By Erika de Papp, DVM, DACVIM
Proteinuria can be caused by a number of different disease processes, and the first step is to determine if the source of the protein is prerenal, renal, or postrenal. Prerenal proteinuria is caused by the presence of proteins in the blood (such as myoglobin, hemoglobin, or Bence Jones proteins) that are not normally present in the plasma, which are subsequently filtered through the kidneys. Evidence of dysproteinemia on lab work would point to a prerenal cause of proteinuria. Postrenal proteinuria is caused by inflammation or hemorrhage in the urinary tract beyond the level of the glomerulus. Some examples include lower urinary tract infection, pyelonephritis, uroliths, neoplasia, and sterile cystitis.1
Once prerenal and postrenal causes have been ruled out, we are left with renal proteinuria. This can be either functional or pathological. Functional proteinuria is a transient phenomenon typically associated with fever or strenuous exercise (humans). Once proteinuria is identified as present and of renal origin, the next step is to evaluate more than one urine sample to see if this is a persistent abnormality, which would indicate pathological proteinuria. Persistent proteinuria is defined as proteinuria that has been present on three or more occasions, two or more weeks apart.
The presence of proteinuria can be noted via a variety of testing methods. The first screening test that is typically used to identify protein is the urine dipstick. This is a semi-quantitative method, and a positive test result in the presence of a quiet sediment warrants a quantitative evaluation with a urine protein:creatinine (UPC) ratio. It is important to note however that the dipstick can result in both false positive and false negative results. Additionally, it is important to take the urine specific gravity into consideration. A protein measurement of 2+ on the dipstick is much more significant in a urine sample with a specific gravity of 1.010 than a specific gravity of 1.060. When performing the UPC, be sure to always run a urinalysis at the same time to be sure the sediment is inactive in the sample that is being evaluated. Lastly, many labs now offer microalbuminuria testing as part of a routine screening process. Persistently elevated levels (> 30mg/dL) should be followed up with a UPC ratio, as the UPC is the test most often used to monitor response to therapy when treating proteinuria.
In dogs, a UPC ≥ 2.0 is usually indicative of glomerular proteinuria. Dogs with tubular renal disease may also have proteinuria but this tends to be mild, with levels ranging from 0.5-2. Any persistent proteinuria with levels ≥ 0.5 should be monitored, with more investigation pursued in the face of progressive proteinuria. In dogs with known chronic kidney disease, a UPC is warranted even if the urine dipstick is negative for protein.
If possible, once proteinuria has been identified, the best way to continue to evaluate it is with pooled urine samples. We have owners collect urine daily for three days and then have them bring in 3 separate, clean (non-sterile) containers. Samples are stored in the refrigerator until submission. We then obtain an equal volume of urine from each container and submit this for a urinalysis and UPC.
In addition to the UA and UPC, evaluation of pathological proteinuria should include a CBC, serum chemistry, SDMA, urine culture to rule out occult infection, and infectious disease testing. In the Northeast it is reasonable to start with a screening tick panel such as a 4Dx or Accuplex but more extensive infectious disease testing may be warranted depending on the history and clinical signs and/or travel history of the patient in question. In Lyme positive dogs, a quantitative C6 level is recommended. Additionally, abdominal ultrasound and chest films may be warranted to rule out underlying disease such as neoplasia.
Renal biopsy is of course the gold standard to evaluate the cause of proteinuria and make a specific histopathologic diagnosis. For animals that are already azotemic we often don’t pursue renal biopsy, as there is some risk for further renal damage and the findings often won’t change the course of treatment. Animals that are non-azotemic but proteinuric are better candidates for biopsy. However, the procedure is not without risk and it is important to confirm that patients have normal coagulation times and are normotensive prior to considering biopsy. Renal biopsy should be considered in patients that are not responding to medical management of proteinuria.
Once pathological proteinuria has been identified, a multifaceted approach is necessary for treatment. This includes the use of angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARB), use of renal prescription diets, omega 3 fatty acid supplementation, consideration of anti-coagulants, and management of hypertension. (See Table 1 for drugs and doses.) The goal with therapy is to reduce the UPC to <1 or reduce it to 50% of baseline. This is based on the fact that a study in dogs with CKD with an initial UPC >1 had a three-fold greater risk of developing uremic crisis and death.2 An additional study in dogs showed that dogs with a UPC <1 lived 2.7 times longer than dogs with a UPC >1.3
Common ACE inhibitors used to treat proteinuria include enalapril and benazepril. These drugs are proposed to work via dilation of the efferent glomerular arteriole, resulting in decreased glomerular transcapillary pressure, among other effects. Enalapril showed a delayed onset and/or progression of azotemia and reduced proteinuria in dogs with GN.4 Dogs with CKD given benazepril had higher glomerular filtration rates and reduced proteinuria compared to placebo treated dogs.5 It is not known which drug is more beneficial for dogs with proteinuria but enalapril and its active metabolite are primarily eliminated via renal routes, whereas benazepril and its active metabolite are mainly eliminated via the biliary system, so this may be something to consider, especially in more azotemic patients.
ARB drugs have been used more recently in veterinary medicine and there is not yet a lot of data, but this class of drug has shown similar reduction in proteinuria in humans with glomerular disease compared to ACE inhibitors. One study in cats with CKD showed that telmisartan was as effective as benazepril in preventing progressive proteinuria during a six month treatment period, and telmisartan resulted in reduced UPC at all time points during the study, whereas benazepril only reduced UPC during early treatment.6 Telmisartan may also be more effective for controlling hypertension than either ACE inhibitors or other ARB drugs. More studies are needed to confirm initial observations but anecdotally we are seeing good responses to this drug.
