CHRONIC RENAL FAILURE
S.P. DiBartola, DVM
LEARNING OBJECTIVES
1. The student will understand the adaptive changes that occur in chronic renal failure (CRF)
for solutes handled by no regulation, limited regulation, and complete regulation.
2. The student will understand the theory of hyperfiltration and how it relates to the
pathophysiology and treatment of CRF.
3. The student will be able to differentiate acute from CRF.
4. The student will understand the pathophysiology underlying the expected laboratory
abnormalities in CRF.
5. The student will understand the rationale underlying conservative medical management of
CRF.
STUDY QUESTIONS
1. What is the difference between renal disease and renal failure? The difference between
azotemia and uremia? (see notes on Clinical Evaluation of Glomerular Function)
2. What are the most common causes of CRF in the dog, cat, horse, and cattle?
3. Clinically, how would you differentiate acute from CRF in the dog?
4. Increased single nephron GFR (hyperfiltration) in diseased kidneys lessens the decrease in
total GFR. What are the potential adverse effects of this adaptive mechanism?
5. How is sodium balance maintained in CRF?
6. What is the major cause of decreased concentrating ability and polyuria in CRF? At what
point in the progression of CRF is impaired concentrating ability detected clinically? How do
cats with chronic renal disease differ from dogs in this regard?
7. How is calcium and phosphorus balance maintained in CRF? What hormone is responsible
for this adaptive mechanism? What are the potential adverse effects of this adaptive
mechanism? How can this mechanism be manipulated in the management of CRF?
8. What factors predispose to hypocalcemia in CRF?
9. How does calcium/phosphorus balance differ in some horses with CRF as compared to the
dog?
10. How does acid-base status in uremia differ in the dog as compared to cattle?
11. How is potassium balance maintained in CRF?
12. What factors predispose to anemia in CRF? Which of these factors is most important in the
pathogenesis of the anemia of CRF?
13. What factors contribute to vomiting in uremia?
14. What factors may contribute to hypertension in CRF?
15. What are the typical historical and physical findings in CRF in the dog?
16. Describe the abnormalities you would expect on the biochemical profile of a dog with
uremia.
17. Describe the nutritional aspects of the medical management of CRF. Include protein intake,
caloric intake, lipids, sodium, phosphorus, and vitamins in your discussion.
18. What is the role of anabolic steroids in the management of CRF?
19. What is the role of hormone replacement in the medical management of CRF (e.g.
erythropoietin, calcitriol)?
20. What is the role of H2 blockers (e.g. cimetidine) in the medical management of CRF?
21. What factors contribute to the prognosis in CRF?
I. Introduction (see notes on Clinical Evaluation of Glomerular Function for discussion of
terminology)
A. CRF occurs when the compensatory mechanisms of the diseased kidneys are no longer
able to maintain the excretory, regulatory and endocrine functions of the kidneys. The
resultant retention of nitrogenous solutes, derangements of fluid, electrolyte, and acidbase balance, and failure of hormone production constitute the syndrome of CRF.
B. Affected renal functions are:
1. Excretory (solutes handled by GFR: urea, creatinine)
2. Regulatory (solutes handled by GFR and some combination of reabsorption and
secretion: water, electrolytes, hydrogen ions)
3. Endocrine (hormone production: erythropoietin, calcitriol)
II. Causes of CRF in domestic animals
A. Dog (CRF is thought to affect 0.5 to 1.0% of the geriatric canine population)
1. Chronic interstitial nephritis of unknown cause (most common pathological
diagnosis)
2. Chronic pyelonephritis (can be difficult to distinguish histologically from 1. above)
3. Chronic glomerulonephritis (can be difficult to distinguish histologically from 1.
above)
4. Amyloidosis
5. Hypercalcemic nephropathy
6. Chronic obstructive uropathy (hydronephrosis)
7. Familial renal disease (e.g. Norwegian elkhound, Lhasa apso, Shih tzu, Samoyed,
Cocker spaniel, and others)*
8. Healing of acute renal failure (see notes on Acute Renal Failure for specific causes)
9. Leptospirosis
B. Cat (CRF is thought to affect 1.0 to 3.0% of the geriatric feline population)
1. Chronic interstitial nephritis of unknown cause (most common pathological
diagnosis)
2. Chronic pyelonephritis (can be difficult to distinguish histologically from 1. above)
3. Chronic glomerulonephritis (can be difficult to distinguish histologically from 1.
above)
4. Amyloidosis (uncommon in mixed breed cats but familial in Abyssinian cats)*
5. Polycystic kidney disease (familial in Persian cats)*
6. Healing of acute renal failure (see notes on Acute Renal Failure for specific causes)
7. Chronic obstructive uropathy (hydronephrosis)
8. Neoplasia (renal lymphoma)
9. Pyogranulomatous nephritis due to feline infectious peritonitis
*See DiBartola SP: Familial Renal Diseases of Dogs and Cats, Ettinger SJ & Feldman EC: Textbook of Veterinary
Internal Medicine: Diseases of the Dog and Cat (ed 5), W.B. Saunders Co., Philadelphia, 2000, pp 1698-1703 for
more information.
C. Horse
1.
2.
3.
4.
Chronic glomerulonephritis (most common)
Chronic interstitial nephritis of unknown cause
Chronic pyelonephritis
Amyloidosis (rare)
D. Cow
1.
2.
3.
4.
5.
6.
7.
Chronic pyelonephritis (E. coli, Corynebacterium renale)
Chronic interstitial nephritis of unknown cause
Renal amyloidosis
Renal infarction due to sepsis (e.g. mastitis, endocarditis, metritis)
Renal vein thrombosis
Leptospirosis
Neoplasia (renal lymphoma)
III. Differentiation of acute (ARF) from chronic renal failure (CRF)
A. Sometimes it is difficult to determine whether the animal is suffering from ARF or CRF.
B. Differentiation is essential because ARF is a potentially reversible disease process
whereas CRF is not.
C. Clinical findings that help differentiate ARF from CRF:
1. Renal size: Small to normal in CRF; normal in ARF. Note: Some chronic renal
diseases in cats can be associated with enlarged kidneys (e.g., renal lymphoma,
polycystic kidney disease).
2. History of previous polyuria and polydipsia: Often (but not always) present in CRF;
absent in ARF.
3. Non-regenerative anemia: Often (but not always) detected at presentation in CRF; not
present initially in ARF.
4. Weight loss and poor haircoat: Often (but not always) detected at presentation in
CRF; usually (but not always) absent in ARF.
5. Enlarged parathyroid glands on ultrasound examination: In one study, dogs with
CRF had significantly larger (3.9-8.1 mm length) parathyroid glands than did normal
dogs (2.0-4.6 mm length) and those with ARF (2.4-4.0 mm length). The size of
parathyroid glands in dogs seemed to be related to body weight.
6. Increased carbamylated hemoglobin concentration: In one study, carbamylated
hemoglobin concentrations were higher in dogs with ARF and CRF than normal
dogs, and dogs with CRF had significantly higher concentrations than did dogs with
ARF. This test is not routinely performed in clinical laboratories.
7. Hypothermia: Occasionally present in ARF; absent in CRF except terminally.
8. Hyperkalemia: Observed with development of oliguria or anuria in ARF or CRF.
Absent with polyuric CRF or ARF.
IV. Pathophysiology of CRF
A. Uremia as an intoxication
1. A uremic toxin is any compound retained due to decreased renal function that can
contribute to the symptomatology of uremia.
2. Many compounds are involved in the pathophysiology of uremia and no single
compound is likely to explain the diversity of uremic symptoms.
3. Urea, guanidine compounds, products of bacterial metabolism (e.g. polyamines,
aliphatic amines, indoles), myoinositol, trace elements, and "middle molecules"
(some hormones and other compounds with molecular weights of 500-3000) have
been considered as potential "uremic toxins."
4. Parathyroid hormone (PTH) probably is the best-characterized uremic toxin. It may
have adverse effects on the brain, heart, and bone marrow but its main detrimental
effect is its role in development of renal osteodystrophy (see section on renal
secondary hyperparathyroidism).
B. Hyperfiltration
1. Renal disease tends to be progressive when a critical number of nephrons has been
destroyed. Glomerular hyperfiltration has been incriminated as one important factor
contributing to the progressive nature of renal disease (see below).
2. Total GFR represents the sum of single nephron GFR (SNGFR) in all the nephrons of
the both kidneys: GFR =  SNGFR where SNGFR is summed up over approximately
1,000,000 nephrons in a dog (500,000 nephrons per kidney) or 400,000 nephrons in a
cat (200,000 nephrons per kidney). In a healthy animal the range of SNGFR is fairly
narrow. (See Figure 1, lower panel.)
