuria where the

UPC is >0.5-1 and >0.2-0.4 respectively.

Blood pressure control and nutritional modification are also important considerations and

part of the standard of care for dogs and cats with renal proteinuria.

Renal biopsy and administration of immunosuppressive agents should be considered in

dogs with glomerular proteinuria that have not responded to standard therapy.

SYNOPSIS

Proteinuria is a negative prognostic indicator for dogs and cats with for chronic kidney

disease and is associated with degree of functional impairment as well as the risk of a

uremic crisis or death. The normal kidney is so highly efficient at preventing passage of

proteins into the filtrate and reabsorbing the proteins that do get through that a normal

3
dog or cat should excrete very little protein and have a urine protein:creatinine ratio that is

<0.4 or <0.2, respectively; persistent proteinuria above this magnitude warrants attention.

Administration of angiotensin converting enzyme inhibitors (e.g., benazepril, enalapril)

and/or angiotensin receptor blockers (e.g., telmisartan), blood pressure control and

nutritional modification are considered a standard of care in dogs and cats with renal

proteinuria. Renal biopsy and administration of immunosuppressive agents should be

considered in dogs with glomerular proteinuria that have not responded to standard

therapy; glomerular proteinuria is uncommon in cats. Targeted patient monitoring is

essential when instituting management of renal proteinuria.

Proteinuria as a Prognostic Indicator in Chronic Kidney Disease

Proteinuria is a negative prognostic indicator for both dogs and cats with chronic

kidney disease. In dogs with chronic kidney disease, an initial urine protein: creatinine

ratio (UPC) of >1.0 was associated with a threefold greater risk of developing a uremic

crisis and death (Jacob et al, 2005). The relative risk of adverse outcomes increased 1.5

times for every increase in the UPC by 1. In another canine study, proteinuria correlated

with the degree of functional impairment, as measured by glomerular filtration rate; dogs

with UPC of <1.0 lived 2.7 times longer on average than dogs with a UPC >1.0 (Wehner et al,

2008).

When nonazotemic cats were prospectively and longitudinally evaluated,

proteinuria was found to be significantly associated with the development of azotemia by

12 months (Jepson et al, 2009). Both proteinuria and serum creatinine were related to

shortened survival in cats with chronic kidney disease (Syme et al, 2006; King et al, 2007).

4
This was true even when cats had UPC as low as 0.2-0.4.

Chronic proteinuria has been shown to be associated with interstitial fibrosis as

well as tubular degeneration and atrophy, although the exact mechanisms of injury are a

subject of debate (Toblli et al, 2012; Pollock et al, 2007). There is some evidence that

reabsorbed proteins and lipids are directly toxic to the tubular epithelial cells, triggering

inflammation and apoptosis. In addition, excessive lysosomal processing of proteins leads

to lysosomal rupture and the intracellular release of cytotoxic enzymes. Proteinuria may

increase the workload of the tubular epithelial cell beyond its capabilities. Proteinacious

casts cause tubular obstruction, which further injures the cells. Glomerular injury results

decreased perfusion of the tubulointerstitium, resulting in cellular hypoxia. Increased

glomerular permselectivity increases the filtration of other substances, such as transferrin,

that cause additional tubular injury.

Because proteinuria is associated with negative outcomes it is imperative that the

practice veterinarian has a thorough understanding of appropriate assessment and

management of proteinuria in dogs and cats with chronic kidney disease.

Normal Renal Handling of Protein

The glomerulus is a complex structure that functions as a filter, across which an

ultrafiltrate of the plasma is formed. This filtration system, made up by the fenestrated

endothelium, glomerular basement membrane and visceral epithelial cells (podocytes) is

freely permeable to water and small dissolved solutes, but retains cells and most

macromolecules, such as proteins. The podocyte is the most differentiated cell in the

glomerulus and essential to the filtration unit (Tobilli et al, 2012). In addition to these

5
factors, glycocalyx has been found to play an important role in maintaining glomerular

permselectivity by restricting the passage of proteins (Singh et al, 2007). The major

determinant of passage into the filtrate is molecular size. Low-molecular weight proteins,

such as insulin and immunoglobulin fragments, pass freely through the filter, but as

molecules increase in size they are retained with increasing efficiency. Only small amounts

of substances larger than 60,000 to 70,000 daltons pass in to the filtrate. The podocyte foot

processes, epithelial slits, basement membrane and endothelium are all rich in negatively

charged glycoproteins that create an ionic charge barrier and impede the passage of

negatively charged molecules more than would be expected based on their size alone.

Albumin, a negatively charged protein with a molecular weight of 69,000 daltons, is

normally largely excluded from the filtrate. Despite this complex filtration system, the

glomerulus normally leaks albumin. Rapid endocytosis and hydrolysis of these proteins by

proximal tubular cells occurs. Filtered albumin and other proteins are ultimately released

to the blood as amino acids. A normal animal should excrete virtually no protein in the

urine, but certainly an amount that is below the limit of detection of routine urine protein

assays (Maack, 2011).

Laboratory Tests for Urine Protein

The urine dipstick, the sulfosalicylic turbidimetric test (SSA, bumin test) or the UPC

can be used to measure total urine protein. The urine dipstick is the most readily available

test of urine protein but is also the least reliable. Both false positives and false negatives

occur. The sensitivity and specificity of the urine protein dipstick are as low as 54% and

69%, respectively, in the dog and 60% and 31%, respectively, in the cat. While the urine

6
dipstick primarily detects albumin, it also measures globulins. The SSA is more reliable

than the urine dipstick for the detection of proteinuria (both albumin and globulin);

however, use of this test requires either having the appropriate reagents and standards on

hand or sending the urine sample to a reference lab. The amount of protein that is present

in the urine of normal dogs and cats is below the lower limit of detection for both of these

tests. When both urine dipstick and SSA test results are available, the results of the SSA test

should be given greater consideration than those of the urine dipstick. Positive results with

either of these tests must be interpreted in light of the urine specific gravity.

