Standard Therapy and Immunosuppression of Dogs with Protein Losing Nephropathy
Department of Clinical Sciences, North Carolina State University CVM, Raleigh, NC, USA
The prevalence of chronic kidney disease (CKD) in dogs may be as high as 1.5%; glomerular disease may be the cause of renal injury in 50% or more of these dogs. Because glomerular diseases are common in dogs and outcomes are not always favorable, there has been an enhanced effort to improve early recognition, diagnosis, and treatment of all renal diseases in dogs, with particular emphasis on proteinuric renal diseases. In support of this effort, the WSAVA Renal Standardization Project developed a classification system for glomerular pathologic findings in dogs. At the same time, the International Renal Interest Society (IRIS) developed clinical guide lines for the management of dogs with glomerular disease. The latter initiative used a formal consensus method for developing several sets of recommendations, including those for standard therapy, immunosuppressive therapy when pathologic diagnosis is known and immunosuppressive therapy without a renal biopsy. The purpose of this presentation is to discuss those recommendations.
Standard therapy is the foundation of care that should be given to all dogs with glomerular disease, regardless of the inciting cause, and includes inhibition of the renin-angiotensin-aldosterone system (RAAS), and the management of dietary intake, hypercoagulability, systemic hypertension and body fluid volume. Standard therapies be considered when the UPC is persistently >0.5.
Inhibition of RAAS. The RAAS can be therapeutically targeted to alter renal hemodynamics, leading to a reduction in proteinuria. Angiotensin-converting enzyme inhibitors (ACEi; e.g., enalapril, benazepril), angiotensin receptor blockers (ARB; e.g., losartan, telmisartan), and aldosterone receptor blockers (e.g., spironolactone) are the agents that target RAAS. For most dogs with glomerular proteinuria, an ACEi is the initial agent used. Typically given once daily initially, more than half of the dogs will eventually need twice daily administration and perhaps additional dosage escalations. Severe worsening (i.e., >30% increase from baseline) of azotemia due to ACEi administration alone seems uncommon; dehydrated dogs may be at highest risk. The ARB most commonly used in dogs with glomerular disease is telmisartan. Early results show great promise with use of this agent.
UPC, urinalysis, systemic arterial blood pressure and serum albumin, creatinine, and potassium concentrations should be evaluated at least quarterly in dogs given a RAAS inhibitor. The UPC, serum creatinine, serum potassium and blood pressure should be evaluated 1–2 weeks after an ACEi or ARB has been added or altered. The desired outcome is a reduction in proteinuria without a severe worsening of renal function (i.e., >30% increase in creatinine), a critical increase in serum potassium or the unlikely development of hypotension (more common with telmisartan). Changes in the magnitude of urine protein are assessed through trends in the UPC over time. Day-to-day variations in the UPC occur. To adjust for this, monitoring requires either averaging 2–3 serial UPC or measuring a UPC in urine that has been pooled from 2–3 collections. The target for reduction is a UPC of <0.5; however, when that is not possible, a partial response with a reduction in the UPC of 50% or more is the alternative target. If this target is not achieved and there are no adverse effects, the dosage may be increased every 4–6 weeks. Dogs with serum potassium concentrations of >6 mEq/L should be monitored closely; therapy should be modified when serum potassium concentrations are >6.5 mEq/L. Pseudohyperkalemia should be eliminated as a cause by measuring the potassium concentration in lithium heparin plasma. True hyperkalemia can be managed by reducing the drug dosage, or by feeding diets that are reduced in potassium.
Modified dietary intake. Modification of dietary intake has a central role in the management of all dogs with kidney disease via delaying progression of kidney disease and reducing proteinuria. The consensus recommendation is that dogs with glomerular disease should be fed a modified protein diet with reduced n-6/n-3 polyunsaturated fatty acids (PUFA) ratio of approximately 5:1 (most commercially available renal diets fulfill this goal). It is unknown if there is additional benefit of supplementing n-3 PUFA beyond providing this dietary ratio. If supplementing, care should be taken to provide adequate antioxidants (e.g., vitamin E). The sodium chloride dietary intake also should be reduced. Salt restriction may enhance the beneficial effects of agents used to inhibit RAAS and reduce fluid retention.
Antithrombotic therapy. Hypercoagulability is a complication of protein losing glomerular diseases; thromboembolism occurs in up to 25% of these dogs. Unfortunately, serum albumin concentrations, antithrombin activity, and UPC cannot be used in isolation to predict hypercoagulability in individual patients. Although unclear when to implement thromboprophylaxis, consensus recommendations call for the daily administration of low-dose aspirin (1–5 mg/kg/day). Clopidogrel may be an effective alternative.