For some patients, a combination of an ACE inhibitor and ARB may have synergistic effects, and allow dose reductions of individual drugs. There is little data currently available in dogs regarding using these classes of drugs together, and studies are needed.
Currently most clinicians are still reaching for an ACE inhibitor as the first line of therapy for proteinuria, but this recommendation may change in the future based on further experience with the ARB class of drugs.
All ACE inhibitors and ARB drugs can reduce glomerular filtration rate (GFR), so it is important to recheck renal values one week after starting a drug in either of these classes, or following a dose change. Generally a <30% increase in creatinine is acceptable for dogs with Stage 1 and 2 CKD, but with stage 3 we hope to see no more than a 10% increase, and with Stage 4 they are fragile enough that any increase in creatinine may warrant discontinuing the drug. Hyperkalemia is also a common side effect and should be monitored. This can sometimes be exacerbated by renal diets that are high in potassium.
Dose escalations can be made every 4 to 6 weeks in dogs that are not having adequate reduction in proteinuria but are maintaining stable azotemia (or non-azotemic); are not excessively hyperkalemic; and are tolerating the drugs clinically. Once a dose maximum is reached, consideration of adding a different class of drug or changing classes of drugs is reasonable (i.e. adding an ARB to an ACEi or changing from an ACEi to an ARB).
Aldosterone levels will increase in some patients treated with ACEi and ARB drugs, due to lack of complete blockade of the renin angiotensin aldosterone system and elevated renin levels, resulting in what is called aldosterone breakthrough.1 In these cases, addition of an aldosterone receptor blocker such as spironolactone may help further reduce proteinuria, if the patient’s aldosterone levels are high.
Because hypertension is common in dogs with proteinuria, blood pressure must be monitored frequently and hypertension treated to avoid further damage to the kidneys, as well as damage to other target organs. The ACE inhibitors and ARB drugs have some anti-hypertensive effect, but typically don’t lead to significant reduction in blood pressure. In cases with systolic pressure consistently above 160 mmHg, addition of a calcium channel blocker is recommended. The drug most commonly used is amlodipine. There is evidence that amlodipine can activate the renin angiotensin aldosterone system, so it is not recommended as single agent therapy for hypertension, and should be used in conjunction with an ACE inhibitor or ARB.7
A modified protein diet, as provided by renal prescription diets, will reduce proteinuria, reduce intraglomerular capillary pressure, and reduce the rate of generation of uremic toxins.8 Renal diets are recommended in all dogs with pathological proteinuria.
In addition to prescription diets, addition of omega 3 polyunsaturated fatty acids may provide additional benefit. Studies have shown that supplementation with fish oil (DHA and EPA specifically) lowered glomerular pressure, decreased eicosanoid series-2 excretion, and provided renoprotection.9
Thromboembolism (TE) is a significant and potentially life threatening complication of proteinuria. Loss of antithrombin III through the glomerulus often parallels a drop in serum albumin, which may mean dogs with more severe hypoalbuminemia are at greater risk of thromboembolism. However, the pathophysiology of development of TE is significantly more complicated than this simple explanation. There is no good evidence in dogs with proteinuria to support which anti-coagulant therapy might be best but currently the IRIS canine GN study group recommends low dose aspirin as a means of thromboprophylaxis.8 Hopefully with growing use of the oral Factor X inhibitors, we will gain more data to help us determine which approach may be best.
For severe and unstable cases, immunosuppression may be considered, even in the absence of renal histopathology. Immunosuppressive protocols are beyond the scope of this article and these cases are best treated at a 24 hour critical care referral center.
Proteinuria can be a challenging clinical problem in our canine patients but with early recognition and intervention, our patients are living longer, better quality lives than even 10 years ago, and continued research in this area will undoubtedly lead to continued progress.
||0.5mg/kg PO SID
||Increase by 0.5 mg/kg to max of 2 mg/kg per day.
Can give BID
||1 mg/kg PO SID
||Increase by 0.5 mg/kg up to max of 2 mg/kg SID
||1-5 mg/kg PO SID
||Aldosterone receptor blocker
||1-2 mg/kg PO BID
||Calcium channel blocker
||0.1 mg/kg PO SID
||Increase to max of 0.75 mg/kg PO SID
|Omega 3 FA (EPA and DHA)
||0.25-0.5 g/kg/day PO
- Vaden SL, Elliott J. Management of proteinuria in dogs and cats with chronic kidney disease. Vet Clin Small Anim 46 2016; 1115-1130.
- Jacob F, Polson DJ, Osborne CA, et al. Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure. J Am Vet Med Assoc 2005; 226:393-400.
- Wehner A, Hartmann K, Hirschberger J. Associations between proteinuria, systemic hypertension and glomerular filtration rate in dogs with renal and non-renal diseases. Vet Rec 2008; 162:141-7.
- Grauer GF, Greco DS, Getzy DM, et al. Effects of enalapril vs placebo as a treatment for canine idiopathic glomerulonephritis. J Vet Intern Med 2000; 14:526-33.
- Tenhundfeld J, Wefstaedt P, Nolte JA. 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 2009; 234: 1031-7.
- Sent U, Gossl R, Elliot J, et al. Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in cats with chronic kidney disease. J Vet Intern Med 2015; 29: 1479-87.
- Atkins CE, Rausch WP, Gardner SY, et al. The effect of amlodipine and the combination of amlodipine and enalapril on the renin-angiotensin-aldosterone system in the dog. J Vet Pharmacol Therap 2007; 30: 394-400.
- Brown S, Elliot J, Francey T, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med 2013; 27: S27-S43.
- Brown SA, Brown CA, Crowell WA, et al. Effects of dietary polyunsaturated fatty acid supplementation in early renal insufficiency in dogs. J Lab Clin Med 2000; 135: 275-286.