Background

Systemic hypertension is a frequently encountered clinical problem in cats with chronic kidney disease (CKD). Unfortunately, hypertension is most often diagnosed when a patient has developed signs of severe end-organ damage, most often blindness, as a consequence. However, improved monitoring of patients at high risk of systemic hypertension, such as those with CKD or hyperthyroidism, as well as apparently healthy geriatric cats is now resulting in the diagnosis of this problem before clinical signs develop. When cats are diagnosed with systemic hypertension treatment with the calcium-channel blocker amlodipine (at a dose of 0.625 mg to 1.25 mg once daily) is very effective at reducing blood pressure to a level at which further ocular damage is unlikely to occur.

In dogs, clinical decision making regarding management of systemic hypertension is more complicated. Although dogs with CKD may be hypertensive few of them develop ocular lesions. This makes the differentiation of truly hypertensive dogs from those with white-coat hypertension difficult and without definitive evidence of end-organ damage it is difficult to decide at what blood pressure it is appropriate to institute anti-hypertensive therapy. Additionally, in dogs hypertension tends to be very difficult to control, often requiring that multiple drugs are given and even then the change in blood pressure is often less than optimal.

Hypertensive Nephropathy in Humans

In humans, systemic hypertension is considered to be a major cause of kidney disease, second only to diabetes mellitus. Blood pressure is also known to be an important determinant of the rate of decline in renal function that occurs in people with chronic kidney disease. In a seminal study, patients with CKD were randomised to either have their blood pressure targeted at a conventional or a lower-than-normal level, and it was found that the patients with the lower-than-normal target for blood pressure had a slower rate of decline in GFR over the period of follow up.¹ However, the magnitude of response to the lower-than-normal blood pressure target was dependent on how proteinuric the patients were; for those that were non-proteinuric there was almost no benefit to the lower-than-normal blood pressure target, whereas for the patients with significant proteinuria the benefits to being in this group were marked.

Mechanisms of Hypertensive Renal Injury

Two pathophysiological mechanisms of renal injury have been described and confusingly they seem to be almost the opposite of one another. The first proposed mechanism is that of glomerular hypertension. It is proposed that as a response to renal injury the remaining nephrons undergo vasodilation of pre-glomerular arterioles resulting in an increase in renal blood flow and glomerular filtration. This effect may be augmented by the actions of angiotensin II in causing constriction of the post-glomerular arterioles, so further increasing glomerular pressures and the resulting hyperfiltration. The second proposed mechanism is that of glomerular ischemia. This may occur as a consequence of chronic hypertension causing narrowing of pre-glomerular arteries and arterioles with a consequent reduction in glomerular blood flow. Although seemingly contradictory these mechanisms are not mutually exclusive and may operate simultaneously in the same kidney.

Hypertension as a Cause of Renal Injury in Dogs and Cats

Experimental models of renal injury (surgical reduction in renal mass) in the dog and cat result in an increase in glomerular capillary pressure, measured by micropuncture techniques, consistent with the hyperfiltration mechanism of renal injury described above.^2,3 Development of hyperfiltration was associated with an increase in protein excretion. Chronic maintenance of this model is associated with development of interstitial fibrosis, moderate inflammatory infiltrate of the interstitium and glomerulosclerosis. What evidence do we have that similar changes occur in dogs and cats with spontaneous, naturally occurring, renal disease?

In a cross-sectional epidemiological study of 94 cats at initial diagnosis of their chronic kidney disease and 42 non-azotemic aged cats, cats with hypertension were significantly more proteinuric than cats with normal blood pressure but similar levels of renal function (see Figure 1).⁴ Similarly, in dogs with naturally occurring CKD, it has also been noted that patients with the highest blood pressure tend to be the most proteinuric (see Table 1).^5,6

The increased proteinuria in hypertensive dogs and cats could be due to an inability of the failing kidney to autoregulate renal blood flow appropriately, with resultant transmission of the elevated systemic blood pressure to the glomerulus. These observations provide circumstantial evidence to support the hypothesis that patients with naturally occurring chronic kidney disease develop proteinuria due to development of glomerular hypertension, since hyperfiltration would be expected to be more severe in individuals with fewer functioning nephrons, and consequently, more marked elevation of plasma creatinine concentration. However, an alternative explanation is that proteinuric renal diseases are more likely to cause systemic hypertension.

