The basics of treating glomerular disease (Proceedings)

The reasons why proteinuria is directly associated with progression of renal disease are multifactorial. As the proximal convoluted cells increase phagocytosis of inappropriately filtered protein, they may be subject to relative hypoxia due to the increased workload, and oxygen radicals and heavy metals may accumulate within tubular epithelial cells during protein catabolism. In addition, non-reabsorbed protein may obstruct renal tubules, leading to individual-nephron obstructive uropathy. Finally, some proteins such as complement and immunoglobulins may activate the immune system within the renal tubules.

Based on the known association between proteinuria and poor clinical outcome, early intervention to decrease proteinuria is an important part of the management of dogs with kidney disease. The current recommendations by an ACVIM consensus panel of nephrologists with a specific interest in glomerular disease and proteinuria are that non-azotemic dogs and cats with urine protein:creatinine (UPC) ratios >2.0 merit protein-reducing interventions regardless of whether or not further diagnostic testing is performed. Treatment should be instituted in azotemic dogs even earlier, when the UPC ratio is greater than 0.5. Intervention is recommended in azotemic cats when the UPC ratio is greater than 0.4.

The first step in the diagnosis and treatment of proteinuria is to determine if the increased protein is of pre-glomerular, glomerular, or post-glomerular origin. Pre- and post-glomerular proteinuria do not require intervention to reduce protein excretion. If glomerular proteinuria is diagnosed then the most important therapy is the identification and treatment of any specific infectious or inflammatory diseases that may be causing the underlying renal dysfunction. Treatment of concurrent diseases may prevent, slow, or reverse renal disease, whereas missing these concurrent conditions will likely not prevent progression to renal failure or nephrotic syndrome even if generalized therapy for proteinuria is begun.

General therapy for proteinuria

      Angiotensin-converting enzyme inhibitors

Reduction of urine protein excretion by inhibition of angiotensin-converting enzyme (ACE) activity is the mainstay treatment for proteinuria of glomerular origin in dogs and cats. The best characterized benefit of these drugs is the reduction of protein excretion into the urine. Preferential vasodilation of the afferent renal arteriole is one of the compensatory mechanisms whereby individual nephron GFR increases during chronic renal failure. Reduction of systemic angiotensin II activation by inhibition of ACE results in further vasodilation, but the preferential dilation of the efferent arterioles occurs over that of the afferent. This results in reduced intraglomerular hydrostatic pressure through a reduction in glomerular 'afterload.' The net effect is a reduction in the amount of filtrate (and protein) that passes into Bowman's space and eventually into the urine.

Although reduction of intraglomerular hydrostatic pressure is the best characterized benefit of ACE inhibitors, additional benefits also include reduced mesangial cell hypertrophy in dogs with experimentally-induced glomerular disease either as an independent benefit of therapy or secondary to reducing intraglomerular hypertension. There is a general reduction in systemic arterial hypertension both via reduced angiotensin II concentration and reduced water and sodium retention (via reduced renin activation). Other mechanisms of vasodilation and modulation of inflammation include prevention of bradykinin degradation, which promotes nitric oxide and prostacyclin production and further induces glomerular efferent arteriolar dilation. Which one(s) of these benefits is most critical for prolonging time until uremic crises or until death in dogs with proteinuria is unknown.

Enalapril is the most commonly used ACE-inhibitor (0.5 mg/kg q12-24h). A maximal reduction in proteinuria is desirable, so beginning with the maximum dose is recommended in non-azotemic patients. Adverse effects with this drug are uncommon. However because ACE-inhibitors reduce blood flow into the vasa recta, when treating severely azotemic animals (I worry when creatinine is >3.5) I begin with the longer dosing interval (q24h), recheck creatinine after four to seven days, and then increase to q12h if there has been no increase in serum creatinine concentration. Other side-effects (particularly in people) include hyperkalemia and anorexia due to gastrointestinal disturbances. In both cases withdrawal followed by restarting at a lower dose can be attempted. In people, ACE inhibitor therapy is a relative-to-absolute contraindication for administration of NSAIDs because of the cumulative reduction in renal medullary blood flow; it is wise to avoid the combination of these drugs in veterinary patients as well.

Other ACE-inhibitors, including benazapril, lisinopril, captopril, ramipril, and quinapril are commercially available. There are very few studies directly comparing these drugs in the experimental setting, and none in animals with naturally-occurring disease. All of these drugs reach therapeutic serum concentrations with appropriate half-lives in healthy dogs with the exception of captopril. Benazapril is an attractive alternative to enalapril because it may be administered q24h with the same apparent effect as q12h enalapril, and because in experimental studies dogs with kidney disease did not require the same dosage adjustments that enalapril may require. However, there are several studies which provide indirect evidence that not all ACE-inhibitors can be relied upon to have equivalent effects in dogs with protein-losing nephropathies. For example, quinapril is more effective than enalapril in reducing severity of echocardiographic variables in Cavalier King Charles Spaniels with asymptomatic mitral regurgitation, serum enalaprilat (the active metabolite of enalapril) concentration increases in dogs with sub-normal GFR, whereas benazeprilat does not, and captopril does not reduce serum ACE activity in healthy dogs as well as other ACE inhibitors. Therefore, I prefer enalapril over benazapril in dogs because the only study on the effects of ACE-inhibitors in dogs with naturally-occurring glomerular disease studied the benefits of enalapril...and why fool around with something that's definitely been shown to work?