Dogs and cats with repeat positive dipstick or SSA results in urine sample that is

free of pyuria or a color change from hematuria should have urine protein losses quantified

by the UPC. The UPC is determined using a quantitative test for total urine protein, the

results of which are expressed as a ratio to urine creatinine thereby eliminating the need to

consider the urine specific gravity when interpreting the results. The ratio correlates well

with 24-hour urine protein losses and can be measured either in-house or as a send out

test. Normal dogs, female cats and neutered male cats should have a UPC that is <0.2 (Table

1). Normal intact male cats can have UPC up to 0.6, most likely due to the excretion of large

amounts of cauxin.

Persistent microalbuminuria is the mildest, and often earliest, detectable form of

proteinuria. Urine albumin can be measured quantitatively through a commercial reference

laboratory using a specifies-specific assay. The urine is diluted to a standard concentration

(1.010) prior to assay, eliminating the need to consider urine specific gravity when

interpreting the test results. Alternatively, some labs report urine albumin as a ratio to

creatinine (i.e., mg albumin/g creatinine). Microalbuminuria is defined as concentrations of

7
albumin in the urine that are greater than normal but below the limit of detection using the

urine dipstick. By this definition, the upper end of urine albumin concentrations that are

still considered to be microalbuminuria is 30 mg/dl (or 300 mg albumin/g creatinine).

Urine albumin concentrations above this are called overt albuminuria. Proteinuria of this

magnitude can often be detected using the UPC.

Clinical Assessment of Proteinuria

Accurate assessment of proteinuria involves 3 key elements: persistence,

localization, and magnitude (Lees et al, 2005). Persistent proteinuria is defined as

proteinuria that has been detected on 3 or more occasions, 2 or more weeks apart.

Persistent proteinuria should be localized as being pre-renal, post-renal, or renal (Table 2).

Identifying the cause of proteinuria in an affected dog or cat is important so that

appropriate therapeutic measures can be implemented. Renal proteinuria that is

glomerular or tubulointerstitial in origin is the most relevant form of proteinuria when

managing dogs with chronic kidney disease. However, it is important to ensure that

proteinuria is not due to pre-renal or post-renal causes because the management of these

disorders varies substantially from the management of chronic kidney disease. Functional

proteinuria is not very common in dogs and cats, or at least poorly documented.

Once pre-renal and post-renal causes of persistent proteinuria are eliminated,

magnitude is used to help determine if renal proteinuria is glomerular or tubulointerstitial

in origin. Magnitude is assessed using a quantitative test for urine protein (generally UPC

but could also be urine albumin). Once pre-renal and post-renal causes of proteinuria have

been excluded, it is recommended that a UPC be evaluated in all dog and cats with

8
persistent proteinuria as determined by dipstick or SSA.

The International Renal Interest Society (IRIS) has recommended substaging dogs

and cats with chronic kidney disease on the basis of their UPC (Table 1). Dogs that have

renal proteinuria and a UPC ≥2.0 usually have glomerular disease, whereas dogs with UPC

<2.0 might have either glomerular disease or tubulointerstitial disease. Glomerular

diseases occur much less commonly in cats but should be suspected when the UPC is ≥2.

Concurrent hypoalbuminuria is added evidence that glomerular disease is present.

Urine sodium-dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) can

be used to help determine if renal proteinuria is glomerular or tubulointerstitial in origin

(Nabity 2010). Finding predominantly low molecular weight proteins is consistent with

tubulointerstitial disease whereas glomerular damage is more likely associated with a

pattern of intermediate and high molecular weight proteins. When there is concurrent

glomerular and tubulointerstitial disease, a mixture of sizes is expected. In addition to SDS-

PAGE, there are certain novel biomarkers that may prove in the future to identify

tubulointerstitial damage is present (e.g., retinol binding protein, kidney injury molecule-

1).

Inhibition of RAAS to Manage Proteinuria

Hemodynamic forces influence the transglomerular movement of proteins and it

follows that altering renal hemodynamics would be effective in reducing proteinuria

(Brown et al, 2013). The renin-angiotensin-aldosterone system (RAAS) has been the major

target system for this approach to reducing proteinuria (Figure 1). Agents that target RAAS

include the angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers

9
(ARB), and aldosterone receptor antagonists (Table 3). Although renin inhibitors are being

used in people, they have not been used to any great extent in dogs and cats. All RAAS

inhibitors have antihypertensive effects although most of them only minimally reduce

blood pressure (i.e., 10-15%). These drugs likely reduce proteinuria by several

mechanisms in addition to the expected decrease in glomerular capillary hypertension.

Likewise, the reduction in proteinuria is greater than would be expected on the basis of

their antihypertensive effects alone. RAAS inhibition is considered a standard of care in

dogs and cats with renal proteinuria where the UPC is >0.5-1 and >0.2-0.4 respectively. The

inhibitors of RAAS reduce proteinuria in populations of animals but the effect in individual

animals might vary. It may take trial and error with different drugs or combinations of

drugs before the target antiproteinuric effect is achieved (see Monitoring Drug Therapy

below); some animals may never achieve target reductions.

Angiotensin Converting Enzyme Inhibitors

ACEi administration has been associated positive outcomes in dogs, cats and people

with chronic kidney disease (Grauer et al, 2015; Tenhundfeld et al, 2009; King et al, 2006;

Mizutani et al, 2006). Enalapril significantly reduced proteinuria and delayed the onset or

the progression of azotemia in dogs with glomerulonephritis (Grauer et al, 2015). In dogs

with partial nephrectomies, enalapril treated dogs had a reduction in glomerular and

tubulointerstitial lesions following 6 months of treatment (Brown et al, 2003). Likewise,

dogs with chronic kidney disease that were given benazepril had higher glomerular

filtration rates and lower UPCs when compared to a placebo-treated group (Tenhundfeld et

al, 2009).

