Page 747 - Small Animal Clinical Nutrition 5th Edition

Chronic Kidney Disease 775

to correlate with the amount of renal tissue ablated
VetBooks.ir (Bourgoignie et al, 1987). In a remnant kidney model in which
renal mass was reduced by 15/16 in dogs, GFR progressively
declined, providing evidence that progressive kidney disease
occurs in dogs if adequate renal tissue is ablated (Brown et al,
1991; Finco et al, 1992). It is generally accepted that naturally
occurring CKD (stages 2 through 4) in dogs and cats tends to
be progressive (Allen et al, 1987; Jacob et al, 2002; Ross et al,
2006; Polzin et al, 2005). Therefore, it appears that after a crit-
ical mass of nephrons becomes nonfunctional in dogs and cats,
either due to renal ablation or natural causes, disease character-
ized by several pathophysiologic adaptations progresses. See
sections below for more detailed information about specific
mechanisms and how they may contribute to progression of
CKD in dogs and cats.

Glomerular Hypertension and Hyperfiltration
Figure 37-2. Vicious cycle of relentless progression of chronic kidney
In normal kidneys, single-nephron GFR and single-nephron disease. After a critical amount of damage has occurred, compensa-
plasma flow are submaximal under basal conditions. Reduction tory mechanisms, which are initially beneficial, are activated and ulti-
of nephron mass leads to hypertrophy of the residual nephrons mately contribute to progressive injury. The amount of damage
with increases in filtration and perfusion of surviving nephrons required to trigger progression probably varies from species to
species and from individual to individual. (Adapted from Churchill J,
to maintain total GFR (Polzin et al, 2005). Although these
Polzin DJ, Osborne CA, et al. The influence of dietary protein intake
compensatory increases in single-nephron GFR and renal plas- on progression of chronic renal failure in dogs. Seminars in Veterinary
ma flow initially help maintain homeostasis, eventually they Medicine and Surgery: Small Animal 1992; 7: 246.)
contribute to progressive kidney damage. Single-nephron GFR
increases are accompanied by glomerular hyperfiltration and
intraglomerular hemodynamic changes, which increase flux of Proteinuria
plasma proteins through the glomerular mesangium.These pro- Proteinuria may mediate progressive renal injury through sev-
teins stimulate mesangial cell proliferation and matrix produc- eral mechanisms (Polzin et al, 2005; Elliott and Syme, 2006).
tion and eventually lead to glomerulosclerosis (Figure 37-3). Impaired glomerular permselectivity allows passage of proteins
Glomerular capillary hypertension is the critical intraglomerular that are not normally filtered including albumin, transferrin
hemodynamic factor responsible for promoting glomerular and complement (Polzin et al, 2005). Proteinuria may result in
injury, perhaps through increasing proteinuria. Decreased die- direct mesangial cell toxicity, fibrosis of glomeruli and subse-
tary protein intake prevents these hemodynamic changes and quent glomerulosclerosis. Progression of CKD in experimental
preserves normal glomerular structure in rats (Brenner et al, models more closely relates to the degree of tubulointerstitial
1982). The impact of dietary protein intake on glomerular disease than to the severity of glomerular lesions. Proteinuria
hemodynamics and structure in dogs and cats is less certain. may injure tubular cells through overloading tubular reabsorp-
As kidney disease develops, the afferent renal arterioles tive mechanisms or by receptor-mediated mechanisms (Polzin
dilate, directly exposing glomeruli to systemic blood pressure; et al, 2005). Proximal tubular cells reabsorb abnormally filtered
this causes glomerular hypertension, which distends the capil- proteins such as albumin through endocytosis and lysosomal
laries. The resultant mesangial stretch stimulates accumulation degradation. Excessive albuminuria can overload this resorptive
of collagen and progressive loss of glomerular function (Figure capacity, causing lysosomal swelling and rupture, leading to
37-4) (Riser et al, 1992). Continued strain on mesangial cells is lysosomal enzyme-mediated injury of tubular cells. Excessive
a stimulus for cytokine release and extracellular matrix produc- albuminuria also increases oxidative stress, which appears to be
tion (Polzin et al, 2005). Mesangial cells are stretched because an important mechanism of progressive renal injury. (See Renal
of their relationship to capillaries and their attachment to the Oxidative Stress.)
glomerular basement membrane. When mesangial cells in cul- Abnormally filtered transferrin, a plasma protein that trans-
ture are stretched and relaxed repeatedly, stretch-induced ports iron, increases absorption of iron by proximal tubular
release of transforming growth factor-β mediates production of cells. Increased intracellular iron concentration of tubular cells
collagen (Cortes et al, 1994). Intraglomerular hypertension also produces reactive oxygen species (ROS) leading to oxidative
may lead to decreased glomerular permselectivity with resultant injury. Complement binds to the luminal membrane of tubular
proteinuria (Polzin et al, 2005). Proteinuria, in turn, may medi- cells and activates the membrane attack complex, culminating
ate progressive injury of glomeruli and the renal tubulointersti- in cellular injury and lysis.These mechanisms contribute to loss
tium (Lees et al, 2005; Polzin et al, 2005). Proteinuria has been of tubular cells and ultimately loss of nephrons. Cellular activa-
associated with more rapid progression of CKD in dogs (Jacob tion of inflammatory genes also stimulates secretion of inflam-
et al, 2005) and cats (Syme et al, 2006). matory mediators into the interstitium, which promotes inter-