Page 52 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

Applied Renal Physiology 41

Absolute or relative deficiency of EPO is the primary chloride to the macula densa, which inhibits renin release.
cause of the anemia of chronic renal failure. 28 Recombi- The release of renin is inhibited by a direct effect of angio-
nant human EPO has been used successfully to correct tensin II on the granular cells, which constitutes a nega-
the anemia of chronic renal failure in human patients. 14 tive feedback loop.
Although initially effective in correcting the anemia of Renin converts the a 2 -globulin angiotensinogen
renal failure in dogs and cats, use of recombinant human (which is synthesized and released by the liver) to angio-
EPO is associated with antibody formation in up to 50% tensin I, and this is the rate-limiting step of the RAS cas-
of treated dogs and cats after 1 to 3 months of treat- cade. Angiotensin-converting enzyme is found in vascular
ment. 11 The resulting anemia can be more severe than endothelium and cleaves the carboxyl-terminal (C-termi-
that present before treatment because the induced nal) two amino acids from the inactive decapeptide angio-
antibodies can cross-react with the animal’s native tensin I to yield the active octapeptide angiotensin II.
EPO. The canine EPO gene has been isolated, 34 and This step in the RAS cascade is not rate limiting, and most
recombinant canine EPO has been used to stimulate of the angiotensin I is rapidly converted to angiotensin II.
erythropoiesis in normal dogs 42 and in those with natu- The effects of angiotensin II restore ECFV. Angiotensin
rally occurring chronic renal failure. 41 It is not as effective II causes arteriolar vasoconstriction in many organs (renal,
when used in dogs that have developed red cell aplasia splanchnic, and cutaneous vascular beds are most sensi-
from previous treatment with recombinant human tive), which increases systemic blood pressure. It enhances
EPO. Recombinant feline EPO also has been synthesized the sensitivity of vascular smooth muscle to and facilitates
and used effectively to treat cats with anemia of chronic the release of norepinephrine from the adrenal medulla
renal failure. 40 Unexpectedly, some cats that initially and sympathetic nerve terminals, thus secondarily affecting
responded to recombinant feline EPO later developed systemic blood pressure. Angiotensin II causes increased
anemia that was refractory to additional treatment with proximal tubular reabsorption of sodium by stimulating
þ
recombinant feline EPO. the Na -H antiporter in luminal membranes of proximal
þ
tubular cells. It causes increased secretion of aldosterone
RENIN-ANGIOTENSIN SYSTEM from the zona glomerulosa of the adrenal cortex, and
The main role of the renin-angiotensin system (RAS) is aldosterone in turn causes increased reabsorption of
defense of the ECFV via sodium homeostasis. The role sodium chloride in the cortical collecting duct. Lastly,
of the kidneys in maintenance of sodium balance is angiotensin II causes alterations in glomerular and
discussed further in Chapter 3. postglomerular hemodynamics that enhance sodium and
Renin is an enzyme synthesized and stored in the gran- water reabsorption. Angiotensin II causes constriction of
ular cells of the JGA (specialized smooth muscle cells in the efferent and afferent arterioles, an effect thought to
the afferent arterioles). The kidneys are the most impor- be mediated by thromboxane A 2 . The efferent arteriole
tant source of renin, but renin is also found in many other constricts more than the afferent so that the FF increases
tissues (e.g., vascular endothelium, adrenal gland, and (i.e., RPF decreases more than GFR). Renal hemodynamic
brain). Local production of angiotensin II in some tissues changes favoring salt and water reabsorption occur in the
may be important in the regulation of local processes postglomerular capillary beds secondary to these glomer-
without having a systemic effect. The RAS of the brain ular hemodynamic changes. These changes include
may be involved in control of systemic blood pressure, decreased peritubular capillary hydrostatic pressure and
secretion of ADH, catecholamine release, and thirst. increased peritubular capillary oncotic pressure. Angioten-
There are three major stimuli for renin release. sin II can cause glomerular mesangial cells to contract,
Decreased renal perfusion pressure caused by systemic potentially reducing the surface area for filtration and
hypotension (pressure below 80 to 90 mm Hg) or ECFV decreasing the ultrafiltration coefficient, K f .Angiotensin
depletion is sensed in the afferent arterioles by the II stimulates release of vasodilator prostaglandins (e.g.,
granular cells, which increase their secretion of renin. PGE 2 and PGI 2 ) from glomeruli. By this mechanism,
Stimulation of cardiac and arterial baroreceptors by the potentially harmful vasoconstrictive effects of angio-
systemic hypotension leads to increased sympathetic tensin II on the kidneys are minimized.
neural activity and increased concentrations of circulating
catecholamines, which in turn stimulate renin release via ACTIVATION OF VITAMIN D
b 1 -adrenergic receptors on granular cells. Lastly, changes Vitamin D 3 (cholecalciferol) is obtained in the diet or by
in distal tubular flow and delivery of chloride affect renin ultraviolet irradiation of the compound 7-dehydrocho-
release. Decreased ECFV or chronic NaCl depletion lesterol in the skin. The liver hydroxylates cholecalciferol
decreases distal tubular flow and delivery of chloride to to 25-hydroxycholecalciferol, which is the predominant
the macula densa (partly as a consequence of enhanced form of vitamin D 3 in plasma. In the kidneys, 25-
proximal reabsorption of water and NaCl), which in turn hydroxycholecalciferol is converted to the active form of
stimulates renin release. Expansion of the ECFV or NaCl vitamin D 3 , 1,25-dihydroxycholecalciferol (calcitriol), by
loading increases distal tubular flow and delivery of the enzyme 25-hydroxycholecalciferol-1a-hydroxylase,