3. During progressive renal disease, the decline in total GFR is offset by an increase in
SNGFR in functional remnant nephrons (so-called glomerular hyperfiltration). Thus,
the normally narrow range of SNGFR widens during development of CRF because
diseased nephrons have low SNGFR and remnant nephrons have supranormal
SNGFR (see Figure 1, middle and upper panels). The mechanisms responsible for this
increase in SNGFR differ among species but result from alterations in the normal
determinants of SNGFR (see notes on Renal Physiology). In rats, for example,
glomerular hyperfiltration is a consequence of increases in transcapillary hydrostatic
pressure and glomerular capillary plasma flow whereas in dogs it results primarily
from increases in Kf and glomerular capillary plasma flow. Experimentally, dogs
develop hyperfiltration after ablation of 75-86% of renal mass.
Figure 1: Widening range of SNGFR as renal disease progresses. The normal situation is depicted in the lower
panel. The middle panel depicts a situation in which some nephrons are non-filtering or have decreased SNGFR and
others have increased SNGFR but the mean SNGFR remains unchanged and total GFR is still normal. The top panel
depicts a situation in which total GFR has been reduced by 50%. In this setting mean SNGFR is reduced, many
nephrons are non-filtering or hypo-filtering, and many are hyper-filtering. From Brenner BM: Nephron adaptation to
renal injury or ablation. Am J Physiol 249:F332, 1985.
4. This adaptation occurs to such an extent that total GFR will increase approximately
40-60% in the remnant renal tissue over a period of 4 weeks after renal ablation. For
example, if one kidney is removed from a dog with GFR of 40 ml/min, GFR will
immediately decline to 20 ml/min but within one month will stabilize at
approximately 30 ml/min due to the effects of hyperfiltration in remnant nephrons.
5. Proteinuria and glomerular sclerosis in remnant nephrons are adverse functional and
morphological consequences of glomerular hyperfiltration that may lead to
progressive deterioration of the remaining renal tissue. These glomerular lesions are
more prominent in rats with experimental renal disease than in dogs in which
tubulointerstitial lesions tend to predominate. Also, proteinuria often is mild in dogs
with remnant kidneys. Thus, rats and dogs may not be comparable in the functional
and morphological changes induced by hyperfiltration.
6. The extent of renal damage that must occur to result in progressive deterioration of
the remnant kidney is not known exactly for all species. In dogs, 85-95% of renal
tissue must be destroyed to result in progression whereas progression occurs in rats
after 75-80% renal ablation.
7. In rats, dietary restriction of protein can abrogate this maladaptive response by
reducing glomerular hyperfiltration. Practically speaking, dietary restriction of protein
in dogs may not prevent hyperfiltration. This observation has led to controversy about
the role of dietary protein restriction in the management of CRF in dogs. In one study,
a diet containing 17% protein did not prevent glomerular hyperfiltration in dogs with
94% (15/16) renal ablation. On the other hand, a diet containing 8% protein has been
shown to result in malnutrition (weight loss, hypoalbuminemia) and increased
mortality in dogs with experimentally-induced renal disease. In dogs, dietary protein
restriction to the extent necessary to abrogate glomerular hyperfiltration may not be
possible without inducing malnutrition.
8. Systemic (as well as glomerular) hypertension occurs in rats after renal ablation but
relatively mild increases in systemic blood pressure are observed in dogs after severe
renal ablation. Thus, research in rats is not necessarily directly applicable to dogs and
other domestic animals with renal disease.
C. Factors contributing to the progression of chronic renal disease
1. Species differences.
a. In experimental rats, renal disease progresses after 75-80% reduction in renal
mass.
b. In experimental dogs, renal disease may not become progressive until there has
been 85-95% reduction in renal mass. We know from clinical experience that
renal disease can be progressive in dogs.
c. Limited information is available in cats. We know from clinical experience that
renal disease can be progressive in cats. Experimentally, cats with 83% reduction
in renal mass fed 52% protein and 0.54% phosphorus or 28% protein and 0.61%
phosphorus did not experience progression over a 12-month period of
observation.
2. Amount of reduction in renal mass (experimental animals) or activity of underlying
primary renal disease (clinical cases). (See above.)
3. Functional and morphologic changes in remnant renal tissue
a. Hyperfiltration increases movement of protein across the glomerular capillaries
into Bowman’s space and the mesangium. (See above for detailed description of
hyperfiltration.)
b. Increased filtration of proteins through the glomeruli causes renal toxicity, which
may contribute to renal disease progression. Magnitude of proteinuria correlates
with rate of progression of renal disease in human patients.
i. The increased filtered load of protein may overload the proximal tubular cells
leading ultimately to rupture of lysosomes and exposure of the tubular cells
and renal interstitium to damaging enzymes.
ii. Tubular cells possess receptors for hormones and growth factors, some of
which are small molecular weight proteins (e.g. IGF-1, transforming growth
factor β) that are filtered excessively and taken up by the proximal tubular
cells where they may promote cellular proliferation and extracellular matrix
deposition leading to tubulointerstitial damage.
iii. Tubular cell overload with protein up-regulates inflammatory and vasoactive
genes (e.g., monocyte chemoattractant protein-1, endothelin) which have
potential toxic effects on the kidney
iv. Fatty acids bound to filtered albumin may contribute to proximal tubular cell
toxicity.
c. A low protein diet may limit intersitital inflammation and fibrosis by decreasing
proteinuria and its deleterious effects.
d. Angiotensin converting enzyme (ACE) inhibitors also may reduce filtration of
protein into Bowman’s space and the mesangium by lowering intraglomerular
hydrostatic pressure and altering the surface area and permeability of the
glomerular capillary wall.
4. Time followed
a. Dogs with 75% reduction in renal mass fed 19, 27, and 56% protein (and 1%
phosphorus) and followed 4 years did not show evidence of progression.
b. 3/10 dogs with 88% reduction in renal mass fed 26% protein and 0.9%
phosphorus developed progression over 21-24 months.
c. 10/12 dogs with 94% reduction in renal mass fed 17% protein and 1.5%
phosphorus developed progression over 24 months.
5. Diet
a. Protein
i. Some studies in human patients with CRF have supported the use of very low
protein diets (0.3-0.6 g/kg/day) for slowing the rate of progression of renal
disease whereas others have not found a beneficial effect of protein restriction.
ii. Prevention of hyperfiltration by feeding an extremely low protein diet may not
be feasible in dogs without induction of malnutrition, but low protein diets
may have other beneficial effects such as amelioration of uremic
symptomatology and reduction in transglomerular protein traffic.
b. Phosphorus
i. Low phosphorus (0.44%) diets caused less renal disease progression in dogs
with 94% reduction in renal mass fed 17% protein.
c. Calories
i. One study of rats with the remnant kidney model indicated that improvement
in proteinuria and renal morphologic changes was due to reduced caloric
intake and not reduced protein intake. The mechanism of this effect is
unknown.
d. Lipids
i. Accumulation of lipids in the mesangium may promote mesangial cell
proliferation, excess production of mesangial matrix components such as
collagen and proteoglycans and ultimately glomerular sclerosis.
ii. Supplementation of the diet with ω-6 PUFA may hasten progression of
chronic renal disease whereas supplementation with ω-3 PUFA may be
renoprotective.
iii. Increasing the amount of ω-3 PUFA relative to ω-6 PUFA in the diet reduces
production of the pro-inflammatory, platelet-aggregating, vasoconstrictive
prostaglandin TXA2 and increases production of vasodilatory prostaglandins
(PGE, PGI) that have the potential to increase GFR and RBF. These effects
may slow renal disease progression. See textbox below for a brief review of
eicosanoids.
iv. Studies of ω-3 PUFA supplementation in rats with the remnant kidney model
of CRF have been produced conflicting results.
v. Studies of dogs with the remnant kidney model of CRF have demonstrated
beneficial effects of ω-3 PUFA as opposed to ω-6 PUFA supplementation
(e.g., decreased cholesterol and triglycerides, lower urinary eicosanoid
excretion, reduction in proteinuria, preservation of GFR, less severe renal
morphologic changes)
Lipids and eicosanoids … a brief review
Eicosanoids are small molecular weight lipids that function as signaling molecules in the local extracellular
environment and function as important biological response modifiers. Animal fats are saturated and don’t serve as
eicosanoid precursors. Plant and fish oils contain fatty acids that are unsaturated (i.e., contain one or more double bonds)
and do serve as eicosanoid precursors. Linolenic (18:3) and eicosapentanoic (20:5) acids are ω-3 polyunsaturated fatty
acids (PUFA) because their first double bond occurs at the third carbon from the -CH3 end of the molecule. Linoleic
(18:2) and arachidonic (20:4) acids are ω-6 PUFA because their first double bond occurs at sixth carbon atom from the CH3 end of the molecule. In the parenthetical expressions above, the first number indicates the number of carbon atoms in
the molecule and the second indicates the number of double bonds (e.g., arachidonic acid has 20 carbon atoms and 4
double bonds). Diets rich in ω-6 PUFA promote incorporation of arachidonic acid into cell membranes whereas those rich
in ω-3 PUFA promote eicosapentanoic acid incorporation. After phospholipase-mediated release of arachidonic or
eicosapentanoic acid from the cell membrane, cyclooxygenases (COXs) generate precursors of the diene (series 2)
prostaglandins (PG) (from arachidonic acid) or precursors of the triene (series 3) PG (from eicosapentanoic acid). PGE
and PGI (prostacyclin) of both series 2 and 3 are vasodilatory and PGI inhibits platelet aggregation (“good”
prostaglandins). Series 2 thromboxane (TXA2) is pro-inflammatory, vasoconstrictive and stimulates platelet aggregation
(“bad” prostaglandin), but series 3 thromboxane (TXA3) is relatively inert. Supplementation of the diet with fish oil
promotes inclusion of eicosapentanoic acid into cell membranes and ultimately release of series 3 PG, which provide
beneficial vasodilatory effects without harmful pro-inflammatory and vasoconstrictive effects.
