(This page is still under construction; Please see qualifier statement)
Recent data in the veterinary and human literature concur regarding the beneficial effects of Angiotensinogen Converting Enzyme (ACE) inhibitors in the management of various stages of renal disease and renal failure. ACE inhibitors, such as enalapril, benazepril, linisopril...and others...are readily employed adjuncts in the management of some cardiomyopathies and congestive heart failure. These indications are independent of that which is to be discussed here for slowing the progression of renal disease and putting off the onset of renal failure. References for portions of this discussion can be found in the Veterinary Forum 12/20/97; Compendium for Continuing Education , 18: pp279, March, 1996; Clinics of North America, (Small Animal), November, 1996; and Hospital Medicine 33: pp11, 1997. A partially altered text version of the latter, which discusses this subject in humans, is available here. The ensuing discussion represents the opinion of the author only. Diagnostic and treatment options for veterinary patients remain solely the responsibility of the attending veterinarian.
Before proceding with the topic at hand, it is important to state the obvious: Early recognition of occult renal disease will, most likely, result in the most favorable long-term clinical outcome via pre-emptive life-style/medical/pharmocological intervention. It is important to realize that in most instances, this is NOT achievable via the routine laboratory screenings...blood work and urinalysis. Dilute urine and/or azotemia resulting from reduced renal functionality are not apparent until 2/3 to 3/4 of kidney function is affected, respectively. By the time such laboratory abberations are noted, much damage has already transpired. The key is to rethink our approach. Raise the index of suspicion based upon signalment (e.g. middle age or geriatric kitty), history...especially of chronic inflammation/infection (e.g. dental-periodontal disease, recurrent urinary tract inflammation-infection, skin or other sources of chronic inflammation), the physical exam..and the "intuitive-gut feeling" based upon the experiences of you, the veterinarian.
|How Do You Determine Whether There is Occult Disease?|
This publication will not focus upon the special laboratory methodolgy required to form a diagnosis of occult renal disease...though that may come in the future. However the following guidelines and suggested screening tests may provide the framework for the veterinarian-detective to begin the investigation:
|The Kidney "Compensates" for Existing Disease and Creates More...in the Process|
Following early injury and loss of functionality of a portion of the kidney, there is an "adaptive" response by healthy portions of the kidney to "take up the slack" created by loss of some nephrons. In this process, there is early stimulation of the RAAS system which in turn, causes local afferent arteriolar dilation, efferent vasoconstriction, & increases in blood volume (via aldosterone stimulation). While all this results in increased glomerular perfusion (due in part to efferent arteriolar vasoconstiction, increased local hydrostatic pressure), and thus enhanced filtration by remaining functional nephrons. ............ this scenario is not all roses! A major side affect of the RAAS induction cycle is glomerular hypertension ; glomerular hypertension further damages remaining functional renal tissues, causing dramatic inflammation, sclerosis and scarring...:so now, the "adapted glomerulus" is also irreversibly injured and ultimately, relegated to the classification of "non-functional". Prior to full loss of glomerular function, the increase in local filtration heightens demand on tubules, causing injury and inflammation and loss of structural integrity that encompasses adjacent interstitium as well. The net effect is to negatively impact the functionality of the secretory/ collecting systems. Hence, glomeruli, tubules and collecting system structures and function are, ultimately, lost yet "adapation" continues unabated:........the cycle repeats.......
|Renal Injury ( See KIDNEY DISEASE on this web site)|
|Temporary Space Reserved for Diagramatic Illustration of Progressive Renal Damage mediated by Renin-Angiotensin-Activating System (RAAS) and Secondary Systemic Effects of Pregressive Renal Disease. Diagram 1 Construction in Progress!|
Diagram 1: Legend:
|Decrease in Overall Kidney Function.....then...|
|Adaptive Response...Activation of RAAS|
|Worsening of Renal Damage, Progressive Loss of Renal Function|
|Secondary Systemic: damage to heart, muscle, marrow,and kidney|
As mentioned earlier...and re-emphasized here...early detection of ongoing renal deterioration is most likely to result in best long term clinical outcome. Traditional "BUNs, Creatinines..." tests will NOT reveal early renal disease. A strong index of suspicion based on physical exam, various laboratory tests, signalment and "gut experience" of the veterinarian is required .