Figure 1. Urine protein-to-creatinine ratio (UPC) in cats with normal renal function or mild, moderate or severe renal failure (RF) and either normal blood pressure or systemic hypertension. i-HT, idiopathic hypertension.

Table 1. Blood pressure and UPC measurements for 45 dogs with azotemic CKD, followed from recruitment to the study until death. Data from Jacob et al. (2005).⁵

Survival Studies in Hypertensive Dogs and Cats

The cats included in the cross-sectional epidemiological study referred to in Figure 1 above were also enrolled in a longitudinal study of survival time.⁴ Cox's proportional hazards model was used to determine the influence of age, gender, plasma creatinine concentration, systolic arterial blood pressure and UPC ratio on survival time. Proteinuria proved to be significantly and independently associated with survival as were age and plasma creatinine concentration. No association was found between systolic blood pressure and survival. However, in spite of this lack of association it is difficult to conclude that blood pressure has no effect on the progression of kidney disease because the hypertensive cats were treated with amlodipine so most of them had normal blood pressure over the period of follow up. Obviously, ethically, it would not be acceptable to have not treated the cats with anti-hypertensive therapy. To overcome this difficulty a second study was performed looking at the survival of cats that had been diagnosed with systemic hypertension and then treated with amlodipine.⁷ During follow-up their blood pressure was measured repeatedly and a 'time-averaged' value calculated; the cats were then grouped into quartiles according to how well their blood pressure had been controlled with treatment. Neither 'time-averaged' nor 'initial' blood pressure was associated with survival. However, these results do not necessarily mean that blood pressure is not important in the initiation or progression of CKD in the cat. This is because the factor that is associated with survival is proteinuria, and proteinuria, in turn, is related to blood pressure. One interesting observation is that the cats with the highest time-averaged blood pressure had the greatest proteinuria. In other words, to some extent, proteinuria predicted a poor subsequent response to anti-hypertensive therapy and that this was associated with decreased survival time.

In dogs with CKD, blood pressure has been associated with survival time.⁵ However, just like the situation in the cat, the inter-relation between blood pressure and survival is complicated by the fact that the most hypertensive patients are also the most proteinuric (see Table 1). It is possible that in dogs the association between blood pressure and survival time will be more marked than in the cat, because none of the anti-hypertensive treatments used in this species have proven to be very effective.

Effect of Anti-Hypertensive Treatment on Proteinuria

Different anti-hypertensive treatments may have variable effects on intra-glomerular pressure due to differences in their predominant sites of action (afferent and/or efferent arteriole) in the kidney, as well as the magnitude of their effect on systemic blood pressure. Theoretically, since ACE-inhibitors cause preferential dilation of the efferent arteriole (through blocking the production of angiotensin II), they will have more effect in reducing glomerular hypertension and proteinuria than some other classes of drug. Certainly, the use of ACE-inhibitors in dogs and cats with CKD has been associated with a reduction in proteinuria.⁸ Disappointingly, however, this has not been associated with an improvement in survival time in cats although a benefit was seen in dogs with glomerular disease. However, although treatment with calcium channel blockers, such as amlodipine, might be expected to worsen glomerular hypertension (and consequently proteinuria) because they cause dilation of the afferent arteriole, this is not seen in practice when these drugs are used to treat cats with systemic hypertension. In fact, proteinuria decreases.⁷ This is presumed to be because of the very marked reduction in blood pressure that occurs when these drugs are given to hypertensive cats.

References

1.  Peterson JC, Adler S, Burkart JM, et al. (1995). Ann Intern Med 123(10):754-62.

2.  Brown SA, Finco DR, Crowell WA, et al. (1990) Am J Physiol 258: F495-503.

3.  Brown SA, Brown CA (1995) Am J Physiol 269: R1002-R1008.

4.  Syme HM, Markwell PJ, Pfeiffer D, Elliott J (2006). J Vet Intern Med 20(3):528-35.

5.  Jacob F, Polzin DJ, Osborne CA, et al. (2005) J Am Vet Med Assoc 226(3):393-400.

6.  Wehner A, Hartmann K, Hirschberger J (2008). Vet Rec 162(5):141-7.

7.  Jepson RE, Elliott J, Brodbelt D, Syme HM (2007). J Vet Intern Med 21(3):402-9.

8.  King JN, Gunn-Moore DA, Tasker S, et al. (2006). J Vet Intern Med 20(5):1054-64.