6. Systemic complications of renal insufficiency may affect progression
a. Systemic hypertension
b. Urinary tract infection
c. Fluid, electrolyte, and acid-base imbalances
7. Therapeutic interventions
a. Angiotensin II and ACE inhibitors
i. Potential detrimental effects of angiotensin II
(A) Increased efferent arteriolar vasoconstriction relative to afferent arteriolar
vasoconstriction increases hydrostatic pressure within glomeruli and
potentially causes intraglomerular hypertension
(B) Contraction of mesangial cells decreases surface area available for
filtration
(C) Increased protein traffic in mesangium and limitation of egress of proteins
(D) Stimulation of renal cellular proliferation leading to glomerular sclerosis
ii. ACE inhibitors (e.g. enalapril, benazepril) may have protective effects in
patients with chronic renal disease due to their ability to block adverse effects
of angiotensin II listed above
(A) Reduction in proteinuria
(B) Limitation of glomerular sclerosis and slowing of progression
(C) Improvement in systemic blood pressure
b. Low protein diet
i. May reduce proteinuria and the adverse effects of increased transglomerular
protein traffic.
ii. May reduce uremic symptomatology due to accumulation of protein
breakdown products.
iii. Probably not possible to reduce hyperfiltration in dogs with CRF using a low
protein diet without also contributing to malnutrition.
D. Concept of external balance for solutes
1. Understanding the compensatory response of the kidneys to chronic progressive renal
disease requires an understanding of the concept of external balance for solutes.
2. We will assume that the kidneys are responsible for excreting 100% of the solutes
discussed (e.g. urea, creatinine, sodium, potassium, calcium, phosphate, hydrogen
ions). This is not really true because the gastrointestinal tract plays a minor role in
excretion of these solutes.
Solute input from diet  BODY  Solute output in urine
3. From this diagram, it can be seen that the composition of the body fluids can be kept
constant only if output equals input. This is the concept of external balance. An
individual animal consumes different amounts of water and solutes each day and the
kidneys must adjust their output of water and solutes if body composition is to be
kept constant.
4. The challenge to the kidneys in a patient with chronic renal disease is to maintain
balance despite advancing disease and progressively declining glomerular filtration
rate (GFR).
5. According to the intact nephron hypothesis of Dr. N. Bricker: "In the presence of a
heterogeneity of morphologic changes in nephrons of diseased kidneys, there is a
relative homogeneity of glomerulotubular balance." That is, despite distortion of
renal architecture by disease, glomerular and tubular function are as closely integrated
in diseased kidneys as in normal kidneys (i.e., glomerulotubular balance is
maintained).
6. In health, as spontaneous increases or decreases in GFR occur, the absolute tubular
reabsorption of filtered solutes changes in a similar direction. Thus, the fraction of the
filtered load that is reabsorbed remains constant despite spontaneous changes in GFR.
This principle has been referred to as glomerulotubular balance, and its mechanisms
are incompletely understood. Changes in peritubular capillary hydrostatic and oncotic
pressure probably play an important role in glomerulotubular balance (see notes on
Renal Regulation of Sodium Balance for more information).
7. For any given solute, the diseased kidney maintains glomerulotubular balance as
GFR declines by decreasing the fraction of the filtered load of that solute that is
reabsorbed and increasing the fraction of the filtered load of that solute that is
excreted. The key to understanding this concept is in the word "fraction."
8. In some instances, the mechanisms of the adaptive changes have adverse effects on
the animal. This is the trade off hypothesis of Dr. Bricker: "The biological price to be
paid for maintaining external solute balance for a given solute as renal disease
progresses is the induction of one or more abnormalities of the uremic state." The
classical example is maintenance of normal calcium and phosphorus balance at the
expense of renal secondary hyperparathyroidism and bone demineralization. Other
examples include bone buffering by carbonate at the expense of bone
demineralization, and bolstering of GFR by glomerular hyperfiltration at the expense
of proteinuria, glomerular sclerosis, and progressive destruction of residual renal
tissue.
9. Some of these "mal"-adaptive mechanisms and their consequences can be prevented
by a proportional reduction in the intake of the solute in question. This strategy will
avoid the need for the kidneys to alter fractional reabsorption and excretion of the
solute being manipulated. Using this approach with dietary phosphorus has been
shown to prevent renal secondary hyperparathyroidism. Unfortunately, this strategy
cannot be practiced in a preventative fashion because we do not know ahead of time
which animals are destined to develop chronic renal disease!
E. The kidneys respond differently to different solutes during development of chronic renal
disease. The three main types of response are (see Figure 2 below):
1. No regulation: This is the response to solutes normally handled by glomerular
filtration alone. Examples are urea and creatinine. At any given time, the plasma
concentrations of these solutes reflect the prevailing GFR.
2. Complete regulation: This is the response to some solutes normally handled by
glomerular filtration and some combination of reabsorption and secretion. Examples
include sodium and potassium. Normal plasma concentrations of these solutes are
maintained until GFR decreases below 5% of normal or until oliguria or anuria
develops.
3. Limited regulation: This is the response to some solutes normally handled by
glomerular filtration and some combination of reabsorption and secretion. Examples
are phosphate and hydrogen ions. Normal plasma concentrations of these solutes are
maintained until GFR decreases below approximately 15-20% of normal
Figure 2: Renal regulation of solute balance. Curve A represents solutes experiencing "no regulation." Curve B
represents solutes experiencing "limited regulation." Curve C represents solutes experiencing "complete regulation."
(From Bricker NS and Fine LG: The Renal Response to Progressive Nephron Loss. In Brenner BM and Rector FC:
The Kidney, ed 2, WB Saunders Co, Philadelphia, 1981, p 1058.)
F. Retention of solutes handled by filtration alone (no regulation)
1. The relationship between the plasma concentrations of such solutes and percentage of
functional nephrons or GFR is a "rectangular hyperbola" (i.e., their concentrations
increase exponentially as GFR declines) (see notes on Clinical Evaluation of
Glomerular Function)
2. There are many examples of such solutes but urea and creatinine are most commonly
discussed because they are used as laboratory tests to evaluate renal function.
Azotemia does not develop until 75% or more of the nephron population has become
non-functional.
3. Some of these retained compounds are thought to be uremic toxins (see above).
G. Water balance (complete regulation)
1. Both the ability to produce concentrated urine (i.e. to conserve water) and the ability
to excrete a water load are impaired in CRF.
2. The development of this concentrating defect is heralded clinically by the onset of
polyuria and compensatory polydipsia.
3. Increased solute load per residual functioning nephron rather than architectural
damage to the tubules and interstitium probably is the most important factor
contributing to the concentrating defect (i.e. the remnant nephrons are experiencing
an osmotic diuresis).
4. Another contributing factor is a limited ability of the distal nephron to respond to
antidiuretic hormone (ADH) possibly due to higher tubular flow rate in remnant
nephrons.
Consider a normal 10 kg dog with normal daily urine output of 333 ml and urine osmolality of 1500 mOsm/kg. These
values imply a solute load of 0.333  1500 or 500 mOsm per day. The same dog with CRF might have a relatively
fixed urine osmolality of 500 mOsm/kg and would require urine output of 1000 ml to excrete the same 500 mOsm.
Renal handling of water in this dog might change as shown below after development of chronic renal disease:
Number of nephrons
Total GFR (ml/min)
SNGFR (nl/min)
Urine output (ml/day)
Urine output (ml/min)
Urine output per nephron (nl/min)
% Filtered water reabsorbed
% Filtered water excreted
Normal
1,000,000
40
40
333
0.23
0.23
99.4%
0.6%
Diseased
250,000
15*
60
1000
0.69
2.76
95.4%
4.6%
Note that the fraction of filtered water that is reabsorbed is decreased in the disease state and the fraction that is
excreted is increased.
* Food for thought: Why isn’t this value 10 nl/min?
