Managing chronic renal failure: What is clinically relevant? (Proceedings)
Hypertension and CRF
It is known that high blood pressure is associated with renal disease in many species including cats and dogs. That this is important is known from many studies including ones involving dogs. A study from the University of Minnesota looked at 45 dogs with spontaneous renal disease.1 They divided the dogs into a high (systolic 161-201 mmHg) intermediate (144-160 mmHg) and low (107-143) blood pressure group. The dogs were in mild to moderate renal failure (BUN around 70 ± 30 mg/dL or 25 + 11 nmol/L; creatinine 3.5 + 1.5 mg/dL or 300 + 130 μmol/L) and all groups were similar in this manner. The high blood pressure group was more likely to die and took less time to develop a uremic crisis (clinical signs with at least a 20% rise in BUN in comparison to previous visit where signs were absent). In fact the high blood pressure group had half the life expectancy of the other groups (300 vs. 600 days). The dogs in the high blood pressure group were also the only ones to have retinal changes (3 of 14). Some dogs were treated with antihypertensive medications if systolic blood pressure was greater than 180 mmHg two consecutive visits or if retinal lesions were seen. This resulted in 11 dogs being treated (amlodipine, diltiazem, enalapril alone or in combination), though only 1 dog responded.
One reason why hypertension is associated with progressive renal damage is the loss of autoregulatory ability by the diseased kidney. Autoregulation allows the kidney to maintain relatively constant renal blood flow and glomerular filtration rate even if mean arterial pressure varies from 70 to 150 mmHg.2 This is one reason why hypertension alone in animals is unlikely to cause renal problems since autoregulation protects the glomerulus from increased systemic blood pressure. Autoregulation has been shown in various rodent models and has also been clearly demonstrated in dogs. In dogs that underwent partial nephrectomy the ability to autoregulate was severely impaired when a 7/8 nephrectomy was carried out, whereas those dogs with ¾ nephrectomy were less compromised.3 Autoregulation at both low and higher pressures was impaired. This means that dogs with renal failure are more likely to have hypoperfusion of the kidney at mean arterial pressures that are usually considered adequate (loss of autoregulation at 100 mmHg MAP). These dogs also are more likely to also pass on elevated systemic blood pressures to the glomerulus, leading to progressive renal function loss. In the 7/8 nephrectomy dogs GFR increased almost linearly with increased MAP.Based upon the association of hypertension with progressive decline of renal function it is vital that blood pressure be measured routinely and repeatedly on all patients with chronic renal disease. Once blood pressures are elevated (on repeated measurement sessions or if ocular lesions are present) it is imperative that appropriate antihypertensive therapy be instituted. Based upon the scientific literature systolic pressures greater than 160 mmHg and diastolic pressures greater than 100 mmHg in patients with renal disease warrant therapy. This is considered a category with moderate risk of target organ damage as determined by the group of clinicians involved with producing a consensus statement on hypertension for the ACVIM.
The reported percentages of dogs and cats that are hypertensive varies from study to study. Percentages greater than 50% have been reported in some studies. Lower percentages have also been seen, in one study of 103 cats with CRF only 20% were hypertensive at initial presentation.4 Hypertension in this study was defined as a systolic blood pressure >175 mmHg (Doppler determination) with ocular lesions or having this degree of elevation at a subsequent visit. The presence of hypertension did not relate to the severity of azotemia, though it was related to lower potassium concentrations. The hypertensive cats in this study were more likely to have cardiovascular abnormalities (gallops, murmurs, arrhythmias) and 70% of the cats had ocular lesions. Of course this study only looked at blood pressure one time, not repeatedly. It is still unknown what percentage of cats will go on to develop hypertension during the time they are in CRF.
In dogs the situation is confusing. One study showed that few dogs with renal insufficiency or failure were hypertensive. 5 This study however used an upper normal value for systolic of 175 mmHg and for diastolic of 111 mmHg. These values are considered hypertensive by many. At the ECVIM meeting in 2004 a presentation was given that presented data on 519 dogs with renal disease. Of these dogs 60% had a systolic pressure > 150 mmHg and 70% a diastolic pressure > 95 mmHg. 6 Experimental models of renal failure in dogs support the concept that CRF leads to elevations in blood pressure in this species as well and that this elevation correlates with poorer outcome.7 Blood pressures increased around 20 mmHg for MAP, DAP and SAP in the more severely affected dogs, in the less affected dogs it was only approximately a 10 mmHg increase. This translated however to a significantly greater loss of renal function (creatinine around 1/3 higher in these dogs). Dogs with surgery and higher blood pressures also tended to be more proteinuric than the lower pressure groups, though the degree of proteinuria was mild (UP:UC of around 2).
Appropriate management of hypertension depends upon a variety of pharmacologic products. In cats with marked hypertension, amlodipine is the drug of choice. This medication has been shown to be effective in both spontaneous and experimental renal disease. The magnitude of decrease in blood pressure has been shown to be approximately 30 mmHg when given at 0.25 mg/kg in cats.8 ACE inhibitors can also be used for hypertension, however blood pressure reduction is usually modest, approximately 5 to 20 mmHg.9,10 The use of ACE inhibitors is however correlated with improved outcome. In cats with induced renal insufficiency benazapril resulted in higher GFR values and lower blood pressures than cats given placebo.9 This study also demonstrated that there is no need for dosage adjustment with benazapril in renal failure/insufficiency. Benazapril has also been shown to reduce glomerular capillary pressure and systemic blood pressure in cats with induced renal insufficiency.11 In an experimental model in dogs use of an ACE inhibitor also reduced blood pressure mildly and glomerular capillary pressure which should aid in limiting progressive renal injury.12