Studies of cats with chronic kidney disease indicate that presence and severity of proteinuria may also be associated with decreased long-term survival. Therefore treatment with ACE-inhibitors to reduce protein excretion may be beneficial (although results are conflicting). I choose to treat cats with chronic kidney disease and proteinuria with benazapril (0.5-1.0 mg/kg q24h), again, because the only efficacy study on ACE-inhibitors for reduction of proteinuria in cats was performed with this drug rather than enalapril.

      Other anti-proteinuric drugs

           Angiotensein receptor blockers

Although ACE-inhibitors are effective at reducing the severity of proteinuria in most patients with protein-losing nephropathies, it is common for the urine protein:creatinine ratio to still be above reference range even when the maximal drug dose is used. In order to further reduce proteinuria, some veterininary nephrologists have begun to use angiotensin II receptor blockers (ARBs, e.g. losartan) in those cases of severe proteinuria where ACE-inhibitors alone are insufficient. The reason why this double-pronged approach makes sense is because the little angiotensin II that is activated can be blocked by the use of ARBs. In addition, ARBs, and losartan in particular, may reduce the risk of thromboembolism in patients with severe proteinuria by interfering with angiotensin-II-mediated platelet activation.

However, whether or not concurrent use of ACE-inhibitors and ARBs truly offers any advantage beyond reduction of proteinuria is unclear. In people, ARBs and ACE-inhibitors are both used as first-line therapy for reduction of proteinuria; both classes of drugs have been documented to reduce UPC, reduce the rate of decline of renal function, and improve long-term outcome. However, concurrent use of a drug from each class, although further reducing UPC, does not seem to likewise further slow renal functional deterioration. In fact, the two drugs together have a higher risk of hyperkalemia (which may be severe), and in some studies the combination have actually lead to worsened outcome for patients with some glomerular diseases, particularly in the presence of concurrent cardiovascular disease.

Equivalent studies have not been performed in dogs as of yet, and as such ARBs are not advocated as first-line therapy, and it is unknown if combination treatment worsens, improves, or does not change prognosis. When used, losartan (Cozaar®) is recommended at a starting dose of 0.5 mg/kg q12h. If creatinine has not increased more than approximately 30% after 4-7 days and the UPC is still increased, then the dose is increased step-wise to 1-2 mg/kg q12h, again rechecking serum creatinine and UPC after each dose adjustment. Anecdotally, gastrointestinal side-effects have been reported.

      Aldosterone receptor antagonists

Despite the use of ACE-inhibitors and ARBs, aldosterone eventually increases almost to pre-treatment concentrations in people with protein-losing nephropathies. This phenomenon, termed 'aldosterone escape,' is likely due to positive feedback loops increasing angiotensin I synthesis and release, and ACE activity, in response to the relative angiotensin II deficiency induced by therapy. In addition to those direct effects described above on systemic and glomerular vascular tone, angiotensin II induces aldosterone synthesis and release from the adrenals. Aldosterone promotes sodium and water retention, increasing glomerular and systemic preload, and is itself a pro-fibrotic agent. Therefore, spironolactone has been advocated by some human nephrologists to combat aldosterone escape, particularly in patients who require chronic anti-proteinuric therapy. There is no evidence on the use of aldosterone antagonists in non-nephrotic veterinary patients, and I am not aware of any anecdotal evidence.

Dietary therapy

Reduction in dietary protein has been shown to reduce urinary protein loss in experimental models of glomerular disease, including in hereditary canine nephritis. Unfortunately whether this dietary therapy results in improved long-term prognosis and whether the reduction in proteinuria also occurs with naturally-occurring glomerular diseases is unknown. Preliminary results from one study did not show reduction in proteinuria in dogs receiving a protein-restricted diet, but the small number of dogs studied and lack of histologic subclassification makes interpretation of the results difficult. Most nephrologists routinely recommend dietary therapy for patients with glomerular disease, regardless of whether or not they are azotemic. Severely protein-restricted diets likely do not provide increased advantage over the moderately-restricted diets. Commercial 'renal diets' are moderately protein restricted, and also have the advantage of sodium restriction and increased omega-3 fatty acid concentration which are theoretically advantageous in dogs with glomerular or tubular renal disease.