5. In most instances, impairment of concentrating ability develops when 67% of the
nephron population has become non-functional. This concentrating defect is
recognized clinically by the presence of isosthenuria (urine osmolality of 300-600
mOsm/kg or USG of 1.007-1.015).
6. Some cats with CRF may retain concentrating ability even after development of
azotemia. In one study, cats with 58-83% loss of functional nephrons could produce
concentrated urine (USG 1.022-1.067). Thus, a cat with azotemia and relatively
concentrated urine does not necessarily have pre-renal azotemia.
7. In some diseases, damage to the distal nephron or distortion of the normal
architecture of the medullary interstitium may play a more important role in the
concentrating defect and account for the early appearance of impaired concentrating
ability (e.g. medullary amyloidosis in cats, pyelonephritis, polycystic renal disease,
obstructive nephropathy, hypercalcemic nephropathy).
8. Animals with chronic renal disease usually retain the ability to produce dilute urine
(i.e. to excrete solute-free water) but the ability to excrete an abrupt water load may
be impaired.
H. Sodium balance (complete regulation)
1. To maintain external balance for sodium as renal disease progresses, the kidneys must
reduce the fraction of filtered sodium that is reabsorbed (and increase the fraction that
is excreted). This adaptation occurs in the distal nephron.
2. Natriuretic substances probably play an important role in this adaptive process. For
example, a higher concentration of atrial natriuretic peptide enhances sodium
excretion by the kidneys in CRF.
3. Patients with CRF are able to stay in sodium balance despite very low GFR but they
are much less flexible than normal individuals in their response to abrupt changes in
sodium intake (i.e., they take longer to excrete an abrupt sodium load).
4. The fractional reabsorption of sodium can only be reduced so far. When GFR falls
below 5% of normal, positive balance for sodium may develop with consequent
expansion of extracellular fluid volume.
5. The ability to conserve sodium also is impaired in CRF. Normal individuals can
reduce sodium excretion nearly to zero but CRF patients have some obligatory loss of
sodium. Potential explanations for this obligatory natriuresis include:
a. Increased solute load per remnant nephron (i.e. the same amount of sodium must
be excreted but by a reduced number of nephrons)
b. Obligatory sodium loss with anions in urine
c. Increased rate of tubular flow in remnant nephrons
6. If sodium intake is gradually reduced over several months, patients with CRF can
gradually reduce sodium excretion possibly by suppression of the high concentrations
of natriuretic substances that developed during adaptation to declining GFR.
I. Potassium (complete regulation)
1. Most animals with CRF have normal serum potassium concentrations. Hyperkalemia
usually does not develop unless the animal becomes oliguric or anuric and this
typically would be a terminal event.
2. Hypokalemia may occur in 10-30% of dogs and cats with chronic CRF due to some
combination of anorexia, loss of muscle mass, vomiting, and polyuria.
3. Potassium balance is maintained by an adaptive increase in the fractional excretion of
potassium as renal disease advances. Increased secretion of potassium per functional
remnant nephron occurs in the distal nephron. Adaptive changes include increases in
the activity of Na+-K+ ATPase and in the basolateral surface area of principal cells in
the cortical collecting ducts. This adaptive response is facilitated by (but does not
require) aldosterone.
4. Experimentally, the adaptive increase in the fractional excretion of potassium can be
blocked by proportional reduction in potassium intake during development of renal
disease.
5. Patients with CRF are less flexible in their response to added potassium. They have a
reduced ability to tolerate an acute potassium load and may require 1-3 days to
reestablish potassium balance when the intake of potassium is abruptly increased.
6. In cattle, increased potassium secretion into the saliva and rumen may become an
important avenue for potassium excretion in renal failure. Serum potassium
concentrations in uremic cattle are variable but often are slightly low.
J. Calcium balance (complete regulation)
1. Normal calcium and phosphorus metabolism requires the interaction of parathyroid
hormone (PTH), 1,25-dihydroxycholecalciferol (calcitriol or activated vitamin D3),
and calcitonin with three organ systems (kidney, gut, and bone) (see Figure 3 below).
Figure 3: Activation of vitamin D and the effects of activated vitamin D and parathyroid hormone (PTH) on the
kidneys, bone, and gut which maintain normal calcium and phosphorus homeostasis.
2. The kidney is the normal site of activation of vitamin D3 (conversion of 25hydroxycholecalciferol to 1,25-dihydroxycholecalciferol).
3. Total serum calcium concentrations are decreased in approximately 10% of dogs with
CRF. Decreased serum ionized calcium concentration is found in 40% of dogs with
CRF. Mechanisms include:
a. "Mass Law" effect due to increased serum phosphorus concentration. The
amounts of calcium and phosphorus that can remain in solution together are
defined by the [Ca]  [Pi] product. When this value is > 60-70, soft tissue
mineralization may occur.
b. Decreased production of calcitriol by the diseased kidneys results in impaired
intestinal absorption of calcium.
c. Complexing of calcium with phosphate in the lumen of the intestinal tract also
impairs calcium absorption.
4. Hypocalcemia in CRF usually is asymptomatic (i.e., tetany is not observed) because
metabolic acidosis leads to an increase in the ionized component of total serum
calcium. This occurs because of a decrease in net negative charge on plasma proteins
that occurs during acidosis.
5. Hypocalcemia may be observed in cattle with uremia due to increased phosphorus
excretion into the rumen and binding of calcium.
6. Approximately 5-10% of dogs with CRF develop hypercalcemia. Hypercalcemia may
cause further damage the kidney by causing renal vasoconstriction and interstitial
mineralization. Possible mechanisms of hypercalcemia in renal failure include:
a.
b.
c.
d.
e.
f.
Reduced urinary excretion of calcium due to very low GFR
Decreased renal degradation of PTH
Hypercitricemia and an increase in the complexed fraction of total serum calcium
Autonomous parathyroid gland secretion of PTH
Increased PTH set point for calcium
Increased intestinal sensitivity to low concentrations of calcitriol
7. Serum ionized calcium concentration usually is normal or low when measured in
dogs with CRF that have increased total serum calcium concentrations.
8. In some hypercalcemic patients with renal failure it can be difficult to determine
which came first -the renal failure or hypercalcemia. Careful consideration of
historical, physical, laboratory, and radiographic findings usually allows the clinician
to decide.
9. Hypercalcemia develops in nephrectomized ponies and in some horses with naturallyoccurring renal disease. The mechanism is unknown but may be because horses
normally absorb large amounts of calcium from their gastrointestinal tract and rely
upon renal excretion of much of this calcium. Large amounts of calcium carbonate
crystals normally are present in equine urine. Despite hypercalcemia, soft tissue
mineralization rarely occurs because the [Ca]  [Pi] product does not exceed 70 as a
result of concurrent hypophosphatemia. Affected horses have low PTH
concentrations and small parathyroid glands at necropsy suggesting that
hypercalcemia is not mediated by hyperparathyroidism.
K. Phosphorus balance (limited regulation)
1. Hyperparathyroidism is a consistent finding in progressive renal disease.
Development of renal secondary hyperparathyroidism classically has been explained
by the effect of phosphorus retention on serum ionized calcium concentration (see
Figure 4 below):
a. Reduction in GFR decreases phosphate excretion and results in
hyperphosphatemia
b. Hyperphosphatemia causes a reciprocal decrease in serum ionized calcium
concentration by the "Mass Law Effect" ([Ca]  [Pi] = constant)
c. Ionized hypocalcemia stimulates the parathyroid glands to synthesize and secrete
PTH
d. The increase in PTH stimulates increased renal excretion of phosphate and
increased release of calcium and phosphate from bone, which return serum
phosphorus and ionized calcium concentrations to normal.
Figure 4: Classical theory of renal secondary hyperparathyroidism. See notes for details.
2. PTH decreases the fractional reabsorption of phosphate in the kidney by decreasing
the Tmax for phosphate reabsorption. The limit of this compensatory response is
reached when GFR declines to approximately 15-20% of normal. As GFR declines
further, hyperphosphatemia must occur.
3. Thus, calcium and phosphorus balance is maintained by a progressive increase in
serum PTH concentration. Chronically increased PTH concentration leads to bone
demineralization and other toxic effects of uremia (e.g. bone marrow suppression,
uremic encephalopathy). This pathophysiologic sequence of events represents a
"trade-off" for the maintenance of calcium and phosphorus balance in progressive
renal disease.
4. The effect of phosphorus retention on renal calcitriol production suggests an alternate
explanation for development of renal secondary hyperparathyroidism:
a. Phosphorus retention and hyperphosphatemia inhibit renal 1α-hydroxylase, which
impairs conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol
(calcitriol)
b. Impaired production of calcitriol reduces gastrointestinal absorption of calcium
c. This contributes to ionized hypocalcemia, stimulation of PTH secretion, and the
consequences of chronic hyperparathyroidism
d. Calcitriol normally causes decreased synthesis and secretion of PTH. This
negative feedback loop is impaired in CRF due to decreased renal production of
calcitriol. In addition, there are decreased numbers of parathyroid gland calcitriol
receptors in uremia with a resultant decrease in the responsiveness of the
parathyroid glands to the inhibitory effect of calcitriol on PTH release
e. Thus, both decreased calcitriol production and decreased numbers of parathyroid
gland calcitriol receptors play a role in development of renal secondary
hyperparathyroidism
5. Renal secondary hyperparathyroidism can be prevented or reversed in dogs with
experimentally-induced chronic renal disease by reducing dietary intake of
phosphorus in proportion to the decrease in GFR.