Identify Underlying Diseases that Predispose to Renal Deterioration: DO AN ANTIGEN SEARCH if signs of Occult Renal Disease is apparent based upon laboratory tests recommended above (certainly, only a short list is given here...). Rule out concurrent cardiovascular disease and hypertension as well. Consider also that there is,already occult renal disease if a predisposing condition is identified
Dietary Modification It is clear that phosphorus restriction is beneficial in the treatment of canine renal disease via decreasing stimulus for PTH (which is, in itself harmful to kidney and to non-kidney tissue!) and decreasing the probabilties of inappropriate soft-tissue mineralization.. Thus, if during your testing for occult renal disease you find elevation of iPTH (and you have ruled out primary hyperparathyroidism), and/or serum phosphorus is already elevated (and no other etiology for this is evident)...then you have occult renal disease and PHOSPHORUS RESTRICTION IS APPROPRIATE. In the presence of occult renal deterioration...even if there is not frank failure, there are those who still recommend phosphorus restriction to about 0.9% to 1.5% on a dry weight basis
Protein Restriction is canine patients with occult renal disease (or even renal failure) appears to be a debatable issue. The benefits are not clear. If there is concurrent proteinuria, it may be advisable to not restrict dietary protein (certainly not less than 2.5-4 gm/kg/day) . However, interestingly, increasing dietary protein levels to compensate for renal protein losses may backfire, as marked elevations in protein levels in food are associated with acceleration of glomerular damage in some animals, thus actually worsening proteinuria.. It thus appears that moderate levels of very high quality, highly digestible protein is appropriate
Treat Renal Secondary Hyperparathyroidism: If Renal Secondary Hyperparathyroidism ( demonstrated via increased iPTH that is NOT associated with primary hyperparathyroidism and increased urinary phosphorus clearance), then consider treatment to prevent damage to kidney and non-kidney tissues that occurs with prolongued elevations in blood parathyroid hormone (A nice discussion of Calcitriol in the treatmentof renal secondary hyperparathyroidism is found in Clinics of North America, Small Animals, November, 1996; and Current Veterinary Therapy, volume X).
Angiotensin-Converting Enzyme-Inhibitors (ACE-Inhibitors): There is now considerable evidence in human and veterinary literature that ACE-inhibitor therapy instituted during the occult phase of renal disease will slow progression and complications of renal damage. The exact mechanismis unclear but is apparently not be related to its local and systemic anti-hypertensive properties. The postulated mechanism(s) are vaguely related to dilatory effects on glomerular efferent arterioles, the concommitant reduction of intraglomerular pressure and decreased damage from hyperfiltration. These drug, by mechanisms not yet appreciated, restore glomerular permiselectivity and significantly reduce renal protein losses. Heretofore in veterinary medicine, this class of medication has been largely employed in the medical management of cardiomyopathies and/or congestive heart failure. Some have used these drugs to manage hypertension, (though, other vaso-active medications e.g. the vaso-specific calcium channel blockers such as amlodipine, are gaining more favor. This issue is addressed elsewhere on this web).
When using ACE inhibitors, remember that it is possible to negatively effect glomerular filtration (...azotemia...) via reduction in glomerular hydrostatic pressure which results from efferent arteriolar vasodilation. Thus, to this author a steady tendency towards elevation of BUN or creatinine after instituting treatment (even if BUN and Creatinine are in still in the normal range) should alert the clinician to consider a dose adjustment (lower). Ironically, overzealous therapy for occult renal disease could hasten development of overt renal failure!
This author plans to update and expand upon particular aspects of the above discussion. Previous publication schedules have been disappointing and in the interest of providing at least some information, this unfinished work is presented along with an adulterated version of a published discussion of this subject, but with reference to human beings.
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