In cats, benazepril administration was associated with reduced glomerular capillary

10
pressure in cats with induced chronic kidney disease (Brown et al, 2001). In cats with

naturally occurring chronic kidney disease, benazepril was associated with a reduction in

proteinuria, even in the subgroup of cats with initial UPC of <0.2; cats with initial UPC >1

demonstrated better appetites when given benazepril vs placebo. Although these drugs

reduce proteinuria in cats, studies have not yet demonstrated a positive event on survival

or progression of chronic kidney disease.

Proposed mechanisms for these effects include decreased efferent glomerular

arteriolar resistance leading to decreased or normalized glomerular transcapillary

hydraulic pressure, reduced loss of glomerular heparan sulfate, decreased size of the

glomerular capillary endothelial pores, improved lipoprotein metabolism, slowed

glomerular mesangial growth and proliferation, and inhibition of bradykinin degradation.

Initially an ACEi is given once daily, but more than half of the dogs will need twice

daily administration eventually and perhaps additional dosage escalations (Figure 2)

(Grauer et al, 2000). Many veterinarians are concerned about administering an ACEi to a

dog or cat that is already azotemic. In people, the renoprotective effects of ACEi are

independent of the baseline renal function and ACEi slowed progressive disease even in

patients with severe renal failure (Ryan and Tuttle, 2008). In reality, it seems to be

uncommon for dogs and cats to have severe worsening of azotemia (i.e., >30% increase

from baseline) due to ACEi administration alone provided animals are clinically stable

prior to the introduction of these agents. Dogs that are dehydrated may be at highest risk

for worsening of azotemia after initiating ACEi therapy; euvolemia should be achieved

before initiating an ACEi to these patients. Furthermore, some caution is warranted when

administering an ACEi to a dog or cat in late stage 3 or stage 4 CKD (e.g., low initial starting

11
dose with small incremental increases).

Many veterinarians wonder if one drug is better than another in animals with

reduced renal function. The pharmacokinetics of ACEi are complicated and the effects of

disease on the pharmacodynamics of these drugs in not necessarily predictable. There is no

scientific basis to support that one ACEi has superior pharmacodynamic action. Benazepril

and its active metabolite, benazeprilat, are largely eliminated by the biliary route with a

smaller fraction being excreted in the urine; impaired renal function does not affect the

clearance of this drug in dogs (Lefebvre et al, 1999). On the other hand, enalapril and its

active metabolite, enalaprilat, are primarily eliminated by the kidney. Animals in IRIS late

stage 3 or stage 4 CKD may require a lower dosage of enalapril to achieve target

antiproteinuric effects.

Angiotensin Receptor Blockers

ARBs block the angiotensin II type 1 receptor. Several ARBs have been studied

extensively in people with glomerular disease and lead to a reduction in proteinuria similar

to that which is seen with ACEi. People treated with losartan had an average reduction in

proteinuria of 35% from baseline during a 3.4 year follow up period; much of this

reduction was in the first 6 months of therapy (Bakris et al, 2008). In irbesartan treated

patients, every 50% reduction in proteinuria during the first 12 months of therapy reduced

the risk of a negative renal outcome by more than half (Bakris et al, 2008).

The use of ARBs in dogs and cats with proteinuric chronic kidney disease is still

being developed. The one that seems to be the most effective is telmisartan; however,

losartan has been used more extensively (Sent et al, 2015; Bugbee et al, 2014). Even though

dogs do not appear to produce one of the major active metabolites of losartan, there is good

12
evidence that losartan exerts pharmacodynamic effects in dogs (Christ et al, 1992).

Contrary to this, pharmacodynamic studies suggest that losartan may not be effective in

cats, at least in attenuation of pressor responses (Jenkins et al, 2015).

Telmisartan is more lipophilic, and has a longer half-life than losartan; its blocking

effects persist for longer than would be predicted from its plasma half-life. Furthermore, it

has a higher affinity for, and dissociates more slowly from, the angiotensin-1 receptor.

Therefore, it is not surprising that telmisartan was shown to be more effective in reducing

proteinuria in people with diabetic nephropathy (Bakris et al, 2008) Telmisartan was as

effective as amlodipine in controlling blood pressure in people with chronic kidney disease

(Nakamura et al, 2007). Similarly telmisartan attenuated angiotensin I-induced blood

pressure response to a greater degree than did benazepril in normal cats (Jenkins et al,

2015). If this is true in dogs and cats, telmisartan might be the initial RAAS inhibitor of

choice when proteinuria and systemic hypertension are both present. A randomized

controlled clinical trial comparing the effects of telmisartan and benazepril on proteinuria

in cats with naturally occurring CKD demonstrated overall, telmisartan was as effective as

benazepril in preventing an increase in UPC occurring over a 6-month treatment period.

Indeed, telmisartan reduced UPC relative to the pre-treatment value at all time points

evaluated in the 6-month trial whereas benazepril only reduced UPC at very early time

points (Sent et al, 2015).

Combined Therapy with ACEi and ARB

There may be an added benefit to combined administration of an ACEi and an ARB

because of the inability of either class of drug to provide complete RAAS blockade when

given alone (Bakris et al, 2008). Although not evaluated in dogs and cats, studies in people

13
have suggested that these drugs may be additive or perhaps even synergistic in reducing

proteinuria (Linas 2008). The dosage of each individual drug might be reduced during

combined therapy, thereby reducing the likelihood of adverse effects. However, the

approach of combining these two agents must be used cautiously in light of a human study

where elderly patients prescribed this combination had a higher risk of kidney failure and

death (McAlister et al 2011). Controlled studies are needed in dogs to determine if the

antiprotienuric effects of ACEi and ARBs are optimized by combination therapy or

monotherapy with individualized dosage escalation.

