Proteinuria

Finding isolated proteinuria (i.e., proteinuria which occurs in absence of other signs of inflammation such as hematuria and/or pyuria) gives rise to two important questions: 1) does proteinuria reflect underlying renal disease, and, if so, 2) will the disease eventually cause morbidity or death? Isolated proteinuria does not always indicate renal disease as strenuous exercise, extremes of heat or cold, stress, fever, seizures, or venous congestion have been reported as causes of isolated proteinuria. These causes are termed functional proteinuria. They are characteristically mild and transient, and therefore are considered non-pathologic. Proteinuria may also result from increased plasma concentrations of certain proteins (e.g., hemoglobin, myoglobin, or immunoglobulin light-chain monomers and dimers) which are small enough to pass through the glomerular barrier into urine. Because they overwhelm tubular reabsorptive mechanisms, they are called overload proteinuria. Proteinuria resulting from immunoglobulin fragments should be suspected when protein is detected by turbidometric techniques for urine protein, but not by dipstick methods.

Because transient proteinuria is often of non-renal origin, persistent proteinuria should be confirmed by repeating the urinalysis after several days. If the second urinalysis confirms proteinuria, further diagnostic inquiry is indicated because persistent proteinuria in absence of active urine sediment is almost invariably a sign of renal structural disease even when other aspects of renal function are normal. The amount of protein excreted by such patients is of considerable diagnostic significance. Heavy proteinuria associated with hypoalbuminemia is called the nephrotic syndrome and indicates generalized glomerular disease. Urinary excretion of lesser quantities of protein may indicate either glomerular or non-glomerular renal diseases (proteinuria in non-glomerular diseases may result from glomerular hyperperfusion/hypertension or renal tubular dysfunction in which tubular reabsorption of filtered proteins is impaired). Urine protein: creatinine ratios may provide guidance in differentiating glomerular from non-glomerular disease. Ratios greater than 3.0 suggest (but do not conclusively prove) glomerular disease.

Modifying the Magnitude of Proteinuria

Administration of angiotensin converting enzyme (ACE) inhibitors reduces the magnitude of proteinuria in humans with diabetic nephropathy, primary glomerular disease, and various other renal diseases. Similar observations have been made in dogs and cats with induced and spontaneous kidney diseases. Mechanism(s) by which ACE inhibitors may reduce proteinuria include: 1) reduced glomerular hypertension, 2) reduced glomerular hyperpermeability due to reduced angiotensin II formation, 3) anti-inflammatory effects, or 4) anti-platelet effects. Reduction of systemic blood pressure alone probably does not account for the antiproteinuric effect. Studies have suggested that the antiproteinuric effect of ACE inhibitors is most likely the result of amelioration of intraglomerular hypertension by postglomerular arteriolar vasodilation.

Glomerular proteinuria should be reduced in dogs and cats with CKD stages 1 through 4. Intervention is indicated when the urine protein-to-creatinine ratio (UPC) exceeds 2.0 in dogs and cats with CKD stage 1, and when the UPC exceeds 0.5 in dogs and 0.4 in cats with CKD stages 2 through 4. Proteinuria has been shown to adversely affect outcomes in humans, dogs and cats with CKD, presumably because proteinuria itself appears to injure the renal tubules, thereby promoting progression of CKD. It is well established in human patients that reducing proteinuria by suppressing the renin-angiotensin-aldosterone system ameliorates the adverse effects of proteinuria on the kidneys. Although qualitatively similar, evidence in dogs and cats is far less compelling. Nonetheless, an ACE inhibitor (e.g., enalapril, benazepril, lisinopril) is recommended for CKD patients that meet the above criteria. Ideally, proteinuria should be reduced below the therapeutic target. However, this is typically difficult and may require higher doses of the ACE inhibitor or addition of angiotensin II receptor blocking drugs (e.g., losartan or irbesartan).