6. “Early” in the course of chronic renal disease, decreased phosphorus intake stimulates
renal 1α-hydroxylase, which results in increased calcitriol production. This increase
in calcitriol results in enhanced intestinal absorption of calcium, increased serum
ionized calcium concentration, and decreased PTH secretion.
7. “Late” in the course of chronic renal disease, the kidneys are unable to produce
sufficient calcitriol to promote normal intestinal absorption of calcium. Regardless,
phosphorus restriction in advanced renal disease still decreases PTH secretion by an
unknown mechanism that is independent of serum ionized calcium or calcitriol
concentrations.
8. Phosphorus restriction may prevent the progression of renal disease by blunting renal
secondary hyperparathyroidism and preventing renal interstitial mineralization,
inflammation, and fibrosis.
9. These observations form the basis for the use of phosphorus restriction in the medical
management of CRF. (See treatment below).
10. Hypophosphatemia can develop in some horses with CRF.
Effect of normal phosphorus intake compared to proportional reduction of phosphorus intake on renal excretion of phosphorus
during progressive decline in glomerular filtration rate
NORMAL PHOSPHORUS INTAKE
GFR (L/day)
60
Phosphorus intake (g/day)
0.24
Serum phosphorus (mg/dL)
4
Filtered load of Pi (g/day)
2.4
Pi excreted (g/day)
0.24
% Pi excreted
10
Pi reabsorbed (g/day)
2.16
% Pi reabsorbed
90
PTH concentration
Normal
40
0.24
4
1.6
0.24
15
1.36
85
High
PROPORTIONAL REDUCTION IN PHOSPHORUS INTAKE
GFR (L/day)
60
40
Phosphorus intake (g/day)
0.24
0.16
Serum phosphorus (mg/dL)
4
4
Filtered load of Pi (g/day)
2.4
1.6
Pi excreted (g/day)
0.24
0.16
% Pi excreted
10
10
Pi reabsorbed (g/day)
2.16
1.44
% Pi reabsorbed
90
90
PTH concentration
Normal
Normal
20
0.24
4
0.8
0.24
30
0.56
70
Very high
20
0.08
4
0.8
0.08
10
0.72
90
Normal
L. Acid Base (limited regulation)
1. The main cause of metabolic acidosis in progressive renal disease is limitation of
renal ammonium excretion.
2. The chronically diseased kidney maintains H+ ion balance primarily by enhanced
renal ammoniagenesis from glutamine. Absolute ammonium excretion falls during
progressive chronic renal disease, but ammonium excretion is markedly increased
when expressed per remnant nephron. On a per nephron basis, the diseased kidney
can increase its ammonium excretion 3-5 fold.
3. This adaptive mechanism is fully expended when GFR falls to 10-20% of normal. At
this point, the diseased kidneys can no longer effectively cope with the daily fixed
acid load and a new steady state is established at a lower than normal plasma HCO3concentration. Compensation may remain adequate until GFR falls to 5% of normal
but such patients are in a precarious state of balance that easily may be disrupted by
other disease states (e.g. acute diarrhea).
4. The metabolic acidosis of CRF usually is not severe despite development of positive
balance for H+ ions. The relatively mild decrease in plasma HCO3- concentration
observed in CRF is due to the large reservoir of buffer (e.g. calcium carbonate) in
bone. The metabolic acidosis of CRF contributes to renal osteodystrophy and
represents another example of the "trade off" hypothesis.
5. The metabolic acidosis of CRF is hyperchloremic (normal anion gap) early in its
course and normochloremic (high anion gap) later in its course when acid metabolites
that titrate HCO3- have accumulated as unmeasured anions (e.g. phosphate, sulfate,
organic anions).
6. Effects of the metabolic acidosis of CRF that are "adaptive" are preservation of serum
ionized calcium concentration by the effects of acidosis on the charge of plasma
proteins and shifting of the hemoglobin-oxygen saturation curve to the right with
improved tissue delivery of oxygen. The latter effect partially compensates for the
anemia of CRF.
7. In cattle, CRF may be associated with metabolic alkalosis rather than metabolic
acidosis. This peculiarity may result from abomasal atony and sequestration of HCl in
the abomasum and forestomachs or from reduced renal excretion of HCO3- (inasmuch
as the urine of cattle normally contains large amounts of HCO3-).
M. Anemia
1. Erythropoietin is a glycoprotein hormone important in the regulation of red cell
production by the bone marrow, and the kidney is the major source of erythropoietin
in the adult animal.
2. Hypoxia (decreased oxygen supply to the kidney) is the major stimulus for
erythropoietin production.
3. The site of synthesis of erythropoietin in the kidney is thought to be a population of
peritubular interstitial cells.
4. Erythropoietin stimulates the final differentiation of committed erythroid progenitor
cells in the bone marrow into mature red blood cells.
5. A nonregenerative (normochormic, normocytic) anemia is common in CRF but
variable in severity.
6. Contributory factors
a. Main cause of anemia is inadequate production of erythropoietin by diseased
kidneys so that the uremic patient cannot meet the demand for new red cells
necessitated by loss from hemolysis and hemorrhage.
b. Life span of red cells in uremic patients is approximately 50% that of healthy
individuals. Thought to be due to a toxic factor in uremic plasma that promotes
hemolysis.
c. Some uremic toxins may impair erythropoiesis (e.g., polyamines, ribonuclease,
PTH).
d. Increased RBC 2,3-diphosphoglycerate due to hyperphosphatemia lowers
hemoglobin affinity for oxygen and enhances oxygen delivery to tissues. This
partially compensates for the anemia but reduces the hypoxic stimulus for
erythropoiesis.
e. Platelet dysfunction promotes insidious ongoing blood loss (e.g. gastrointestinal
hemorrhage).
7. Serum erythropoietin concentrations are decreased or normal in dogs and cats with
CRF. A normal concentration of erythropoietin in an anemic animal with CRF
represents an inadequate response.
8. Recombinant human erythropoietin has been used successfully to correct the anemia
of CRF in human patients. This product also is effective in correcting the anemia of
CRF in dogs and cats, but it use in these species can be associated with antibody
formation that limits its usefulness (see notes in treatment section below).
N. Hemostatic defects
1. Uremia is characterized by abnormal hemostasis and a predisposition to hemorrhage.
2. Gastrointestinal blood loss usually is observed in dogs.
3. Qualitative platelet function defect (platelet numbers are normal) is most important.
Risk of hemorrhage is best correlated with the buccal mucosal bleeding time
(normally < 2-3 min). Other coagulation tests (e.g. OSPT, APTT, ACT) usually are
normal.
4. Abnormalities of platelet function include abnormal platelet aggregation, abnormal
platelet factor 3 release, abnormal platelet adhesiveness, decreased clot retraction, and
decreased thromboxane production by platelets.
5. Platelet dysfunction thought to be due a uremic toxin. Guanidines and PTH are
suspected but not proved to be involved.
O. Gastrointestinal disturbances
1. Oral lesions
a. Foul oral odor due to accumulation of aliphatic amines
b. Stomatitis
c. Erosions and ulcers of the buccal mucosa and tongue (often lateral margins of
tongue). Ulcers may be due to excretion of urea into saliva and breakdown to
ammonia by oral bacteria.
d. Tongue tip necrosis may result from fibrinoid necrosis and arteritis with focal
ischemia, necrosis, and ulceration.
2. Gastroenteritis with gastrointestinal hemorrhage is most important (especially in
uremic dogs). Many factors may contribute:
a. Uremic alterations in mucus layer may cause back diffusion of acid
b. Bleeding due to platelet dysfunction
c. Erosions due to ammonia production from urea by bacteria in gastrointestinal
tract
d. Ischemia due to vascular lesions
e. Increased concentration of gastrin due to impaired renal excretion
3. Vomiting is common in uremic dogs (much less so in cats). Stimulation of
chemoreceptor trigger zone by a uremic toxin may be the cause.
P. Immune dysfunction
1.
2.
3.
4.
Infection is a common cause of death in uremia
Chemotaxis is impaired
Cell-mediated immunity is impaired to a greater extent than humoral immunity
Cause of defective cell-mediated immunity is unknown
Q. Neurologic complications
1. Uremic encephalopathy may occur when GFR decreases to less than 10% of normal.
a. Encephalopathy is more related to the rapidity of onset of uremia than to its
severity. It is more likely to occur in ARF than CRF.
b. Calcium deposition in the brain due to increased PTH may be play an important
role.
c. Amino acid alterations due to malnutrition or uremic toxins may alter
neurotransmitters.
d. Clinical signs reported in affected dogs were facial twitching, head bobbing,
abnormal behavior, tremors, and seizures.