Aldosterone Breakthrough

Complete blockade of the RAAS system is generally not achieved with RAAS

inhibitors. In the absence of angiotensin converting enzyme, angiotensin II is produced by

other kinases and is therefore, not completely suppressed by an ACEi alone. Blockade of the

angiotensin II type 1 receptor with an ARB, may give rise to a compensatory increase in

renin activity, and therefore and incomplete block of the RAAS (Laverman et al, 2002).

Combination therapy increases the degree of blockade, but it is still may not be more than

75-80% complete.

Serum aldosterone increases over time in some people treated even with maximal

dosages of RAAS inhibitors, a phenomenon referred to as aldosterone breakthrough. The

incidence of aldosterone breakthrough in people treated with RAAS inhibitors for chronic

kidney disease, systemic hypertension or heart failure is between 10 and 53% (Bomback

and Klemmer 2007). Prolonged hyperaldosteronism can have adverse effects on the heart,

systemic blood vessels and glomeruli. Therefore, it is not surprising that some people that

experience aldosterone breakthrough during treatment for various glomerular diseases

14
have more negative outcomes (e.g., higher magnitude proteinuria, greater reduction in

glomerular filtration rate) (Horita et al, 2006; Schjoedt et al, 2004). Preliminary studies

have demonstrated that aldosterone breakthrough may occur in up to one-third of dogs

with proteinuric renal diseases that are receiving RAAS inhibitors (Ames, unpublished

data). More study is needed to determine if aldosterone breakthrough is associated with

poorer treatment outcomes in dogs.

Aldosterone Receptor Antagonists

Aldosterone-receptor antagonists have been shown to reduce proteinuria and

stabilize kidney function in an additive fashion to ACEi and/or ARB in people, particularly if

they have evidence of aldosterone breakthrough before adding the aldosterone-receptor

antagonist (Bianchi et al, 2006). Eplerenone may be the drug of choice in people because

the relative lack of binding to androgen and progesterone receptors produces fewer

endocrine side effects. However, endocrine side effects of spironolactone in dogs are less

problematic and the preference is unclear in veterinary medicine. Although spironolactone

has been used most commonly in veterinary medicine, there is little evidence supporting

the efficacy of this drug in dogs in the management of glomerular disease. Sprionoloactone

should only be effective if serum or urine aldosterone concentrations are increased,

indicative of aldosterone breakthrough. This drug could be tried in dogs that have high

serum or urine aldosterone concentrations and persistent proteinuria in spite of treatment

with an ACEi and/or ARB. The drug should not be used in cats until more is known about

its efficacy and safety in this species.

Monitoring Drug Therapy

The UPC, urinalysis, systemic blood pressure and serum albumin, creatinine and

15
potassium concentrations (in fasting samples) should be monitored at least quarterly in all

animals being treated for proteinuric renal disease. However, those that are having new

drugs introduced or dosage modifications being made for drugs already being

administered should be monitored more frequently (Figure 2). One to 2 weeks after an

ACEi or ARB is added or changed, the UPC, serum creatinine, serum potassium and

systemic blood pressure should be evaluated to verify that the recent change in therapy has

not resulted in a severe worsening of renal function (i.e., >30% increase in serum

creatinine), a concerning increase in serum potassium concentrations, or hypotension (an

unlikely occurrence with these drugs).

Day-to-day variations in the UPC occur in most dogs with glomerular proteinuria,

with greater variation occurring in dogs with UPC >4 (Nabity et al, 2007); variations also

occur in cats but these have not been as well characterized. Changes in urine protein

content are most accurately measured by assessing trends in the UPC over time. Because

there is greater day-to-day variation in dogs with UPC >4, consideration should be given to

either averaging 2-3 serial UPC or measuring a UPC in urine that has been pooled from 2-3

collections (LeVine et al, 2010). In one study, demonstration of a significant difference

between serial values in proteinuric dogs required a change by at least 35% at high UPC

values (near 12) and 80% at low UPC values (near 0.5) (Nabity et al, 2007). Thus a

reduction in UPC near these reported magnitudes without an increase in the serum

creatinine concentration is required to indicate improvement or response to therapy.

Making Therapeutic Adjustments for RAAS Inhibitors

An ACEi is the initial therapy in most dogs and cats with proteinuria, with the typical

starting dosage of 0.5 mg/kg q24h (Figure 2). However, the ARB telmisartan may soon

16
become a reasonable alternative for an initial agent. In dogs and cats, the ideal therapeutic

target is a reduction in the UPC to <1 without inappropriate worsening of renal function.

Because this ideal target is not achieved in most animals, a reduction in UPC of 50% or

greater is often the target. The degree to which worsening of renal function is tolerated will

in part depend upon the stage of CKD the dog is in. Dogs with stage 1 and 2 CKD can have

an increase in serum creatinine of up to 30% without modifying therapy. The goal in dogs

with stage 3 CKD would be to maintain stable renal function, allowing only for a 10%

increase in serum creatinine. If renal function deteriorates beyond these allowances,

therapeutic adjustments may be indicated. Dogs with stage 4 CKD are generally intolerant

of worsening of renal function and any deterioration may have clinical consequences.

Whereas RAAS inhibitors can be used in this subset of patients, the initial starting doses

and incremental dose increases should be very low and renal function should be monitored

closely; therapeutic adjustments may be needed to maintain baseline renal function.

