Introduction

Many dogs with glomerular disease (GD) seem to have poor outcomes when treated with current therapies. For example, a recent study reported a median survival of 12.5 days for dogs with nephrotic syndrome and particularly poor outcomes when azotemia was present. The IRIS Canine Glomerulonephritis Study Group recognized these difficulties and published specific recommendations to provide guidance for the diagnosis and the therapy of GD, aiming specifically at improving outcomes. These recommendations form the basis of this report.

Standard Therapy

Standard therapy is the foundation for care of dogs with GD, and it is recommended for use in all affected animals regardless of the causation of the disease. It targets the management of proteinuria, the inhibition of the renin-angiotensin-aldosterone system (RAAS), dietary modifications, the treatment of systemic hypertension, and the management of altered fluid balance.

RAAS Blockade

Because hemodynamic forces influence the glomerular filtration of proteins, altering renal hemodynamics is expected to be effective in reducing proteinuria. The RAAS has been the major target for this approach to reduce proteinuria with agents including angiotensin-converting enzyme inhibitor (ACEi), angiotensin-receptor blockers (ARB) and aldosterone-receptor blockers (e.g., spironolactone). The multiple mechanisms of these agents are not fully understood but they appear to reduce proteinuria to a greater extent than would be expected from their antihypertensive effects alone.

Typically, ACEi are given once daily initially, but most dogs will eventually need twice-daily administration and perhaps additional dosage escalations. The ARBs in clinical use (e.g., losartan, telmisartan) block the angiotensin II Type 1 receptor and reduce proteinuria similarly to ACEi. There are currently only very limited data on ARBs in dogs with GD, but the availability of these drugs is likely to change our practice in the coming years. By interfering with renal compensation mechanisms, RAAS blockade may initially worsen azotemia and the serum creatinine should therefore be monitored closely, especially in dehydrated dogs or those with more severe azotemia. Caution is clearly warranted with dogs in IRIS Stage 4. Treatment of humans with RAAS blockers, even at high dosages, is commonly associated with an escape of aldosterone inhibition and its progressive increase over time. Anecdotal evidence supports the presence of a similar aldosterone escape in dogs. More efficient dual blockade with ACEi and ARB is however not recommended due to the risk of life-threatening hyperkalemia. Although spironolactone (aldosterone receptor blocker) has been shown to reduce further proteinuria in people, only anecdotal evidence supports the efficacy of this drug in dogs in the management of GD at this stage.

Introduction of a new drug or dosage modifications are indications for frequent monitoring. One to 2 weeks after a treatment change, UPC, serum creatinine, serum potassium, and blood pressure should be measured to verify treatment efficacy (reduction in UPC) and safety (< 30% increase in serum creatinine, stable serum potassium, and absence of hypotension). Dogs with marked azotemia (IRIS Stages late 3 to 4) should be monitored even more carefully, already after 3–4 days.

Dietary Therapy

Nutrition plays a central role in the management of kidney diseases in veterinary medicine. In dogs, the progression of CKD and the magnitude of proteinuria may be modified by adjusting dietary intake. Supplementation with n-3 PUFA may offer renoprotection in the long term and is recommended for dogs with GD, using commercially available "kidney diets" with n-6:n-3 ratios close to 5:1. The generally accepted benefits of modification in dietary protein in canine GD are to reduce intraglomerular pressure, magnitude of proteinuria and generation of uremic toxins. There is evidence that dietary modification including (but not restricted to) protein reduction reduces proteinuria and slows progression to CKD. It is further likely that dogs with nephrotic GD are salt-sensitive and that salt restriction enhances the antihypertensive efficacy and renal hemodynamic effects of some RAAS-based antihypertensive agents.

Antithrombotic Therapy

Thromboembolism is a recognized complication of GD in dogs with reported prevalence rates as high as 25%, mostly in the form of venous thrombi. Although the relationship between magnitude of proteinuria and development of thromboembolism has not been well established in dogs, it is generally accepted that the risk of thromboembolism increases as the concentrations of antithrombin and serum albumin decrease consequent to proteinuria.

There is no evidence base to recommendations on when intervention is justified or on which drugs to use for thromboprophylaxis in dogs with GD. The current recommendation remains low-dose aspirin (0.5–5 mg/kg daily). Preliminary evidence suggests that clopidogrel (Plavix, 1.1 mg/kg q24h) may also be effective in reducing platelet activity, but comparative data supporting its use despite additional costs are lacking at the time.