2. Uremic neuropathy is an insidious, distal, symmetrical polyneuropathy ("dying back
neuropathy") indistinguishable from other metabolic neuropathies.
a. May occur when GFR decreases below 10% of normal.
b. Decreased nerve conduction velocity but there may be no obvious clinical signs.
R. Cardiopulmonary complications
1. Myocardial or pericardial complications are extremely rare in animals.
2. Systemic hypertension may be present in one-third to two-thirds of dogs and cats with
CRF and in as many as 80% of dogs with glomerular disease.
a. Normal blood pressure in dogs and cats is similar to that of human beings (i.e.
systolic 120 mmHg, diastolic 80 mmHg). Interaction with human beings increases
the blood pressure of dogs and cats (so-called “white coat effect”)
b. Factors contributing to hypertension in CRF include:
i. Renal ischemia with activation of renin-angiotensin-aldosterone system
ii. Plasma volume expansion when sodium excretion is impaired at very low
levels of GFR (ie. < 5% of normal)
iii. Sympathetic nervous system stimulation
iv. An intra-renal mechanism for sodium retention plays an important role in
glomerular disease (see notes on Glomerular Diseases)
c. Clinical and pathological manifestations of systemic hypertension
i. Ocular abnormalities
(A) Blindness
(B) Retinal detachment
(C) Retinal hemorrhages
(D) Retinal vascular tortuosity
ii. Cardiovascular abnormalities
(A) Enlargement of left ventricle
(B) Medial hypertrophy of arteries
(C) Murmurs and gallops
3. Uremic pneumonitis
a.
b.
c.
d.
Extremely rare
May be asymptomatic or may result in severe dyspnea
Alveolar pulmonary infiltrates may occur with or without clinical signs
Histologically may see vascular congestion, thickened alveolar septa,
mononuclear infiltrates, and fibrin-rich alveolar edema fluid
S. Metabolic complications: Many small peptides are normally filtered by the kidney,
reabsorbed, and degraded in the proximal tubular cells. Loss of this clearance function
can result in metabolic derangements because many of these peptides are hormones (e.g.
insulin, gastrin)
1. Peripheral insulin resistance and mild fasting hyperglycemia (< 200 mg/dl) are
common in uremia. This finding is not clinically significant.
2. Excess glucagon may contribute to negative nitrogen balance and tissue catabolism.
3. Excess gastrin increases stimulation of acid secretion in the stomach and contributes
to uremic gastroenteritis (see above)
4. Altered metabolism of thyroid hormones
a. CRF is an important cause of the "euthyroid sick syndrome"
b. Can cause confusion in diagnosis of hyperthyroidism in older cats
5. Plasma cortisol concentrations are normal to slightly increased.
6. Increased mineralocorticoids may contribute to hypertension.
7. Impaired production of erythropoietin and calcitriol (discussed elsewhere in these
notes)
V.
Clinical history in CRF
A. Polyuria and Polydipsia
1. May be the first abnormalities noted by observant owners of dogs and cats. Nocturia
may be noted (animal begins waking owner up to go out to urinate).
2. These signs typically go unrecognized in horses and cattle due to differences in
husbandry.
3. Some owners misinterpret polyuria as incontinence because the animal is urinating in
the house when it never did so in the past. The owner must be questioned carefully to
differentiate incontinence (lack of voluntary control; dribbling) from polyuria (normal
voluntary control; increased volume of urine).
B. If polyuria and polydipsia are not recognized, nonspecific signs of uremia may the be
first abnormalities the owner detects
1.
2.
3.
4.
5.
6.
VI.
Vomiting: Common in uremic dogs but not in other species
Anorexia
Weight loss: May be prominent in uremic cats and horses
Lethargy
Diarrhea: A relatively uncommon late finding in uremic dogs
Pica may occur in uremic horses (e.g., eating soil or straw bedding)
Physical findings in CRF
A. Weight loss
B. Poor haircoat (dull, dry)
C. Oral lesions (most common in dogs)
1.
2.
3.
4.
Foul oral odor
Stomatitis
Buccal mucosal and tongue ulcerations
Tongue tip necrosis
D. Pallor of mucous membranes due to anemia
E. Dehydration
F. Osteodystrophy
1. Fibrous osteodystrophy is most dramatic in young growing dogs with uremia (socalled "rubber jaw")
2. Loose teeth and loss of lamina dura dentes in maxilla and mandible
3. Pathologic fractures are rare
G. Subcutaneous edema or ascites suggest the possibility of nephrotic syndrome (see notes
on Glomerular Disease). Ventral edema may occur in horses with CRF.
VII.
Laboratory Findings in CRF
A. Hemogram
1. Nonregenerative anemia (normochromic, normocytic)
a. May be masked by dehydration (evaluate total protein concentration together with
hematocrit)
2. Mature neutrophilia and lymphopenia (stress of chronic disease)
3. Normal platelet numbers but platelet function may be abnormal
B. Biochemistry
1. Serum potassium concentration usually normal unless oliguria or anuria develop
2. Serum calcium concentration normal to slightly low; occasionally high (especially in
horses with CRF)
3. Hyperphosphatemia develops when 85% of nephrons become nonfunctional.
Hypophosphatemia may occur in horses with CRF.
4. Decreased bicarbonate concentration due to metabolic acidosis (usually wellcompensated). Metabolic alkalosis has been observed in uremic cattle.
5. Mild hyperglycemia due to insulin resistance
6. Azotemia develops when 75% of nephrons have become non-functional
C. Urinalysis
1. Isosthenuria develops when 67% of nephrons become non-functional (USG 1.0071.015). Cats occasionally retain concentrating ability after onset of azotemia (see
above).
2. Persistent proteinuria without an active sediment suggests glomerular disease (see
notes on Glomerular Disease)
3. Pyuria and bacteriuria suggest urinary tract infection but do not localize it.
D. Radiology
1. Decreased renal size is compatible with CRF but normal renal size does not rule out
CRF.
2. Some chronic renal diseases (especially in cats) can be associated with enlarged
kidneys (e.g. polycystic renal disease, renal lymphoma)
Percentage loss of functional nephrons required to produce the various clinical and laboratory features
of CRF
LABORATORY ABNORMALITY
Defective concentrating ability
Azotemia
Metabolic acidosis
Hyperphosphatemia
Hypernatremia
VIII.
% OF NEPHRONS NON-FUNCTIONAL
> 67%
> 75%
> 80%
> 85%
> 95%
Conservative Medical Management of CRF
A. General principles of management
1. Search for potentially reversible causes of renal failure (e.g. pyelonephritis,
hypercalcemia, obstructive nephropathy)
2. Eliminate reversible factors that may be aggravating renal failure
a. appropriate intravenous fluid therapy to resolve pre-renal azotemia (may require
1-5 days) (do not pass judgement on the animal until it has been rehydrated)
b. concurrent infections should be treated with appropriate antibiotics
3. Maintain fluid, electrolyte, acid-base, and caloric balance while preventing
accumulation of metabolic waste products
4. Minimize effects of lost endocrine functions of the kidney
B. Dietary management
1. Free access to water at all times
2. Protein restriction
a. Potential benefits are to reduce uremic symptomatology by decreasing the
production of toxic metabolites of protein metabolism and to decrease
hyperfiltration in remnant nephrons.
b. A low protein diet does not reduce the metabolic workload of the kidney because
most of the metabolites of protein catabolism are excreted primarily by
glomerular filtration and most of the metabolic energy expended by the kidneys
results from sodium reabsorption.
c. Moderate protein restriction is indicated to relieve uremic symptomatology and
promote patient well-being but it is NOT clear that moderate protein restriction
will prevent hyperfiltration in dogs and cats. Whether chronic renal disease is
necessarily progressive and whether or not moderate protein restriction will
prevent progression in dogs and cats are unanswered questions.
d. When in the course of progressive renal disease protein restriction should be
started is uncertain. It is not recommended early in the course of renal disease
before symptomatic accumulation of protein catabolic products has become a
problem.
e. Original guidelines for protein restriction in dogs with CRF were introduced in
1972. At that time, 0.6 g/lb/day of high quality (biologic value 90-100) protein
was recommended. Guidelines for institution of this diet were as follows:
i. BUN stable and > 80 mg/dl
ii. serum creatinine stable and > 2.5 mg/dl
iii. serum phosphorus stable and > 6.0 mg/dl
This degree of dietary protein restriction may lead to malnutrition in dogs and is
NOT recommended. Currently, a minimum protein intake of nearly twice this
amount (i.e. 1 g/lb/day) is recommended for dogs with CRF. See example below
for methods of expressing protein intake.
f. Feeding moderately restricted protein diets (e.g. 15-17% protein) to dogs with
CRF is preferable to feeding extremely high or low protein diets. A gradual
transition from the previous diet to the prescribed diet over 2-4 weeks is
recommended.
g. Owners formulating homemade diets for their pets with CRF should use eggs as
the primary protein source because of the high biological value of egg protein.
h. On a low protein diet, BUN will decrease due to dietary manipulation alone and
will no longer be a good indicator of renal function. A decrease in BUN when the
animal is on a low protein diet does not imply improved renal function. Serum
creatinine concentrations however are not influenced to a significant extent by
diet.
i. The nutritional needs of cats differ from dogs. Dogs require that a minimum of
approximately 4 to 5% of calories come from protein whereas cats require that a
minimum of 20% of calories come from protein. These represent MINIMUM
requirements and do not provide for bodily nitrogen reserves. Cats also seem to
prefer diets higher in fat and require a source of taurine in their diet. It has been
recommended that cats with renal failure receive a minimum of approximately 2
g/lb/day protein.
j. Stable body weight, stable serum albumin concentration, and decreased BUN are
indications that a low protein diet is being used successfully.