If the target reduction in UPC is not achieved, the plasma potassium concentration is

<6 and any changes in renal function fall within the tolerable limit, dosages may be

increased every 4-6 weeks. If the target reduction in UPC is not achieved with a maximal

dosage an ACEi, the next step should be to add an ARB. Alternatively an ARB can be used as

monotherapy in dogs who appear to be intolerant of an ACEi.

Managing Hyperkalemia

Hyperkalemia appears to be a common side effect of RAAS inhibition in dogs with

kidney disease but is probably uncommon in cats. Pseudohyperkalemia, often associated

with thrombocytosis, can also occur in dogs and needs to be ruled-out by measuring the

potassium concentration in lithium heparin plasma before taking further action. Because of

17
the cardiotoxic effects of potassium, dogs or cats with true hyperkalemia of > 5.5 mEq/L

should be monitored closely; therapy should be modified if serum potassium

concentrations are >6 to 6.5 mEq/L. When plasma potassium concentrations are >6mEq/L,

an ECG should be evaluated for cardiac conduction disturbances. True hyperkalemia can be

managed by reducing the ACEi or ARB drug dosage, discontinuing spironolactone

administration, or by feeding diets that are reduced in potassium (note that renal diets may

be supplemented with potassium). The use of an intestinal potassium binder (e.g.,

kayexelate) has been limited in dogs. Rarely hyperkalemia would be severe enough to

warrant hemodialysis. Potassium-reduced home-prepared diets that were formulated by a

veterinary nutritionist have been shown to effectively correct hyperkalemia long-term in

dogs with chronic kidney disease (Segev et al, 2010).

Management of Hypertension

The kidney is one of the target organs for hypertensive damage and sustained

hypertension may lead to an increased magnitude of proteinuria, rate of decline of renal

function, frequency of uremic crises and mortality (Jepson et al, 2009, Finco et al, 2004;

Brown et al, 2007). The goal of antihypertensive therapy is to reduce the blood pressure so

that the risk of continued target organ damage is minimized (Table 4). Inhibitors of RAAS

are generally only weak antihypertensive agents, leading to a reduction in blood pressure

by only about 10-15%. Dogs and cats that have sustained systolic blood pressures ≥160

mmHg while being administered a RAAS inhibitor have a moderate to high risk of future

target organ damage and may need additional therapeutic consideration. In these animals,

the first step is to increase the dose of the RAAS inhibitor. If the upper end of the dosage

18
range is being administered and the risk of target organ damage remains moderate to high,

the next step is to add a calcium channel blocker. Amlodipine is usually used with a starting

dose of 0.2-0.4 mg/kg q24 hours but can be incrementally increased to a total daily dose of

0.75 mg/kg, which can be divided to q12h. There is evidence that amlodipine will activate

the RAAS system; therefore it should not be used as monotherapy for the management of

hypertension in dogs (Atkins et al, 2007). However in cats monotherapy may be more

appropriate because giving multiple drugs is harder, amlodipine alone may bring the UPC

down to <0.2 in hypertensive cats and amlodipine-induced increases in plasma renin

activity are not associated with an increase in aldosterone in cats (Jepson et al, 2014).

Systolic blood pressure should be monitored during therapy and maintained >120

mmHg in treated dogs and cats. High salt intake should be avoided although salt restriction

alone will not adequately reduce blood pressure.

Diet

In animal models of chronic kidney disease, the magnitude of proteinuria can be

reduced by dietary modification – specifically by modifying the polyunsaturated fatty acid

ratio and protein content (Brown et al, 2013). Dietary supplementation with n-3

polyunsaturated fatty acids or feeding a diet that has a reduced n-6/n-3 ratio that is close

to 5:1, as found in most commercially available renal diets is expected to alter the long term

course of renal injury and reduce the magnitude of proteinuria. It is generally accepted that

feeding a renal diet that is modified in protein content reduces intraglomerular pressure as

well as the magnitude of proteinuria and the generation of uremic toxins. However, the

magnitude of this reduction in proteinuria is small. Renal diet alone should not be expected

19
to adequately reduce proteinuria in most animals.

Renal Biopsy

Nearly 60% of dogs with glomerular proteinuria will have either immune-complex

mediated glomerulonephritis or amyloidosis (Schneider et al, 2013), both of which may

represent an aberrant or excessive immune or inflammatory response to an infectious,

neoplastic or inflammatory condition. Cats rarely get glomerulonephritis but a percentage

of these cats would also be expected to have developed this secondary to a systemic

disease. Therefore, in dogs or cats with glomerular proteinuria it is indicated to pursue

extended diagnostic testing, the extent of which might vary depending upon patient

characteristics and potential exposure to regional infectious agents (Littman et al, 2013). It

is possible that complete or partial resolution of proteinuria will follow successful

treatment of any causative systemic diseases.

Renal biopsy should be considered in animals with persistent glomerular range

proteinuria that do not have any contraindications to renal biopsy and have not responded

to standard therapy (Littman et al, 2013). Some of the more common contraindications to

biopsy include chronic kidney disease with serum creatinine >5 mg/dL, uncontrolled

hypertension, pyelonephritis, renal cystic disease, coagulopathy, hydronephrosis, and

severe anemia. When biopsy samples are processed correctly, clinical decisions regarding

the diagnosis, treatment, and prognosis can be made from the information obtained

through renal biopsy in dogs. Experienced personnel should be involved with procuring,

preparing and interpreting the renal biopsy that has been processed for light, electron, and

immunofluorescence microscopy.