Blockade of the renin-angiotensin system limits both angiotensin II and aldosterone while retarding progression of renal disease. Recent studies have implicated aldosterone as an important pathogenic factor in this process. Selective blockade of aldosterone, independent of renin-angiotensin blockade, reduces proteinuria and glomerular lesions in rats with experimental CKD. Where blockade of the renin-angiotensin system ameliorates proteinuria and glomerular injury, selective reinfusion of aldosterone restores proteinuria and glomerular lesions despite continued blockade of the renin-angiotensin system. This observation suggests an independent pathogenic role for aldosterone as a mediator of progressive renal disease. Aldosterone appears to promote progressive renal injury through both hemodynamic effects and direct cellular actions. It appears to have fibrogenic properties in the kidneys, perhaps in part by promoting production of the profibrotic cytokine TGF-β. Experimental studies have shown that the aldosterone-receptor antagonist eplerenone may attenuate proteinuria and renal damage, independent of its effect on blood pressure. While ACEI initially cause an acute reduction in aldosterone concentration, this effect is not sustained. It has been proposed that use of aldosterone-receptor antagonists in addition to ACEI will have additional benefits toward protecting the kidneys. However, the role of this form of therapy has yet to be established. Administration of angiotensin converting enzyme (ACE) inhibitors reduces the magnitude of proteinuria in humans with diabetic nephropathy, primary glomerular disease, and various other renal diseases. Similar observations have been made in dogs with spontaneous glomerulonephritis. Mechanism(s) by which ACE inhibitors may reduce proteinuria include: 1) reduced glomerular hypertension, 2) reduced glomerular hyperpermeability due to reduced angiotensin II formation, 3) anti-inflammatory effects, or 4) anti-platelet effects. Reduction of systemic blood pressure alone probably does not account for the antiproteinuric effect.

Studies have suggested that the antiproteinuric effect of ACE inhibitors is most likely the result of amelioration of intraglomerular hypertension by postglomerular arteriolar vasodilation. Studies have shown that high dietary protein intake may have an adverse effect on the magnitude of proteinuria and hypoalbuminemia in humans. Reducing dietary protein intake in humans with nephrotic syndrome limits proteinuria while stabilizing protein nutrition. We have observed similar effects in some dogs. Changes in the magnitude of albuminuria were detected within 14 days of diet change in humans and dogs. Based on these findings, it is recommended that protein intake should be limited in dogs and cats with moderate to severe proteinuria. However, the response to limiting protein intake should be monitored. If reducing protein intake reduces the magnitude of proteinuria, and does not adversely affect renal function or serum albumin concentration, such therapy should be continued. However, adverse nutritional effects of protein restriction may not become apparent for weeks or months.

Hypertension

Diagnosis of "hypertension" should be based on a series of blood pressure determinations performed during at least 3 different hospital visits. Except when systolic pressures are above 200 mm Hg and/or clear evidence of end-organ injury is present, rapid diagnosis and pharmacological intervention is unnecessary and unwise.

Table 1. Arterial blood pressure (AP) stages for dogs and cats.

Chronic kidney disease is the most common recognized cause for arterial hypertension in dogs and cats. In these species, hypertension has been linked to renal, ocular, neurological and cardiac complications. In dogs with naturally occurring chronic renal insufficiency/failure, higher initial blood pressure has been reported to be a risk factor for uremic crisis and mortality. In addition, retinopathy and hypertensive encephalopathy were detected in 3 of 14 dogs with blood pressure values exceeding 180 mmHg in this study. However, firm evidence that pharmacologically lowering blood pressure will prevent or ameliorate the renal and extrarenal complications of arterial hypertension in dogs is lacking.

Lethargy, blindness, retinal hemorrhage and detachment, cerebral hemorrhage, seizures, stupor, and ventricular hypertrophy have been reported in cats with hypertension. Although it is likely that elevated blood pressure promotes progressive renal injury in cats, the lone study to address this question has failed to confirm this relationship. However, in contrast to dogs, there are studies supporting the value of therapeutic intervention for hypertension in cats. Subcutaneous administration of the antihypertensive drug hydralazine was reported to reduce the prevalence of seizures that developed as a consequence of hypertension following renal transplantation. In a study using a surgically induced model of hypertensive renal insufficiency, only 2 of 10 cats receiving the antihypertensive agent amlodipine developed evidence of hypertensive retinal lesions, whereas these lesions developed in 7 of 10 cats receiving placebo.