Methods of expressing protein intake Consider a canned food that is 4.3% protein as fed and contains 73.3% moisture.
On a dry matter basis, this food contains 16.1% protein. This is because in 100 g of food, only 26.7 g is dry matter (the
rest is water) and 4.3 g protein/26.7 g dry matter = 16.1%. If (on a dry matter basis) the food contains 16.1% protein,
27.3% fat, and 52.8% carbohydrate:
% (DMB)
Protein
Fat
Carbohydrate
16.1
27.3
52.8
Total



kcal/g*
3.5
8.5
3.5
kcal
=
=
=
57.8
232.0
184.8
474.6 kcal
The kcal from protein would be 57.8/474.6 or 12.2%. Assuming that a dog would eat 30 kcal/lb/day, 12.2% of these
calories will come from protein: 0.122  30 = 3.65 kcal/lb/day from protein. Protein has a caloric density of 3.5 kcal/g.
Hence the dog will consume 3.65/3.5 = 1.04 g/lb/day of protein.
* These figures are different from the caloric density figures typically seen in textbooks: fat 9 kcal/g, carbohydrate 4
kcal/g, and protein 4 kcal/g. The adjusted figures shown here are based on the fact that foods are not 100% digestible.
3. Caloric needs
a. Adequate non-protein calories to maintain body condition should be provided by
carbohydrate and fat
b. 30 kcal/lb/day are recommended as a general guideline but older animals may eat
fewer calories normally (e.g., 20 kcal/lb/day)
4. Lipids
a. Supplementation of the diet with ω-6 PUFA may hasten progression of chronic
renal disease whereas supplementation with ω-3 PUFA may be renoprotective.
b. The ideal ω-6 to ω-3 ratio in the diet is not known. Studies demonstrating the
beneficial effects of ω-3 PUFA in dogs with renal ablation have employed very
low ratios (e.g., 0.2:1) that are not commercially achievable. An ω-6 to ω-3 ratio
of somewhere between 5:1 and 15:1 may be reasonable. Alternatively, the diet
can be supplemented with 1 to 5 grams per day of ω-3 PUFA. Two to 4 weeks are
required for potential benefits to be observed.
5. Sodium chloride
a. Increased FRACTIONAL sodium excretion in CRF allows maintenance of sodium
balance during the course of progressive renal disease (refer to material about
maintenance of solute balance in progressive renal disease above).
b. In dogs and cats with CRF and hypertension and in those with glomerular disease
that have sodium retention and edema, sodium restriction is advisable.
c. In the absence of edema, hypertension, primary glomerular disease, or congestive
heart failure, no abrupt changes in sodium intake should be made.
d. Patients with CRF are less flexible in adjusting to changes in dietary sodium load.
Any changes should be made slowly beginning with a dietary intake of sodium
similar to the animal's previous diet and changing gradually over the next month
to the desired level of sodium intake. Many commercial pet foods provide more
sodium than needed (often about 1%) and commercial products marketed for dogs
and cats with CRF provide about 0.2-0.3% sodium. Gradually switching an
animal to one of these latter products will result in gradual sodium restriction and
this probably is appropriate.
6. Sodium bicarbonate
a. The metabolic acidosis of CRF often is well-compensated and routine treatment
may not be necessary.
b. If metabolic acidosis is severe (total CO2  12 mEq/L), NaHCO3 may be added to
the treatment regimen. The dosage should be adjusted to maintain the serum
bicarbonate level  14 mEq/L and the additional sodium intake should be taken
into consideration. One teaspoon of NaHCO3 contains approximately 5 grams of
NaHCO3 and 1,300 mg sodium. Potassium gluconate or potassium citrate are
alternative sources of base that provide potassium and do not pose the problem of
additional sodium.
7. Potassium
a. Hyperkalemia usually is not a problem in CRF. The kidneys can maintain normal
serum potassium concentrations at 5% of normal GFR if urine volume is
adequate.
b. Hypokalemia in dogs and cats with CRF may be treated with oral potassium
gluconate or citrate
8. Water soluble vitamins (B-complex and C) should be supplied in the diet of dogs and
cats with CRF because the ability of the diseased kidney to conserve these vitamins is
not known.
C. Phosphorus restriction
1. Early phosphorus restriction in CRF has been shown in rats, cats, and dogs to blunt or
reverse renal secondary hyperparathyroidism. In a study of dogs with 94%
nephrectomy fed diets containing 17% protein with 0.5% or 1.5% phosphorus,
outcome was worse in the dogs fed the higher phosphorus diet. Tubulointerstitial
lesions also were worse in dogs on the higher phosphorus diet. In another study, renal
secondary hyperparathyroidism was documented in 84% of cats with naturallyoccurring CRF and responded (as assessed by serum phosphorus and PTH
concentrations) to dietary phosphorus restriction.
2. Because extremely phosphorus-depleted diets are unpalatable, phosphorus-binding
agents may be given orally to trap phosphorus in the gut and hasten its excretion.
These drugs should be given with meals or within 2 hours of feeding to maximize
their binding of dietary phosphorus.
3. When CRF is diagnosed, phosphorus restriction is initiated by feeding a low
phosphorus, low protein diet. If necessary, oral phosphorus-binding agents can be
added as necessary to the treatment regimen for additional reduction in serum
phosphorus concentration:
a.
b.
c.
d.
e.
Amphojel®, Alternagel®: Al(OH)3
Basalgel®: Al2(CO3 )3
Tums®, Os-Cal®: CaCO3
Phos-Lo®, Phos-Ex®: Calcium acetate
Renagel® (sevelamer hydrochloride) (does not contain aluminum or calcium)
4. In human patients, chronic aluminum intoxication causing bone disease and
encephalopathy has been recognized as an important complication of aluminumcontaining phosphorus binders and it is felt that there is no safe dosage of aluminumcontaining phosphorus binder that will provide sufficient phosphorus restriction
without risk of aluminum intoxication. Consequently, calcium-containing phosphorus
binders have replaced aluminum-containing phosphorus binders in human patients
with CRF. It is not clear yet that aluminum intoxication is a problem in dogs and cats
that do not live as long during treatment of their CRF as many people do.
Consequently, aluminum-containing phosphorus binders are still used by many
veterinary clinicians.
5. Amphojel® initially is used at a dosage of 30 mg/kg q8h or 45 mg/kg q12h given
with food. An attempt should be made to maintain serum phosphorus < 6.0 mg/dl.
6. Calcium carbonate (Tums®: 500 mg CaCO3 per tablet; Os-Cal 500®: 1.25 grams
CaCO3 per tablet) also may be used at a starting dosage of 30 mg/kg q8h or 45 mg/kg
q12h given with food. It has the advantage of not containing aluminum that may be
toxic if absorbed from the gastrointestinal tract.
7. Calcium acetate is more effective than the other aluminium or calcium-containing
phosphorus binders and may be used at a slightly lower dosage.
8. The animal should be monitored for development of hypercalcemia whenever
calcium-containing phosphorus binders are used.
9. Constipation may be a complication of phosphorus binders. Constipation may be
managed by addition of lactulose to the treatment regimen.
