Diagnosis, management of hypertension, proteinuria in dogs with chronic kidney disease

By altering pre-glomerular resistance, healthy kidneys can maintain relatively stable glomerular capillary pressures despite variations in systemic blood pressure. This process is termed "renal autoregulation."

Autoregulation can be reduced when renal disease results in loss of nephrons. Compromised autoregulation allows high systemic blood pressure to be transmitted to glomerular capillaries. This glomerular hypertension has been documented by micropuncture studies in dogs with surgically reduced renal mass. In these models, glomerular hypertension was associated with systemic hypertension, proteinuria and tubulointerstitial lesions.

Systemic hypertension is relatively common in dogs with chronic kidney disease (CKD); systemic hypertension has been observed in as many as two-thirds of cases. In a recent study of client-owned dogs with naturally-occurring CKD, 29/45 (64 percent) had systolic blood pressure > 144 mm Hg and 14/45 (31 percent) had systolic blood pressure > 161 mm Hg (Jacob, JAVMA 222:322-329, 2003).

Glomerular proteinuria can result from immune-mediated disease, amyloidosis or structural abnormalities involving the glomerular capillary wall. Proteinuria associated with CKD often is accompanied by systemic hypertension. Protein leakage through the glomerular capillary wall also can arise as a consequence of intraglomerular hypertension.

Finally, proteinuria can occur as a result of tubulointerstitial disease that compromises reabsorption of protein from the glomerular filtrate. Whether caused by capillary wall lesions, intraglomerular hypertension or tubulointerstitial lesions, excessive quantities of protein in the glomerular filtrate may cause additional glomerular lesions as well as downstream tubulointerstitial lesions; both of which can lead to loss of more nephrons.

Hypertension

Systemic hypertension in dogs has largely been thought to be secondary to another disease, as opposed to idiopathic (primary or essential). Described and potential etiologies of secondary hypertension include acute and chronic kidney disease, hypothyroidism, hyperadreno-corticism, hyperaldosteronism, pheochromocytoma, diabetes melli-tus and obesity.

Of these conditions, CKD has the greatest association with systemic hypertension.

Systemic hypertension may contribute to progressive nephron loss by causing irreversible glomerular damage via increased intraglomerular pressures and glomerulosclerosis. In dogs with CKD, autoregulation is impaired and inappropriate dilation of the afferent glomerular arteriole occurs, which diminishes its ability to protect the glomerulus from variations in systemic blood pressure.

Although the exact mechanism of the CKD-associated hypertension is not known, a combination of glomerular capillary and arteriolar scarring, decreased production of renal vasodilatory prostaglandins, increased responsiveness to normal pressor mechanisms, and activation of the renin-angiotensin system secondary to impaired sodium excretion and excessive renin secretion may be involved.

The increased renin secretion leads to increased production of angiotensin II and aldosterone. In addition to its pressor effects, angiotensin II has a direct stimulatory effect on the sympathetic nervous system, increasing vascular tone, and resulting in CKD vasoconstriction of the efferent arteriole, which further contributes to the intraglomerular hypertension. Angiotensin and aldosterone also may cause tissue remodeling and fibrosis of the kidneys.

The consequences of systemic hypertension are usually dependent on the magnitude and duration of the blood pressure elevations. Acute ocular and central nervous system abnormalities can occur associated with hemorrhage or edema formation. Renal damage associated with hypertension tends to be more chronic and characterized by glomerular lesions (e.g., glomerulosclerosis) and proteinuria. Finally, functional/adaptive changes like ventricular hypertrophy can occur due to increased after-load in patients with hypertension. Diagnosis and treatment of hypertension in dogs with CKD may prevent development of retinal lesions or may limit or slow progression of renal and cardiac lesions.

Proteinuria

In addition to being a diagnostic marker of the severity of renal disease, renal proteinuria may be a mediator of glomerular and tubular injury. Recent findings have demonstrated that proteinuria is associated with increased risk of developing progressive CKD in dogs.

In addition, studies have shown that therapies that reduce the magnitude of proteinuria often are renoprotective. Proteinuric renal disease is often associated with systemic hypertension, which can conversely exacerbate renal proteinuria and therefore, it is difficult at times to separate the effects of high systemic and intraglomerular pressures and proteinuria.