Systemic Hypertension (SHT)

The rationale for treatment of SHT in dogs with GD is to minimize or prevent target organ damage to the kidney, eyes, brain or cardiovascular system. Clinical experience indicates that RAAS inhibitors reduce BP only slightly (~ 10–15%), but they will typically be used already for their antiproteinuric effect in affected dogs. Most clinicians consider the addition of a calcium channel blocker (i.e., amlodipine) as an appropriate next consideration if necessary. Re-evaluation at 1 day to 4 months intervals is recommended, depending on severity and stability of SHT and stage of disease. In dogs, a key predictive parameter for antihypertensive efficacy is the effect on the magnitude of proteinuria and a benefit is predicted if the antihypertensive regimen is antiproteinuric (reduces UPC ≥ 50%, preferably to < 0.5).

Fluid and Diuretic Therapy

Alterations of fluid homeostasis are common in dogs with GD. They include excesses, deficits, and intercompartmental maldistribution, and they may require interventions, although restoration of disturbed fluid balance can be very challenging, a likely a consequence of our poor understanding of the mechanisms underlying edema formation and of our limited ability to evaluate accurately the animal's fluid balance.

Treatment of nephrotic edema is addressed primarily through treatment of the underlying etiology and reduction in proteinuria, a more specific treatment being reserved for animals with significant respiratory distress, abdominal discomfort, or other severe complications caused by fluid accumulation. Overfilled, stable nephrotic dogs typically do not require fluid therapy either, even for short elective anesthesia such as required for renal biopsy. Unstable nephrotic animals necessitating anesthesia, however, require a thorough global evaluation and the need for intervention has to be assessed individually. If deemed absolutely necessary, fluid administration should remain very conservative and be re-evaluated frequently. Severe pleural and abdominal effusions are more efficiently removed by thoraco- and abdominocentesis, respectively. Underfilled dogs with or without edema may require careful and conservative volume expansion for acute clinical manifestations, peri-operatively, or for worsening azotemia.

When diuretic intervention is absolutely indicated, furosemide (preferentially for pulmonary edema) or spironolactone (preferentially for pleural or peritoneal effusions) are often recommended as the initial choices, aiming for a slow progressive decrease in the edema. Overaggressive treatment should be avoided because the resulting hypovolemia can worsen azotemia, venous stasis and thromboembolic disease.

Immunosuppressive Therapy

The IRIS Study Group recommends empirical application of immunosuppressive therapy for dogs with severe, persistent, or progressive glomerular disease with evidence of active immune-mediated pathogenesis on kidney biopsy. For diseases associated with profound proteinuria, hypoalbuminemia and nephrotic syndrome, or rapidly progressive azotemia, single drug or combination therapy with rapidly acting agents is recommended. Mycophenolate (alone or in combination with rapidly tapered prednisolone) is preferred. For more stable GD, the Study Group recommends mycophenolate or chlorambucil alone or in combination with azathioprine on alternate days. Therapeutic effectiveness should be monitored serially by changes in proteinuria, renal function, and serum albumin concentration. In the absence of overt adverse effects, at least 8–12 weeks of drug therapy should be provided before altering or abandoning an immunosuppressive trial.

Although there is no substitute for a pathologic diagnosis in dogs with GD, there are times when renal biopsy cannot be performed because of medical, practical or financial limitations. Immunosuppressive drugs should not be given when the source of proteinuria is unknown, they are otherwise contraindicated, or a familial nephropathy or amyloidosis is likely. However, they should be considered when dogs are already treated with standard therapy and the azotemia is progressive or hypoalbuminemia is severe. Thorough client communication as well as close and careful patient monitoring is essential.

References

1.  IRIS Canine GN Study Group, Standard Therapy Subgroup, Brown SA, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27(S1):S27–43.

2.  IRIS Canine GN Study Group, Established Pathology Subgroup, Segev G, et al. Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med. 2013;27(S1):S44–54.

3.  IRIS Canine GN Study Group, Subgroup on Immunosuppressive Therapy Absent a Pathologic Diagnosis, Pressler B, et al. Consensus Guidelines for immunosuppressive treatment of dogs with glomerular disease absent a pathologic diagnosis. J Vet Intern Med. 2013;27(S1):S55–59.