20
 From a therapeutic standpoint, the primary purpose of the renal biopsy is to

determine if immunosuppressive therapy is indicated or not. Finding electron-dense

deposits in subendothelial, subepithelial, intramembranous, or mesangial locations of the

glomerulus by EM or demonstrating positive and unequivocal immunofluorescent staining

for immunoglobulins and/or complement in an immune-complex and antiglomerular

basement membrane pattern of deposition in peripheral capillary loops or the mesangial

compartment with IFM provides compelling evidence to initiate a trial of

immunosuppressive therapy (Segev et al, 2013). Probable evidence of an

immunopathogenesis can be documented by LM with one of the following: red granular

staining of capillary walls with Masson’s trichrome, spikes along the GBM or holes within

the GBM with Jones Methenamine sliver stain. These findings would be expected in just

under 50% of dogs with glomerular disease (Schneider et al, 2013). When renal biopsy

results are not available it becomes more difficult to make a decision about using

immunosuppressive treatment because approximately 50% of dogs with glomerular

disease would be expected not to have an immunopathogenesis of their disease. Consensus

recommendations are to consider immunosuppressive drugs in the treatment of dogs with

glomerular disease when the source of proteinuria is clearly glomerular in origin, the drugs

are not otherwise contraindicated, the dog breed and age of disease onset are not

suggestive of a familial nephropathy, amyloidosis has been deemed unlikely and the serum

creatinine is >3.0 mg/dl or progressively increasing, or the serum albumin is <2.0 g/dl

(Pressler et al, 2013).

Immunosuppressive Agents

21
 Empirical administration of immunosuppressive or anti-inflammatory therapy has

been recommended for dogs that have no known contraindications for the specific drugs

being considered and have severe, persistent, or progressive glomerular disease in which

there is renal biopsy-supported evidence of immune-mediated pathogenesis (Segev et al,

2013). Dogs with more severe disease or rate of progression should be treated more

aggressively than those with more stable disease. Single agent or combination therapy for

rapid onset of immunosuppression should be considered in dogs with high magnitude

proteinuria with hypoalbuminemia, NS, or rapidly progressive azotemia (Segev et al, 2013).

Mycophenolate, or cyclophosphamide, with or without short-term administration of

glucocorticoids, has been suggested as the first choice. Glucocorticoids should be limited to

short-term therapy because of the potential association with corticosteroid excess and

proteinuria. Dogs with stable or more slowly progressive disease that have only partial or

no response to standard therapy might be given drugs that have a either a rapid or a more

delayed onset of drugs, such as mycophenolate, chlorambucil or cyclophosphamide.

Cyclosporine has also been suggested as a first choice for stable or slowly progressive dogs.

It is important to note that this is the only drug that has been studied prospectively in dogs

with glomerular disease and was found to be of no benefit, although there were flaws in the

design of that study (Vaden et al, 2995).

All dogs treated with immunosuppressive therapy for their glomerular disease

should be monitored closely. Treatment should be discontinued or adjusted if adverse drug

effects develop. In the absence of adverse effects, 8-12 weeks of therapy should be

provided before changing the course of treatment. If the therapeutic response is

suboptimal at the end of 8-12 weeks, an alternate drug protocol should be considered.

22
However, if after 3-4 months a therapeutic response has not been achieved, consideration

should be given to discontinuing immunosuppressive drug administration. If after this

time, a response has been noted, the drug dose or schedule should be tapered to one that

maintains the response without worsening of proteinuria, azotemia or clinical signs (Segev

et al, 2013).

References

1. Jacob F, Polson DJ, Osborne CA, et al. (2005). Evaluation of the association between

initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic

renal failure. J Amer Vet Med Assoc 226, 393-400.

2. Wehner A, Hartmann K, and Hirschberger J. (2008). Associations between proteinuria,

systemic hypertension and glomerular filtration rate in dogs with renal and non-renal

diseases. Vet Rec 162: 141-147.

3. Jepson RE. Brodbelt D, Vallance C, et al. (2009). Evaluation of predictors of the

development of azotemia in cats. J Vet Intern Med 23:806-813.

4. Syme HM, Markwell Pj, Pfeiffer DU, et al. (2006). Survival of cats with naturally

occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med

20:528-535.

5. King JN, Tasker S, Gunn-Moore DA, et al. (2007). Prognostic factors in cats with chronic

kidney disease. J Vet Intern Med 21:906-916.

6. Toblli JE, Bevione P, DiGennaro F, et al. (2012). Understanding the mechanisms of

proteinuria: therapeutic implications. Int J Nephrol. 1-13. doi:10.1155/2012/546039

23
7. Pollock CA, Poronnik P. (2007). Albumin transport and processing by the proximal

tubule: physiology and pathophysiology. Curr Opin Nephrol Hypertens 16:359-364.

8. Singh A, Satchell SC, Neal CR, et al. Glomerular endothelial glycocalyx constitutes a

barrier to protein permeability. J Am Soc Nephrol 18:2885-2893.

9. Maack T. (2011). Renal handling of proteins and polypeptides. Compr Physiol. 2039-

2082. http://dx.doi.org/10.1002/cphy.cp080244

10. Lees GE, Brown SA, Elliot J, et al. (2005). Assessment and management of proteinuria in

dogs and cats: 2004 ACVIM forum consensus statement (small animal). J Vet Intern Med

19:377-385.

11. Nabity MB. (2010). Urinary biomarkers of chronic kidney disease in veterinary

medicine: where do we stand? Paper presented at the American College of Veterinary

Pathologists/American Society of Veterinary Clinical Pathology Concurrent Annual

Meetings, Baltimore, 30 October – 3 November.

12. Brown S, Elliot J, Francey T, et al. (2013). Consensus recommendations for standard

therapy of glomerular disease in dogs. J Vet Intern Med, 27:S27-S43.

13. Grauer GF, Greco DS, Getzy DM, et al. (2000). Effects of enalapril vs placebo as a

treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 14:526-533.