Unless there is evidence for hypertension-related organ injury (e.g., retinal lesions or neurological signs) or the systolic blood pressure is greater than 200 mmHg, the decision to initiate anti-hypertensive therapy is not an emergency. Before initiating therapy for arterial hypertension, the patient's blood pressure should generally be established based on blood pressure determinations performed at three successive clinic visits. Every effort should be made to minimize the risk that measured elevations in blood pressure represent a transient "white coat" effect, rather than a sustained elevation in blood pressure.

Patients with CKD and blood pressure values exceeding 160/100 mmHg should be considered for treatment. While specific values for diagnosis of arterial hypertension have not been established for dogs and cats, current evidence suggests that concurrent CKD may place them at increased risk for sustaining additional renal injury or developing complications associated with elevated blood pressure. Findings in two studies suggested that ocular lesions associated with elevated blood pressure occurred in cats with systolic blood pressure values exceeding about 160 mmHg. Similarly, in study in dogs with naturally occurring chronic renal insufficiency/failure, the risk for uremic crises and increased mortality was reported to be increased in a group of dogs with systolic blood pressure values above 160 mmHg. However, this cut-off point was arbitrarily chosen in this study and should not be interpreted as the lower limit of hypertension.

The optimum endpoint for antihypertensive therapy has not been established for dogs and cats with CKD. In the absence of such information, treatment for arterial hypertension should be initiated cautiously with the goal of reducing blood pressure to at least below 160/100 mm Hg. Except in patients with acute, severe ocular or neurological lesions, rapid reduction in blood pressure is not necessary. Particularly in dogs, it may take weeks to months to achieve satisfactory blood pressure control.

Angiotensin converting enzyme inhibitors (ACEI) such as enalapril and benazepril, and calcium channel blocking (CCB) drugs such as amlodipine have potential renoprotective benefits and are therefore appropriate options for renal patients with hypertension. Angiotensin converting enzyme inhibitors generally produce a relatively small reduction in blood pressure. However, because of their beneficial role in altering intraglomerular hemodynamics, proteinuria, and the profibrotic effects of the intrarenal renin-angiotensin system, ACEI may have renoprotective effects even in absence achieving adequate blood pressure control. In a recent study, the ACEI enalapril reduced the severity of renal lesions that develop in dogs with surgically reduced renal mass. Further, in dogs with naturally occurring glomerulopathies, the ACEI enalapril significantly reduced proteinuria and may have been beneficial in stabilizing renal function. On this basis, they appear to be the preferred antihypertensive agent for dogs with CKD. However, the role of the renin-angiotensin-aldosterone system (RAAS) and ACEI therapy in cats with CKD and hypertension is more controversial. Evidence that activation of the RAAS is consistently central to the genesis of hypertension in cats is contradictory, and ACEI have not been found to be consistently effective in lowering blood pressure in cats with CKD. Therapy using either benazepril or enalapril may be initiated in dogs or cats with CKD at a dose of 0.25 to 0.5 mg/kg given orally every 12-24 hours.

Calcium channel blockers preferentially antagonize preglomerular vasoconstriction, which theoretically, should not reduce glomerular hypertension. However, CCB have additional renoprotective properties. They may prevent renal injury by limiting renal growth, by reducing mesangial entrapment of macromolecules, and by attenuating the mitogenic effects of diverse cytokines and growth factors (e.g., platelet-derived growth factor and platelet-activating factor). In addition, amlodipine inhibits the in vitro proliferation of mesangial cells. However, clinical trials in humans have provided conflicting results as to the renoprotective effect of CCB beyond their antihypertensive effects. Controlled studies on the renoprotective effects of amlodipine in dogs and cats have not been published. However, our clinical experience has been that they are effective antihypertensive agents in dogs and cats with CKD. Further, their use in cats has been associated with a reduction in proteinuria. Because it is usually highly effective, has few side-effects, and has a relative rapid onset, the long-acting dihydropyridine calcium antagonist amlodipine is the antihypertensive of choice for most cats with CKD. Amlodipine is prescribed at a dose of 0.625 mg for cats less than 4 kg, and 1.25 mg for cats greater than 4 kg. In cats with CKD, amlodipine typically reduces systolic blood pressure by about 30 to 50 mmHg within the first one to two months of therapy. Dosage may be doubled if needed. In dogs, we generally employ amlodipine in the dose range of 0.1 to 0.5 mg/kg given every 24 hours, most often combined with and ACE inhibitor.