Diagnosis of hypertension and proteinuria

Current recommendations are that blood pressure be measured in a quiet area prior to performing a physical examination on the patient, typically after a five- to 10-minute period of acclimation to the hospital setting. The ACVIM Panel on Hypertension suggests discarding the first measurement, then obtaining a minimum of three, preferably five to seven, consecutive measurements with less than 10 percent to 20 percent variability in systolic blood pressure. The animal's disposition, cuff size, measurement site, as well as all measured values, should be entered in the medical record. Many suggest that hypertension be documented on more than one occasion before accepting the diagnosis.

Diagnosis and management of proteinuria in dogs with CKD should be accomplished in a step-wise fashion.

The specificity of the dipstick screening test for proteinuria is poor, and therefore confirmation of traditional dipstick-positive proteinuria should be accomplished with a more specific follow-up test, such as the sulfo-salicylic acid (SSA) turbidimetric test, urine protein/creatinine ratio (UP/C) or species-specific albuminuria assay (e.g., quantitative ELISA or ERD® test).

The second step in assessment of proteinuria is to determine its origin. Proteinuria of renal origin can adversely affect the prognosis of dogs with CKD and, therefore, physiologic or benign proteinuria and pre- and post-renal proteinuria should be ruled out. Subsequently, via serial monitoring, it should be determined if the proteinuria is persistent or transient and, if persistent, is the magnitude stable, increasing, or decreasing over time?

Persistent proteinuria is defined as at least two positive tests at two-week intervals. Renal proteinuria is persistent and most commonly associated with a normal urine sediment (although hyaline casts may be observed).

Renal proteinuria in dogs with CKD appears to be a negative predictor of survival. For example, in 45 client-owned dogs with spontaneous CKD, the relative risk of uremic crises and mortality was approximately three times higher in dogs with UP/C > 1.0 (n=25) compared with dogs with UP/C < 1.0 (n=20).

In addition, the risk of adverse outcomes was approximately 1.5 times greater for every one-unit increase in UP/C ratio. The decline in renal function, as measured by serum creatinine concentration, also was greater in dogs with higher UP/C ratios (Jacob, Am J Vet Res 226:393-400, 2005).

Management

Gradual reduction of dietary salt often is recommended as the first line of treatment for hypertension. Renal failure diets have reduced sodium content; however, there are no studies that document the efficacy of this treatment.

In many cases, vasodilators are necessary to control systemic hypertension. Initial treatment with an angiotensin-converting enzyme inhibitor (ACEI) is appropriate in dogs with CKD because of the beneficial effects on intraglomerular pressure and proteinuria.

In those cases where systemic hypertension persists after initiation of ACEI treatment, or is initially > 180 mm Hg, a calcium-channel antagonist (CCA) can be added. The overall risk of target organ damage to the eyes, brain, heart and kidneys is thought to be minimal if systolic blood pressure is maintained at <150 mm Hg.

Direct-acting vasodilator drugs like ACEI and CCA are the most successful in achieving acute reduction of blood pressure, but sympathetic nervous system-mediated increases in heart rate and aldosterone-mediated sodium and water retention may modulate the effects of the vasodilation over time.

Combining antihypertensive treatments with different modes of action may block the compensatory effects caused by one medication when used alone. For example, diuretics, aldosterone antagonists and beta-blockers, which may have minimal antihypertensive effect alone, may produce additive effects when given in combination with ACEI or CCA.

A UP/C > 0.5 in azotemic dogs or a UP/C > 1.0 in non-azotemic dogs should be treated with an ACEI and/or dietary protein reduction. A follow-up UP/C test should be performed in 30 days.

A positive response to treatment is a 50 percent reduction in the baseline UP/C. If after 30 days there is a less than 50 percent decrease in the UP/C, the dose of the ACEI can be increased.

Clinical trials have demonstrated the utility of ACEI and/or dietary treatment in dogs and found that benefits of treating with this combination have included decreased proteinuria, lowered systolic blood pressure, improved renal excretory function, decreased glomerular basement membrane splitting, improved outcome and prolonged survival.

(Effects of enalapril vs. placebo as a treatment for canine idiopathic glomerulonephritis, Grauer, J Vet Intern Med 14:526-533, 2000) (Treatment of X-linked hereditary nephritis in Samoyed dogs with angiotensin-converting enzyme inhibitor, Grodecki, J Comp Pathol 117, 209-225, 1997).