14. Tenhundfeld J, Wefstaedt P, Nolte JA. (2009). A randomized controlled clinical trial of

the use of benazepril and heparin for the treatment of chronic kidney disease in dogs. J

Am Vet Med Assoc 234:1031-1037.

15. King JN, Gunn-Moore DA, Tasker S, et al. (2006). Tolerability and efficacy of benazepril

in cats with chronic kidney disease. J Vet Intern Med 20:1054-1064.

16. Mizutani H, Koyama H, Watanabe T, et al. (2006). Evaluation of the clinical efficacy of

24
 benazepril in the treatment of chronic insufficiency in cats. J Vet Intern Med 20:1074-

1079.

17. Brown Sa, Finco DR. Brown CA, et al. (2003). Evaluation of the effects of inhibition of

angiotensin converting enzyme with enalapril in dogs with induced chronic renal

insufficiency. Am J Vet Res 64:321-327.

18. Brown SA, Brown CA, Jacobs G, et al. (2001). Effects of the angiotensin converting

enzyme inhibitor benazepril in cats with induced renal insufficiency. Am J Vet Res

62:375-383.

19. Ryan MJ, Tuttle KR. (2008). Elevations in serum creatinine with RAAS blockade: why

isn’t it a sign of kidney injury? Curr Opin Nephrol Hyperten 17:443-449

20. Lefebvre HP, Laroute V, Concordet D, Toutain PL. (1999). Effects of renal impairment on

the disposition of orally administered enalapril, benazepril, and their active

metabolites. J Vet Intern Med, 13: 21-27.

21. Bakris G, Burgess E, Weir M, et al. (2008). Telmisartan is more effective than losartan in

reducing proteinuria in patients with diabetic nephropathy. Kidney Int 74:364-369.

22. Sent U, Gossl R, Elliot J, et al. (2015). Comparison of efficacy of long-term oral treatment

with telmisartan and benazepril in cats with chronic kidney disease. J Vet Intern Med

29:1479-1487.

23. Bugbee AC, Coleman AE, Wang A, et al. (2014). Telmisartan treatment of refractory

proteinuria in a dog. J Vet Intern Med 28:1871-1874.

24. Christ DD, Wong PC, Wong YN, et al. (1992). The pharmacokinetics and

pharmacodynamics of the angiotensin II receptor antagonist losartan potassium (DuP

753/MK 954) in the dog. J Pharm Exp Therapeutics 268:1199-1205.

25
25. Jenkins TL, Coleman AE, Schmiedt CW, Brown SA. (2015). Attenuation of the pressor

response to exogenous angiotensin by angiotensin receptor blockers and benazepril

hydrochloride in clinically normal cats. Am J Vet Res 76:807-813.

26. Nakamura T, Inoue T, Suzuki T et al. (2007). Comparison of renal and vascular

protective effects between telmisartan and amlodipine in hypertensive patients with

chronic kidney disease and mild renal insufficiency. Hypertens Res 31:841-850.

27. Linas SL. (2008). Are two better than one? Angiotensin-converting enzyme inhibitors

plus angiotensin receptor blockers for reducing blood pressure and proteinuria in

kidney disease. Clin J Am Soc Nephrol 3:S17-S23.

28. McAlister FA, Zhang J, Tonelli M, et al. (2011). The safety of combining angiotensin-

converting enzyme inhibitors with angiotensin-receptor blockers in elderly patients: a

population-based longitudinal analysis. Canadian Medical Assoc Journal 183:E309-

E311.

29. Laverman GD, Navis GJ, Henning RH, et al. (2002). Dual blockade of renin-angiotensin

system blockade at optimal doses for proteinuria. Kidney Int 62: 1020-1025.

30. Bomback AS, Klemmer PJ. (2007). The incidence and implications of aldosterone

breakthrough. Nat Clin Pract Nephrol 3: 486-492.

31. Horita Y, Taura K, Taguchi T, et al. (2006). Aldosterone breakthrough during therapy

with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in

proteinuria patients with immunglobulin A nephropathy. Nephrology 11:462-466.

32. Schjoedt KJ, Andersen S, Rossing P, et al. (2004). Aldosterone escape during blockade of

the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with

enhanced decline in glomerular filtration rate. Diabetologia 47:1936-1939.

26
33. Bianchi S, Bigazzi R, Campese VM. (2006). Long-term effects of spironolactone on

proteinuria and kidney function in patients with chronic kidney disease. Kidney Int

70:2116-2123.

34. Nabity MB, Boggess MM, Kashtan CE, et al. (2007). Day-to-day variation in the urine

protein:creatinine ratio in female dogs with stable glomerular proteinuria caused by X-

linked hereditary nephropathy. J Vet Intern Med 21:425-430.

35. LeVine DN, Zhang D, Harris T, et al. (2010). The use of pooled versus serial urine

samples to measure urine protein:creatinine ratios. Vet Clin Path 39:53-56, 2010.

36. Segev G, Fascetti AJ, Weeth LP, Cowgill LD. (2010). Correction of hyperkalemia in dogs

with chronic kidney disease consuming commercial renal therapeutic diets by a

potassium-reduced home-prepared diet. J Vet Intern Med 24:546-550.

37. Finco D. (2004). Association of systemic hypertension with renal injury in dogs with

induced renal failure. J Vet Inter Med 18:289-294.

38. Brown S, Atkins C, Bagley R, et al. (2007). Guidelines for the identification, evaluation,

and management of systemic hypertension in dogs and cats. J Vet Intern Med 21:542-

558.

39. Atkins CE, Rausch WP, Gardner SY, et al. (2007). The effect of amlodipine and the

combination of amlodipine and enalapril on the renin-angiotensin-aldosterone system

in the dog. J Vet Pharmacol Therap 30:394-400.