10. Sevelamer HCl (Renagel®) is a new phosphorus binder used in human patients on
dialysis
a. Sevelamer does not contain aluminum or calcium
b. Dosage in humans is 800 to 1600 mg three times per day taken with meals. Based
on this dosage, 10 to 20 mg/kg q8h given with food may be considered in small
animals.
c. May be associated with gastrointestinal side effects including constipation
d. At extremely high dosages (6 to 100 times the recommended dosage in humans)
may be associated with impaired absorption of folic acid and vitamins K, D, and
E
11. If the patient is not hyperphosphatemic at the time of initial evaluation, phosphorus
restriction still may be beneficial in reversing existing renal secondary
hyperparathyroidism. The patient must be monitored carefully to prevent
development of hypophosphatemia. Fractional excretion of phosphorus can be
monitored but is not a very sensitive indicator of renal hyperparathyroidism. All
serum phosphorus determinations should be made in the fasting state. Serial PTH
determinations are an ideal way to monitor treatment of renal hyperparathyroidism
D. H2 receptor antagonists may have beneficial effects in renal failure. Gastrin
concentrations are increased in uremic dogs and cats. H2 receptor antagonists block
gastrin-mediated increases in gastric acid secretion and may be helpful in the treatment of
hemorrhagic gastroenteritis in uremic dogs and cats.
1. The dosage of cimetidine is 5-10 mg/kg q12h followed by 5 mg/kg q12 to q24h.
Cimetidine inhibits hepatic metabolism of many drugs by interference with
microsomal enzymes or decreased hepatic blood flow and caution should be
exercised when using cimetidine with other drugs especially ketoconazole,
theophylline, phenytoin, propranolol, lidocaine, quinidine, procainamide,
metronidazole, warfarin, and meperidine.
2. Other H2 blockers (e.g. ranitidine [Xantac®], famotidine [Pepcid®]) are less likely to
result in adverse drug reactions when used in combination with other drugs. In
addition, famotidine may be used q24h at a dosage of 1 mg/kg in dogs and cats.
E. Endocrine replacement therapy
1. Recombinant human erythropoietin (Epogen®)
a. This drug has been used to correct the nonregenerative anemia of CRF in some
dogs and cats.
b. Dogs and cats treated with Epogen® demonstrate resolution of anemia, weight
gain, improved appetite, improved haircoat, and improved sociability with their
owners.
c. Epogen® is NOT approved for used in animals and there is a 20-40% risk of antiEPO antibody formation that may result in severe anemia and subsequent
transfusion dependence. Antibodies tend to form 30-90 days after initiation of
therapy and are heralded by a marked increase in the M:E ratio of the bone
marrow. This represents a serious side effect of Epogen® in animals.
d. The starting dosage is 100 U/kg SQ 3 times a week.
e. Hematocrit must be monitored closely during therapy and the dosage adjusted to
achieve and maintain a target hematocrit of 30-40%. The frequency of
administration is decreased to 2 times per week as soon as the animal’s hematocrit
enters the target range. Always measure the hematocrit by the same method so
that the values obtained can be compared to one another (i.e. do not compare
packed cell volumes determined by table top centrifuge to hematocrits calculated
on a Coulter Counter). Small sequential decreases in hematocrit or PCV while an
animal is being treated with Epogen® are presumptive evidence of anti-EPO
antibody formation.
f. Other adverse effects observed during treatment of dogs and cats with Epogen®
include vomiting, seizures, hypertension, uveitis, and mucocutaneous
hypersensitivity-like reactions.
g. Due to adverse effects and expense, Epogen® is reserved for animals with severe
and symptomatic anemia (e.g. PCV < 12-15%).
h. Iron supplementation should be provided during (and ideally before) Epogen®
treatment to insure that the animal is iron replete
i. Studies using canine and feline recombinant erythropoietin and studies of gene
therapy to transfer the feline erythropoietin gene in cats are in progress and may
lead to improved treatments for the anemia of CRF in dogs and cats
2. Vitamin D (calcitriol or 1,25-dihydroxyvitamin D) therapy
a. In the kidney, 25-hydroxyvitamin D is converted to the active form of vitamin
D3, 1,25-dihydroxyvitamin D (calcitriol) by the enzyme 25-hydroxyvitamin
D-1α-hydroxylase (1α-hydroxylase) which is found in the tubular cells (see
Figure 3 above)
b. The activity of 1α-hydroxylase is closely regulated
i. It is stimulated by PTH and hypophosphatemia
ii. It is inhibited by its product (calcitriol)
iii. There is an inverse relationship between dietary calcium intake and the
activity of the enzyme. Hypercalcemia impairs and hypocalcemia stimulates
calcitriol production
c. The major effects of 1,25-dihydroxyvitamin D (calcitriol) are:
i. increased intestinal absorption of calcium (and phosphate)
ii. a permissive effect on PTH-mediated bone resorption of calcium and
phosphorus
iii. negative feedback control on PTH synthesis by the parathyroid glands
(relative lack of this effect plays an important role in the development of renal
secondary hyperparathyroidism in patients with CRF)
iv. increased renal tubular reabsorption of calcium (and phosphate)
d. Calcitriol synthesis is impaired in "early" CRF due to inhibition of 1-α
hydroxylase by hyperphosphatemia. This inhibition may be relieved by dietary
phosphorus restriction and if necessary administration of phosphorus binders. In
“late” CRF, there may be insufficient renal mass to produce adequate amounts of
calcitriol. Calcitriol supplementation then is indicated in management of CRF
patients. Calcitriol has primary value by virtue of its ability to feed back to
calcitriol receptors in the parathyroid glands and decrease PTH synthesis by the
parathyroid glands.
e. Calcitriol must only be used after hyperphosphatemia has been adequately
controlled by a low protein/phosphorus diet and oral phosphorus-binding agents
f. If the Ca  P solubility product is > 60-70, calcitriol therapy should be avoided
because of the risk of soft tissue mineralization
g. A very low dosage of calcitriol (2.5-3.5 ng/kg/day) has been used in dogs and cats
with CRF to prevent or reverse renal secondary hyperparathyroidism. Serial
serum calcium concentrations are monitored to avoid development of
hypercalcemia. Serum PTH concentrations fall dramatically in dogs and cats with
CRF that are treated with calcitriol.
F. Anabolic steroids
1. Many products are available but there are no long-term studies demonstrating their
efficacy in dogs and cats with CRF:
a.
b.
c.
d.
methyltestosterone
stanozolol (Winstrol-V®)
oxymetholone (Anadrol®, Adroyd®)
nandrolone decanoate (Deca-Durabolin®)
2. Stanozolol had equivocal effects in one short-term study of dogs with experimentallyinduced CRF. Total amount of food consumed, lean body mass, and nitrogen balance
increased but there was no significant effect on body fat, bone mineral, or food
consumption per kg of body weight.
3. Stanozolol has a narrow margin of safety in cats and is hepatotoxic. It resulted in
increased liver enzyme activities and vitamin K-responsive coagulopathy. Hepatic
lipidosis and cholestasis were observed histologically.
G. Blood pressure control
1. Oscillometric or Doppler methodology can be used reliably in dogs, but Doppler
methodology is more reliable in cats.
2. Difficulty to decide if a cat is truly hypertensive due to “white coat artifact”
3. Measurement
a.
b.
c.
d.
e.
f.
Patient, trained technician
Quiet, undisturbed environment
Sufficient time for acclimation
Correct cuff size
Several sequential measurements
Take average of sequential readings
4. Decision to treat
a. Systolic pressure > 170-180 mm Hg
b. Increased blood pressure and ocular abnormalities compatible with hypertension
(see above under cardiopulmonary complications of CRF)
5. Treatment
a. Low salt diet (most commercial diets formulated for for dogs and cats with CRF
are low in sodium)
b. Diuretics
i. Furosemide (must be cautious to prevent dehydration and development of prerenal azotemia)
ii. Thiazides (e.g., hydrochlorothiazide)
c. ACE inhibitors (e.g., enalapril, benazepril)
i. Effect on blood pressure may be modest
ii. Other potentially beneficial effects in CRF patients (see elsewhere in notes)
iii. Enalapril dosage: 0.5 mg/kg PO q12 h or q24h
d. Amlodipine (vascular calcium channel blocker)
i.
ii.
Helpful in hypertensive cats (0.625 to 1.25 mg PO q24h)
May try 0.18 mg/kg PO q24h in dogs
e. Hydralazine (arterial vasodilator)
f. Prasozin (α1 adrenergic blocker)
g. Propranolol (nonspecific β blocker)
H. Situations that may be stressful to the animal are avoided if possible
1. Management whenever possible on an outpatient basis
2. Owners can be taught to administer subcutaneous fluids to their animal at home. This
is particularly convenient in cats and small dogs. The additional fluid support can
have important beneficial effects on the animal's quality of life.
IX.
Course and prognosis
A. Ultimately poor if renal disease is documented to be progressive by serial examination
1. Rate of progression varies among individual animals. May live months to years. Try
plotting 1/serum creatinine vs time (slope is an indication of rate of progression)
2. Findings suggestive of a poor prognosis
a.
b.
c.
d.
e.
f.
Severe intractable anemia
Advanced osteodystrophy
Inability to maintain fluid balance off fluids
Progressive azotemia despite fluid therapy and conservative medical management
Progressive weight loss
Intractable hypercalcemia
g. Severe endstage lesions on biopsy
REFERENCES AVAILABLE ON REQUEST
Revised: June 27, 2001