Antihypertensive therapy. All dogs with glomerular disease should undergo repeat measurement of systemic blood pressure and assessment of the patient for target organ damage. An ACEi is the first line antihypertensive agents and a calcium channel blocker (e.g., amlodipine besylate) is a second agent, when needed. Animals presenting with systolic pressures >200 mm Hg or with evidence of target organ damage (e.g., choroidopathy) should be given both drugs because monotherapy with an ACEi is unlikely to provide adequate control. Because telmisartan may be as effective at lowering blood pressure as amlodipine, it may be adequate as a single agent in some animals. If renal function worsens after initiating treatment with one of these agents, the drug should be temporarily withdrawn and reinstituted at a lower starting dose.
Body fluid volume. Dogs with glomerular disease may have fluid excesses, deficits, or maldistribution, which may need to be corrected if the dog has decompensated or is being prepared for anesthesia. Correcting body fluid imbalances in dogs that are hypoalbuminemic from glomerular disease is a very difficult therapeutic challenge. Fluid therapy can exacerbate edema and hypertension and diuretics can exacerbate azotemia or uremia. As such, those who have experience and expertise in critical care are the best people to deliver these therapies to dogs with glomerular disease. Fluid therapy should be given only when needed to help control clinical signs or provide support to those dogs that have inadequate fluid intake.
Immunosuppressive therapy should be considered in dogs that have severe, persistent, or progressive glomerular disease and ICGN documented via appropriate evaluation of a renal biopsy specimen. However, there are practical and medical reasons why a biopsy might not be performed. Sometimes veterinarians must decide about immunosuppressive therapy in dogs with glomerular disease absent a pathologic diagnosis. Immunosuppressive therapy should not be administered if there is any doubt that the proteinuria is of glomerular origin, administration of the specific drug is medically contraindicated, or there is a high index of suspicion that the dog has amyloidosis or a non-immune-mediated familial disease. Immunosuppressive drugs should be considered absent a pathologic diagnosis when standard therapy has been implemented but azotemia is progressive, serum creatinine is >3.0 mg/dl or serum albumin is <2.0 g/dl. The risks of this therapy need to be clearly understood.
The immunosuppressive protocol may vary based on severity of clinical signs and rate of progression of the glomerular disease. More aggressive protocols may be best for dogs with severe, rapidly progressive disease. The rapidity of which the drug becomes active is of less concern when the disease is more slowly progressive. Drugs to consider are glucocorticoids, mycophenolate, cyclosporine, cyclophosphamide, chlorambucil, and azathioprine, alone or in combination.
Patients receiving immunosuppressive drugs should be monitored for drug-specific adverse effects and therapeutic response. A therapeutic response is a reduction in the magnitude of proteinuria with improvement/stabilization of renal function and increases in serum album in. A reduction in proteinuria is a UPC of <0.5 (complete response) or 50% reduction from baseline (partial response). Improvement or stabilization in renal function is a sustained reduction in serum creatinine to <1.4 mg/dl (complete response) or by >25% of baseline (partial response). A meaningful increase in serum albumin is a sustained increase to >2.5 mg dl (complete response) or either to 2.0–2.5 mg/dl or by >50% of baseline (partial response). Secondary goals of therapy include improved blood pressure regulation, resolution of edema, and stabilization of body weight. If there are no unacceptable adverse drug effects, treatment should be continued for 8–12 weeks. If there is a partial or complete response, therapy should continue for at least 12–16 weeks. If there has not been a partial or complete response by 8–12 weeks, the protocol should be changed or discontinued. If there is no response by 3–4 months, all immunosuppressive therapy should be discontinued, tapering as needed.
1. IRIS Canine GN Study Group Standard Therapy Subgroup, Brown S, Elliott J, et al. Consensus recommendations for standard therapy of glomerular disease in dogs. J Vet Intern Med. 2013;27:S27–S43.
2. IRIS Canine GN Study Group Established Pathology Subgroup, Segev G, Cowgill LD, et al. Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med. 2013;27:S44–S54.
3. IRIS Canine GN Study Subgroup on Immunosuppressive Therapy Absent a Pathologic Diagnosis, Pressler B, Vaden S, et al. Consensus guidelines for immunosuppressive treatment of dogs with glomerular disease absent a pathologic diagnosis. J Vet Intern Med. 2013;27:S55–S59.
4. IRIS Glomerular Disease Study Group, Goldstein RE, Brovida C, et al. Consensus recommendations for treatment of dogs with serology positive glomerular disease. J Vet Intern Med. 2013;27:S60–S66.