40. Jepson RE, Syme JM, Elliot J. (2014) Plasma renin activity and aldosterone

concentrations in hypertensive cats with and without azotemia and in response to

treatment with amlodipine besylate. J Vet Intern Med 28:144-155.

41. Schneider SM, Cianciolo RE, Nabity MB, et al. (2013) Prevalence of immune-complex

27
 glomerulonephridities in dogs biopsied for suspected glomerular disease: 501 cases

(2007-2012). J Vet Intern Med 27:S67-S75.

42. Littman MP, Daminet S, Grauer GF, et al. (2013). Consensus recommendations for the

diagnostic investigation of dogs with suspected glomerular disease. J Vet Intern Med

27:S19-S26.

43. Segev G, Cowgill LD, Heiene R, et al. (2013). Consensus recommendations for

immunosuppressive treatment of dogs with glomerular disease based on established

pathology. J Vet Intern Med 27:S44-S54.

44. Pressler B, Vaden S, Gerber B, et al. (2013). Consensus recommendations for

immunosuppressive treatment of dogs with glomerular disease absent a pathologic

diagnosis. J Vet Intern Med 27:S55-S59.

45. Vaden SL, Breitschwerdt E, Armstrong PJ, et al: (1995). The effects of cyclosporine

versus standard care in dogs with naturally occurring glomerulonephritis. J Vet Intern

Med 9:259-266.

28
Table 1: International Renal Interest Society classification of proteinuria in dogs and cats
with chronic kidney disease.
Substage Cat* Dog
Nonproteinuric (NP) <0.2 <0.2
Borderline Proteinuric (BP) 0.2-0.4 0.2-0.5
Proteinuric (P) >0.4 >0.5
*Applies to normal female and neutered male cats; normal intact male cats may have a UPC
as high as 0.6.

29
Table 2. Categorization of Potential Causes of Proteinuria in Dogs and Cats
Category Mechanism Potential Causes
Pre-renal Greater than normal delivery  Hemoglobinuria from intravascular
of low molecular weight hemolysis
plasma proteins to the  Myoglobinuria from rhabdomyolysis
normal glomerulus  Immunoglobulin light chains from
multiple myeloma or lymphoma
Renal Abnormal renal handling of
normal plasma proteins
caused by one of the
following subcategories:
Functional Altered renal physiology in  Strenuous exercise
(Physiological) response to transient  Fever
stressor  Seizure
 Exposure to extreme heat or cold

Glomerular Altered permselectivity of  Any cause of glomerular injury or

the glomerular basement dysfunction (e.g.,
membrane membranoproliferative
glomerulonephritis,
glomerulosclerosis, amyloidosis)

Tubular* Impaired tubular recovery of  Any cause of renal tubular

plasma proteins that are dysfunction (e.g., acute tubular
normally found in the necrosis, Fanconi syndrome)
glomerular filtrate

Interstitial* Exudation of proteins from  Interstitial nephritis

the interstitial space into the
urinary space
Post-renal Entry of protein into the  Urinary tract infection
urine in association with  Urolithiasis
exudation of blood or serum  Transitional cell carcinoma
into the lower urinary or  Vaginitis
genital tracts
* Tubular and interstitial can be difficult to separate in a clinical setting and are often
referred to as tubulointerstitial.

30
Table 3: Inhibitors of RAAS used in dogs and cats with chronic kidney disease
Class Drug Initial Dose Escalating Dose Strategy
Angiotensin Benazapril 0.25-0.5 mg/kg Increase by 0.25-0.5 mg/kg to a
converting PO q24 hr* maximum daily dose of 2
enzyme Dog or cat mg/kg; can be given q12h
inhibitors
Enalapril 0.25-0.5 mg/kg Increase by 0.25-0.5 mg/kg to a
PO q24 hr* maximum daily dose of 2
Dog or cat mg/kg; can be given q12h

Lisinopril 0.25-0.5 mg/kg Increase by 0.25-0.5 mg/kg to a

PO q24 hr* maximum daily dose of 2
Dog or cat mg/kg; can be given q12h

Ramipril 0.125 mg/kg Increase by 0.125 mg/kg q24h

PO q24h to a maximum of 0.5 mg/kg
Dog q24h; usually given q24h

Imidapril 0.25 mg/kg Increase by 0.25 mg/kg q24h to

PO q24h a maximum of 2 mg/kg q24h;
Dog usually given q24h

Angiotensin Telmisartan** 0.5-1.0 mg/kg Increase by 0.25-0.5 mg/kg to a

receptor PO q24h maximum daily dose of 5
blockers Dog mg/kg; usually given q24h
Dog or cat

Losartan*** 0.25-0.5 mg/kg Increase by 0.25-0.5 mg/kg to a

PO q24 hr maximum daily dose of 2
Dog mg/kg; can be given q12h

Aldosterone Spironolactone**** 0.5-2 mg/kg

receptor PO q12-24h
blocker Dog

*Smaller starting doses should be used in animals with in stage 3 or 4 CKD or if there are
concurrent medical problems that have the potential to lead to dehydration or reduced
appetite.
**Can be used a single agent or combined with an ACEi.
***Concurrent administration of an ACEi is generally recommended.
****Only recommended in dogs with glomerular disease that have increased serum or
urine aldosterone concentrations and have failed or not tolerated an ACEi or ARB.

31
Table 4: Staging of blood pressure in dogs and cats according to the risk for future target
organ damage.
Blood Pressure Stage Systolic Diastolic
(mmHg) (mmHg)
APO – Risk none to minimal <150 <95
AP1 – Low risk 150-159 95-99
AP2 – Moderate risk 160-179 110-119
AP# - High risk 180 120

32
Figure Legends

Figure 1. The renin-angiotensin-aldosterone system and its inhibitors.

33
Figure 2. Making adjustments to RAAS inhibition therapy in dogs with renal proteinuria.

34