Management of Proteinuria
World Small Animal Veterinary Association World Congress Proceedings, 2014
Liesel van der Merwe, BVSc, MMedVet (Med)
South Africa

Proteinuria is a symptom and must be confirmed to be of renal origin. A variety of renal diseases cause proteinuria, and they may or may not require immunosuppression in addition to the standard therapy. Ensure that all secondary causes of proteinuria, such as infectious diseases, hyperadrenocorticism, disseminated malignancies and immune disorders have been considered and excluded or treated. Glomerular disease (UPC > 3) is estimated to account for 50% of chronic kidney disease in dogs. The presence of nephrotic syndrome and azotaemia indicates a poor outcome. The severity of glomerular disease is normally reflected by the magnitude of proteinuria measured by urine protein creatinine ratio (UPC). UPC should be measured serially, as it is normally quite variable (it can be pooled).

RAAS Modifiers

Altering renal haemodynamics is effective in reducing proteinuria, and the RAAS system is targeted in therapy.

Angiotensin Converting Enzyme Inhibitors (ACEi)

Decrease efferent arteriolar resistance, thus decreasing intraglomerular blood pressure. Additional effects are reduced heparin sulphate clearance, decreased glomerular pore size and slowed glomerular mesangial growth. Enalapril has been shown to significantly reduce proteinuria and delay progression of azotaemia. An ACEi should be the initial treatment in dogs with proteinuria and target of effective treatment should be a reduction of UPC by 50%. ACE typically given OID, but more than half of the patients eventually need BID administration and dose escalations. Dosages of benazepril and enalapril can be slowly increased in 0.5 mg/kg/d increments to a maximum of 2 mg/kg/day.

It is uncommon for dogs to develop significant worsening azotaemia due to decreased renal blood flow due to the reduced pressure (> 30% increase in creatinine), although caution is recommended using the drug in dogs with IRIS stage IV renal failure. Even though enalapril is excreted only though the kidneys, vs. benazepril which also has biliary excretion route, there is no fixed idea of what dose reduction can be applied in advanced chronic kidney disease (CKD).

Angiotensin Receptor Blockers (ARB)

Scant canine evidence is that these drugs are effective in reducing proteinuria. Telmisartan is more lipophilic, has a longer t ½ and a greater affinity for the receptor than losartan in humans with diabetic nephropathy. Experimental dose is 1 mg/kg PO Q24. Blockade of the RAAS may be more complete (but still maximises at only 75–80%) with combined therapy of ACEi and ARB, as ARB therapy may cause a compensatory increase in renin, and ACEi may incompletely block the formation of angiotensin II in the kidney. Limited use of combination therapy in dogs has shown that it appears safe and is associated with a reduction of proteinuria in most animals, and a mild increase in creatinine and potassium in only some animals.

Aldosterone Receptor Blocker Therapy

Aldosterone "escapes" the inhibition of ACEi over time despite increased dosages as well as ARBs. Aldosterone increases absorption of Na+ and excretion of K+. Monitoring of treatments affecting the RAAS should comprise of UPC, urinalysis, blood pressure, electrolytes, serum albumin and creatinine at least 3–4x/year and should be performed 1–2 weeks after any dosage adjustment or additional medication added.

Hyperkalaemia is a relatively common side effect of RAAS inhibition in dogs and may be worse with combined therapy. It can be managed by decreasing the drug dosage, discontinuing spironolactone and feeding diets with reduced potassium or dosing an intestinal potassium binder.

If the target of reduction of UPC by 50% is not reached and there are minimal elevations in creatinine or potassium, then increase dosage incrementally every 4–6 weeks starting with ACEi at 0.5 mg/kg bid to a max of 2 mg/kg/day. If still ineffective - then add ARBs.

Dietary Modification

Nutrition is central in managing renal disease in veterinary patients.


Altered long-term course of renal injury and magnitude of proteinuria. Fish oils (DHE and EPA, n6:n3 = 5:1) lower glomerular pressure and are renoprotective as they decrease renal eicosanoid production. Dietary supplementation at ratios 5:1 delayed progression to CKD. Supplementation of higher levels of n3 may be beneficial, as has been shown in canine osteoarthritis. Consider a dosage of 0.25–0.5 g/kg/day. Antioxidants also need to be added: 1.1 U vit E/g of supplemented fish oil.


Reduction of dietary protein reduces intraglomerular pressure, the magnitude of the proteinuria and the rate of generation of uraemic toxins. The use of lower protein diets has also been proven beneficial in chronic kidney disease.


Normal dogs are not as salt sensitive as people, although those with kidney disease may be more so due to dysregulation of the RAAS. Salt restriction enhances the antihypertensive and renal haemodynamic effects of some of the RAAS interfering drugs.

Anti-Thrombotic Therapy

Venous thromboembolism is a recognised complication of proteinuric disease in dogs with a prevalence of 25%. Serum concentrations of albumin and antithrombin decrease with severe proteinuria and pro-coagulant factors such as factors V and VIII, fibrinogen levels and platelet activity increase. In humans inactivity in patients with nephrotic syndrome is a contributing factor. Thrombo-prophylactic dugs used and studied in dogs are limited to mainly heparin and aspirin. In humans, vitamin K antagonists are used, but monitoring is intense and complications common, and it is thus not recommended in dogs. Current recommendation is that aspirin is supplemented at doses of greater than 1 mg/kg, up to 5 mg/kg daily. This is based on recent studies showing that 0.5 mg/kg/day and 1 mg/kg/day may be ineffective anti-thrombolytic dosages. Clopidogrel (1.1 mg/kg/d) is as effective, but not more so, than aspirin.

