Monitoring for and Treatment of Neoplastic, Infectious, or Noninfectious Inflammatory Disorders

NIN disorders responsible for glomerular disease may not be detected at first presentation. Because occult diseases may become overt months after initial diagnostic testing, continued observation and evaluation of any newly developed clinical signs or abnormal findings on physical examination are necessary. Identification and treatment of any underlying NIN disorder is perhaps the most important step in the management of dogs and cats with persistent proteinuria. Following treatment, animals should be evaluated for resolution of proteinuria, which may occur slowly over a period of months.

Reduction of Proteinuria

Intraglomerular hydrostatic pressure is a primary determinant of net protein movement across the glomerular filtration barrier. Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor blockers (ARBs), and aldosterone receptor antagonists inhibit the renin-angiotensin-aldosterone system (RAAS) and reduce glomerular capillary bed hydrostatic pressure, thus reducing proteinuria (Figure 188-1). Although the precise mechanisms by which these agents exert their beneficial effects have not been fully elucidated, it appears that reduction in proteinuria is greater than would be expected from their antihypertensive effects alone.

ACE inhibitors preferentially decrease efferent glomerular arteriolar resistance, which leads to decreased or normalized glomerular transcapillary hydrostatic pressure and also may preserve renal function by additional, less well-described mechanisms. Treatment of dogs with glomerular diseases with enalapril significantly reduces proteinuria and delays onset or progression of azotemia and therefore is considered a standard of care (Grauer et al, 2000). ACE inhibitors are administered once or twice daily; if the magnitude of azotemia is relatively stable and there has been only partial or no reduction in proteinuria after 4 to 8 weeks, the dosage may be increased to the upper end of the recommended ranges (e.g., enalapril or benazepril 2 mg/kg PO per day). Although serum creatinine concentration should be monitored after therapy is begun, it is uncommon for dogs and cats to become azotemic or to experience severe worsening of preexisting azotemia (i.e., >30% increase from baseline) as a result of ACE inhibitor administration alone. Although differences exist in the elimination pharmacokinetics of enalapril and benazepril, there is no evidence that one ACE inhibitor is pharmacokinetically superior to others in either dogs or cats. In people, up-titration of doses of ACE inhibitors beyond current recommendations maximizes reduction of proteinuria and recently has been suggested to improve prognosis (Schjoedt et al, 2009); similar studies have not been performed yet in dogs or cats.

Although ARBs are used commonly in people with glomerular disease, their use in dogs still is being developed. Losartan is the most commonly used ARB. Even though dogs do not produce one of the major active metabolites, losartan does have anti-RAAS pharmacodynamic effects and anecdotally has an antiproteinuric effect in dogs with glomerular disease. In theory there may be an added benefit to combined therapy with an ACE inhibitor and an ARB because monotherapy with either drug class likely does not provide complete RAAS blockade. Studies in people have suggested that these drugs may have additive or synergistic effects in reducing proteinuria, although there have not been any equivalent studies in dogs (Linas, 2008). In addition, because the dose of each individual drug can be reduced during combined therapy, adverse effects in people may be reduced; however, elderly patients prescribed this combination have a higher risk of kidney failure and death.

Serum aldosterone concentrations increase over time (known as aldosterone escape) in people treated with maximal dosages of ACE inhibitors or ARBs, which may have adverse effects on the heart, systemic blood vessels, and glomeruli (Bakris, 2008). Aldosterone receptor antagonists reduce proteinuria and stabilize kidney function, acting in an additive fashion with ACE inhibitors and ARBs in people. Spironolactone (1.0 to 2.0 mg/kg q12h PO) is used most commonly in veterinary medicine; however, there are no published data examining its usefulness in the treatment of dogs or cats with glomerular disease. This drug likely would be most effective in animals with high serum aldosterone concentrations and persistent proteinuria despite treatment with an ACE inhibitor, ARB, or both. Anecdotal experience suggests that spironolactone is not very effective in reducing proteinuria in dogs with glomerular disease.

Hyperkalemia is a common adverse effect of RAAS inhibition in dogs with kidney disease. Thrombocytosis also is common in dogs with glomerular disease, and therefore pseudohyperkalemia should be excluded as a cause of increased serum potassium concentration before therapy is modified. True hyperkalemia can be managed by reducing the dosage of ACE inhibitor, ARB, or spironolactone; feeding a reduced-potassium diet; or administering a gastrointestinal potassium binder (e.g., Kayexalate).

Treatment with antihypertensives often leads to a reduction in the magnitude of proteinuria in patients with high blood pressure. ACE inhibitors and ARBs are relatively weak antihypertensive agents and do not routinely reduce blood pressure by more than 10 to 15 mm Hg; additional antihypertensive agents (e.g., amlodipine) may be required if hypertension persists. Treatment with amlodipine alone also may result in reduction of proteinuria, but typically to a lesser degree than that seen with ACE inhibitor or ARB therapy. In addition, amlodipine may induce preferential dilation of the afferent glomerular arteriole, thereby increasing intraglomerular hydrostatic pressure, as well as RAAS activation in dogs and potentially also cats (Atkins et al, 2007). Some clinicians recommend that amlodipine not be administered to a dog or cat with chronic kidney disease without simultaneous administration of an ACE inhibitor.