Improving outcomes with chronic renal disease (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. 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. 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. 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. 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. ACE inhibitors can also be used for hypertension, however blood pressure reduction is usually modest, approximately 5 to 20 mmHg.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. 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. 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.

CRF and diet

Diets have been a mainstay of treating chronic renal failure for decades. There has been considerable research done on trying to ascertain what dietary factors influence renal disease. Restricting dietary protein has been a cornerstone of renal diets. This is based upon the marked exacerbation of signs of uremia associated with feeding high protein diets. It needs to be remembered that certain species, especially cats, are obligate carnivores and require higher protein diets. Significant protein restriction can result in protein-calorie malnutrition. There are many other potential positive effects of renal diets including increased potassium concentrations, decreased phosphate levels, decreased sodium and improved acid-base status.

Scientific publications support the positive effects of dietary management of CRF in dogs and cats with spontaneous renal disease. In one study 50 cats were enrolled. Of these 29 were fed a veterinary renal diet whereas 21 were not because of lack of compliance (by cat or owner). The veterinary diet led to lower phosphate, urea and PTH concentrations as well as more than doubling the lifespan of the patients. A retrospective study compared 175 cats on maintenance diets to 146 cats on various renal diets. Survival time was 7 months for the convential diets and 16 months for the renal diets.14 A randomized clinical trial in dogs showed similar results. Dogs fed a renal diet took longer to develop a uremic crisis, had less azotemia, and had a longer lifespan.

Renal secondary hyperparathyroidism

With renal disease, hyperparathyroidism develops. Initially the kidney is not able to excrete phosphorus which results in increased PTH secretion. PTH decreases reabsorption of phosphate by the kidney. In addition the kidney is responsible for the final step that produces active vitamin D. Since vitamin D levels are low, less calcium is absorbed. Usually vitamin D and calcium have a negative feedback effect on the parathyroid gland. The increase in PTH concentration has several effects. PTH liberates calcium from the bone, however it also liberates more phosphate as well. In humans this is well recognized as metabolic bone disease, a painful and debilitating consequence of chronic renal disease. Increased PTH also leads to mineralization of the kidneys and other soft tissues and plays a role in the progressive renal injury.

There has been much interest in blunting secondary hyperparathyroidism. One approach is to use calcitriol, or active vitamin D. This is meant to provide negative feedback on the parathyroid gland and thereby blunt the spike in PTH concentrations. This can only be done in early renal disease however as it will increase phosphate and calcium concentrations. In many clinical cases phosphate concentrations are too high to allow the safe use of calcitriol without risking increased soft tissue mineralization. The other approach is to feed a diet low in phosphorus. This has resulted in lower phosphate concentrations and a decrease in PTH concentration.

In addition to using diets, aggressive use of phosphate binders can also be beneficial. These substances bind phosphorus in the food so that it will pass through the GI tract without being absorbed. In most instances aluminum salts have been used, though calcium containing products are also available. The predominant drawback to these products is that they reduce the palatability of the diet. In addition, recently aluminum toxicity was reported in 2 dogs on aluminum containing phosphate binders. Recent work with a chitosan and calcium product has shown promise. A significant decrease in phosphate concentration occurred as well as a decrease in urea concentration. This could of course be because of decreased food intake, though in healthy cats given the product food intake remained fairly constant. It may in fact be because chitosan causes reduced ammonia absorption and protein digestibility. Chitosan chewing gum has been found to be effective in reducing phosphorus levels in humans with hyperphosphatemia resistant to diet and oral phosphate binders. In addition recent studies suggest that renal secondary hyperparathyroidism is evident even before phosphorus concentrations rise.

References

Jacob F, Polzin DJ, et al. Association between initial systolic blood pressure and risk of developing a uremic crisis or of dying in dogs with chronic renal failure. JAVMA 2003;222:322-329.

Navar L. Renal autoregulation: perspectives from whole kidney and single nephron studies. Am J Physiol 1978;234: F357-F370.

Brown SA, Finco DR. Navar LG. Impaired renal autoregulatory ability in dogs with reduced renal mass. J Am Soc Nephrol 1995;5:1768-1774.

Syme HM, Barber PJ, Markwell PJ, Elliot J. Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation. JAVMA 2002;220:1799-1804.

Michell AR, Bodey AR, Gleadhill A. Absence of hypertension in dogs with renal insufficiency. Renal Failure 1997;19:61-68.

Cowgill LD. Systemic hypertension in dogs with renal failure. 14th ECVIM Congress, Barcelona, 2004.

Finco DR. Association of systemic hypertension with renal injury in dogs with induced renal failure. JVIM 2004;18:289-294.

Mathur S, Syme H, et al. Effects of the calcium channel antagonist amlodipine in cats with surgically induced hypertensive renal insufficiency. AJVR 2002;63:833-839.

King JN, Strehlau G, Wernsing J, Brown SA. Effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of benazapril in cats. J Vet Pharmacol Therap 2002;25;371-378.

Miller RH, Lehmkuhl LB, et al. Effect of enalapril on blood pressure, renal function, and the renin-angiotensin-aldosterone system in cats with autosomal dominant polycystic kidney disease. AJVR 1999;60:1516-1525.

Brown SA, Brown CA, et al. Effects of the angiotensin converting enzyme inhibitor benazapril in cats with induced renal insufficiency. AJVR 2001;62:375-383.

Brown SA, Finco DR, et al. Evaluation of the effects of inhibition of angiotensin converting enzyme with enalapril in dogs with induced renal insufficiency. AJVR 2003;64:321-327.

Elliott J, Rawlings JM, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Sm Anim Pract 2000;41:235-242.

Plantinga EA, Everts H, et al. Retrospective study of the survival of cats with acquired chronic renal insufficiency offered different commercial diets. Veterinary Record 2005;157:185-187.

Jacob F, Polzin DJ, et al. Clinical evaluation of dietary modification for treatment of spontaneous chronic renal failure in dogs. JAVMA 2002;220:1163-1170.

Wagner E, Schwendenwein I, Zentek J. Effects of a dietary chitosan and calcium supplement on Ca and P metabolism in cats. Berl Münch Tierärzt Wschr 2004;117:310-315.