Immunosuppression

Immunosuppression is an inappropriate non-specific treatment for proteinuria, and should only be reserved for specific types of glomerular diseases. For example, prednisone induces mesangial cell proliferation and proteinuria in healthy dogs, and glomerular disease and proteinuria are common in dogs with hyperadrenocorticism. Likewise, cyclosporine is of no clinical or biochemical benefit in dogs with naturally-occurring glomerular diseases.

Aspirin therapy

Although hypoalbuminemia and its consequences (edema, ascites) are the most commonly noted sequelae of severe proteinuria, other proteins of similar charge and similar or smaller size as albumin are also lost in the urine. Dogs with severe hypoalbuminemia should be assumed to be hypercoagulable due to loss of antithrombin III and other anticoagulant proteins. Antithrombin III can be measured by several commercial laboratories, but studies which have evaluated serum concentrations of this protein in dogs with protein-losing nephropathies have reported a general correlation with serum albumin concentration. As a result, I do not routinely measure antithrombin III unless I clinically suspect thromboembolism despite a normal or only slightly decreased serum albumin concentration. Aspirin (0.5 mg/kg q24h) inhibits platelet aggregation independently of anticoagulant proteins. I generally begin aspirin therapy in dogs when serum albumin concentration is less than 2.5 g/dl.

Oncotic and diuretic support

Occasionally, dogs with severe hypoalbuminemia will present with peripheral edema or ascites. Fluid therapy designed to increase plasma oncotic pressure (synthetic colloids, plasma, or albumin) usually have a transient effect and are unsuitable for long-term support of animals with hypoalbuminemia. I only use oncotic support for those patients who present with life-threatening fluid accumulation that requires immediate intervention, such as patients with pulmonary edema or pericardial effusion. Because of the large volumes of synthetic colloids typically required to raise plasma oncotic pressure back to a range that inhibits fluid extravasation, in these cases I instead use plasma in cats and small dogs, and human albumin and synthetic colloids in large dogs, with the expectation that benefits will fade within 48 hours. Unfortunately, there is a high frequency of side-effects in normal dogs receiving human albumin, including immediate and delayed anaphylaxis; therefore this drug should definitely be used with caution, and only when absolutely necessary.

Patients with significant edema/ascites may require chronic diuretic administration to prevent discomfort or life-threatening complications. Furosemide is commonly used because of its wide availability, low cost, and ease of dosing. However spironolactone may actually be preferable because of its potassium-sparing and aldosterone-inhibiting properties, in addition to the anti-proteinuric effects discussed above. Any patient administered diuretics should be closely monitored for dehydration, as patients with glomerular disease are predisposed to development of azotemia through progressive tubular damage; prolonged dehydration may thus cause rapid progression of disease.

Specific therapy for treatment of amyloidosis

A number of drugs have been recommended for dogs with amyloidosis. Colchicine is the drug of choice for treatment of Shar Peis. Although colchicine is known to interfere with the mitotic spindle and inhibits secretion of serum amyloid A in vitro, its effects have not been fully explained. In people predisposed to developing Familial Mediterranean Fever (FMF), an inherited disease that shares many characteristics with renal amyloidosis of Shar Peis, administration of colchicine is highly successful in preventing amyloid deposition. Some people with early renal disease due to FMF may in fact have reduction or resolution of proteinuria after starting colchicine therapy. Although no long-term reports exist on treatment of Shar Peis with amyloidosis, at least two Shar Peis with liver failure secondary to hepatic amyloidosis had long-term survival with colchicine administration. Based on experience in people with FMF, the ability of this drug to prevent amyloid deposition is independent of its success or failure in decreasing the number of fever episodes. Therefore, if given to Shar Peis, owners should continue administration regardless of whether lameness or fever persist. Dogs receiving colchicine may develop dose-related gastrointestinal side effects.

Dimethylsulfoxide (DMSO) has also been advocated for treatment of amyloidosis in people and dogs (80 mg/kg/day divided TID, given as a 10% solution PO or SQ). Although DMSO does cause amyloid fibrils to dissolve in vitro, it is now believed that the beneficial effects may be instead due to the drug's anti-inflammatory effects. Efficacy studies in animals have been conflicting. Most beneficial effects have been documented in experimental non-canine models. Of the few reports of DMSO use in dogs with naturally occurring amyloidosis, one had significant improvement with long-term therapy, two survived for at least 10 months, and nine others had no improvement or DMSO was discontinued soon after initiating therapy due to side-effects. In the first dog, hypoalbuminemia resolved over the course of 12 months; however, two concurrent inflammatory conditions were also successfully treated, making the actual benefit of the DMSO difficult to determine. Unfortunately, this drug can cause local irritation and an unpleasant odor, and administration by owners is difficult. However, because of the lack of alternative drugs for treatment of amyloidosis other than colchicine, DMSO is still occasionally recommended in non-Shar-Pei dogs with amyloidosis, and I will offer it to dedicated or desperate owners.