Page 749 - Small Animal Clinical Nutrition 5th Edition

Chronic Kidney Disease 777

more phosphate is excreted and serum phosphorus concentra-
VetBooks.ir tion is maintained within the normal range. However, as CKD
progresses and more nephrons become nonfunctional, a greater
concentration of PTH is required to maintain serum phospho-
rus concentration and eventually hyperphosphatemia develops.
The primary consequence of hyperphosphatemia is develop-
ment and progression of hyperparathyroidism. Although hy-
perparathyroidism helps maintain serum phosphorus concen-
trations initially, it has other effects that may be harmful. PTH
stimulates resorption and release of minerals (e.g., phosphate)
from bone, which increases the amount of phosphate that
remaining nephrons must excrete. Increased PTH concentra-
tion correlates with histologic evidence of renal tissue inflam-
mation and mineralization; therefore, hyperparathyroidism
may damage the kidneys (Finco et al, 1992, 1992a; Ross et al,
1982; Brown et al, 1991).

Chronic Renal Hypoxia
The kidney has a very high rate of oxygen consumption, the
majority of which is expended reabsorbing sodium. With kid-
ney damage, surviving nephrons increase sodium resorption
and correspondingly increase oxygen consumption. The renal
medulla concentrates urine by means of the countercurrent sys-
tem of blood vessels and tubules that actively absorb sodium.
The major determinant of medullary oxygen demand is the rate
of active absorption in the medullary thick ascending loop,
which is a relatively hypoxic environment. Hypoxia of the renal
medulla can predispose to acute and chronic renal injury
Figure 37-5. Relationship of serum parathyroid hormone concentra-
because the kidneys are extremely susceptible to hypoxic injury tions to serum creatinine concentrations in 35 normal dogs and 333
(O’Connor,2006; Eckardt et al,2005; Brezia and Rosen,1995). dogs with uremia. (Adapted from Nagode LA, Chew DJ.
In CKD, increased fibrosis in the kidneys may result from Nephrocalcinosis caused by hyperparathyroidism in progression of
intrarenal hypoxia due to increased oxygen consumption by renal failure: Treatment with calcitriol. Seminars in Veterinary
Medicine and Surgery: Small Animal 1992; 7: 206.)
surviving nephrons. Acute kidney injury often is associated
with altered intrarenal microcirculation and oxygenation (Ro-
senberger et al, 2006). Hypoxia deprives tissues of energy and
induces various regulatory mechanisms. The transcription fac-
tor, hypoxia-inducible factor, is involved in cellular regulation of
development of new blood vessels, blood vessel tone, glucose
metabolism and cell death. Kidney disease activates hypoxia-
inducible factor, which presumably is renoprotective during
oxygen deprivation (Eckardt et al, 2005). Hypoxia induces
profibrogenic changes in proximal tubular epithelial cells and
interstitial fibrosis (Norman and Fine, 2006). Hypoxia causes
release of cytokines such as TGF-β and platelet derived growth
factor, which stimulate intrarenal production of collagen.
Furthermore, anemia may contribute to progression of CKD
because anemia reduces oxygen delivery within the kidney, fur-
ther promoting hypoxia and progressive renal damage (Rossert
and Froissart, 2006).
A variety of mechanisms regulate medullary oxygen home-
ostasis; these include medullary vasodilators (e.g., nitric oxide,
Figure 37-6. The pathogenesis of secondary renal hyperparathy-
prostaglandin E , adenosine, dopamine and urodilatin) and roidism. Key: PTH = parathyroid hormone, 1,25(OH) Vit. D = 1,25-
2
2
vasoconstrictors (e.g., endothelin, angiotensin II and vaso- dihydroxycholecalciferol.
pressin).Tubuloglomerular feedback controls glomerular filtra-
tion and, indirectly, medullary oxygen demand. Reduced glomerulus, reducing glomerular filtration and subsequent
resorption of sodium activates signals that constrict the delivery and resorption of sodium from the tubule. A related