Anti-Hypertensive Therapy

Chronic sustained increases in blood pressure produced target organ damage (TOD) in the kidneys, heart, eyes and brain. In the kidney, this manifests as accelerated decrease of renal function, increased proteinuria and increased frequency of uraemic crises. Hypertension can occur at any stage of CKD, but is more common in advanced disease. Systolic blood pressure (SBP) < 150 mm Hg has minimal risk of end organ damage, SBP 150–159 mm Hg mild, 160–180 mm Hg moderate and SBP > 180 mm Hg a high risk. Treatment is recommended if SBP exceeds 160 mm Hg and diastolic pressure exceeds 100 mm Hg.

RAAS inhibitors typically only reduce the blood pressure by about 10–15%. This together with their antiproteinuric effect is sufficient to start off with in patient showing no signs of hypertensive. If the hypertension is significant, then additional antihypertensive drugs will be required. If the ACEi is ineffective in reducing the SBP, a calcium channel blocker, amlodipine, is added. Additional medications which can be added include diuretics - especially in patients with nephrotic syndrome - and alpha or beta blockers. In nonsevere hypertension situations, up to early stage 3 CKD, 2–4 weeks is allowed between dosage adjustments. In patients with late stage 3 to stage 4 CKD, check within 3–5 days and adjust treatment accordingly. In dogs, a decrease in proteinuria by at least 50% is a measure of effective antihypertensive therapy.

Fluid and Diuretic Therapy

Nephrotic syndrome (NS) is defined as proteinuria, decreased serum albumin, hyperlipidemia and oedema. The oedema is classically explained by decreased plasma colloid oncotic pressure which causes fluid shifts into the interstitial compartment. Experimentally severe hypoalbuminaemia alone is seldom enough to cause oedema. Almost 40% of the albumin is contained within the interstitial space so there is a loss in both compartments which balances transcapillary oncotic gradient. There is evidence of inappropriate renal tubular sodium retention and excessive volume expansion in NS in rodents.

Patients with NS are by definition overhydrated. The interstitial overhydration can be accompanied by intravascular hypo- or hypervolaemia. This may be difficult to clinically assess. Evaluate serial body weight (fluid retention), skin turgor, CRT, heart rate, peripheral pulse and systemic BP. In humans, indirect markers of vascular expansion such as natriuretic peptides and echocardiography are used. In general, if you are not sure, treat the patient as volume overloaded. Even if you determine that the patient is hypovolaemic, fluid replacement should be cautious.

Effusions in nephrotic patients should only be drained if compromising organ function. In most cases, diuretics can be administered to slowly reduce the oedema. Rapid reduction may exacerbate hypovolaemia and cause worsening azotaemia, venous stasis and thromboembolism. Furosemide is indicated but needs to reach therapeutic levels at the loop, which doesn't always happen in CKD. Increased dosage frequency may be required in nephrotic patients. Spironolactone can be added if potassium levels allow. Monitoring should be daily in critical patients: hydration and blood volume, body weight, urine production, electrolytes, creatinine and BUN.

Immunosuppressive Therapy

To decide on whether immunosuppressive therapy, in addition to the standard therapy, is necessary or not requires a proper diagnosis and renal biopsy. This may not always be advisable or possible due to various constraints. Immune complex deposition is seen in 48% of biopsies for GN.

Without an exact diagnosis, immunosuppressive therapy is generally contraindicated and is ineffective in most familial nephropathies and if there is concurrent infection, diabetes or Cushing's disease. Immunosuppressive drugs should be considered in patients receiving standard therapy with a serum creatinine > 265 µmol/L (3 mg/dL) or progressive azotaemia or in the presence of hypoalbuminaemia (< 2.0 g/dL). Recommendations are anecdotal clinical experience. Glucocorticoids can cause proteinuria in dogs (reversible) the side effects of fluid retention, negative nitrogen metabolism and thromboembolic potential may make prednisolone less beneficial. Alkylating agents such as cyclosporin or chlorambucil, together with prednisolone may be indicated - the former in acute progressive cases, and the latter in chronic cases. Azathioprine has a delayed onset of action so is only of benefit in the chronic disease, possibly in combination with chlorambucil. Mycophenolate is suggested in the acute cases - alone or in combination with prednisolone. Initial monitoring assessments should be performed 1–2 weeks after initiation and every 2 weeks for 6 weeks thereafter monthly for 3 months and then at 3-month intervals.


1.  IRIS Canine GN Study Group Standard Therapy Subgroup, Brown S, Elliott J, Francey T, Polzin D, Vaden S. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27:S27–S43.

2.  IRIS Canine GN Study Group Standard Therapy Subgroup, Littman MP, Daminet S, Grauer GF, Lees GE, van Dongen AM. Consensus recommendations for the diagnostic investigation of dogs with suspected glomerular disease. J Vet Intern Med. 2013;27:S19–S26.

3.  IRIS Canine GN Study Subgroup on Immunosuppressive Therapy Absent a Pathologic Diagnosis, Pressler B, Vaden S, Gerber B, Langston C, Polzin D. Consensus on guidelines for immunosuppressive treatment of dogs with glomerular disease absent a pathologic diagnosis. J Vet Intern Med. 2013;27:S55–S59.

4.  IRIS Canine GN Study Group Established Pathology Subgroup, Segev G, Cowgill LD, Heiene R, Labato MA, Polzin DJ. Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med. 2013;27:S44–S54.


Speaker Information
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Liesel van der Merwe, BVSc, MMedVet (Med)
South Africa

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