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Long-term Medical Management of Feline
Chronic Renal Failure
Introduction
Chronic renal failure (CRF) is a common cause of illness in cats,
especially in older cats, and the incidence of CRF is increasing.1
In 1990, there were 45 cases of CRF for every 1000 cats admitted to
veterinary teaching hospitals. In 2000, the number increased to 96 cases
per 1000 cats.
Unless the underlying cause of the initial renal injury can be
discovered and treated, CRF invariably progresses. In some instances,
even after identifying the initial cause of the renal injury, a
threshold or “trigger-point” has already been reached, and
self-perpetuating mechanisms of kidney destruction are activated. In
most cases, an underlying cause for the initial renal insult cannot be
found.
CRF is incurable. With the exception of a kidney transplant, it
is difficult or impossible to improve kidney function in cats with
chronic renal failure. It is possible, however, to delay the progression
of renal failure, improve the cat’s quality of life, and extend a cat’s
survival time through a variety of diet and drug interventions.
Acute management for CRF cats that are clinically ill
Therapy for CRF can run the gamut, from a simple dietary change
to a hospital stay of several days duration, depending on severity and
how early the disease has been detected. For cats hospitalized with
renal failure, fluid therapy remains the cornerstone of treatment.
Administering fluid to cats with CRF corrects dehydration and increases
urine production, reducing azotemia. Fluid therapy corrects acid/base
imbalances, and helps to restore normal phosphorus and potassium levels.
This is crucial, as increased levels of phosphorus and decreased levels
of potassium can accelerate progression of the renal damage.2,3
Cats with CRF may have trouble conserving water-soluble vitamins
(the B vitamins and vitamin C) due to excessive loss through urine4,5,
and these vitamins can be replaced through the fluid therapy as well.
Nutrition is an essential part of the therapy for CRF. Many cats
hospitalized with CRF have decreased or absent appetite. During
hospitalization, nutritional support can be achieved either through
force feeding, tube feeding, or intravenous feeding, depending on the
severity of the inappetance, the degree of malnutrition, and the cat’s
demeanor.
Nausea is a common occurrence for cats with CRF. The kidneys are
responsible for excreting the hormone gastrin.
As such, cats with CRF often have hypergastrinemia, which leads
to production of excessive amounts of gastric acid.6 This may
contribute to the anorexia and vomiting seen in many cats with CRF.
Administration of H2-receptor antagonists such famotidine,
either subcutaneously or orally, may be beneficial in this regard.
A major objective of acute therapy is to significantly decrease
the level of azotemia. A
reduction of blood urea nitrogen (BUN) and creatinine to normal levels,
however, is often impossible and should not necessarily be the
practitioner’s goal. During hospitalization, BUN and creatinine levels
are measured every two or three days until a plateau is reached.
After several days, many cats will have improved clinically and
can be released from the hospital to the owner. A typical hospital stay
lasts from three to six days.
It should be made clear to the owners of a cat with CRF that the
treatment the cat received while hospitalized does not return the
kidneys to normal, and that a conscientious home maintenance program
will be necessary for the remainder of the cat’s life.
The focus of this article is on the long term management of CRF
in cats.
Long term management and
prevention of the progression of CRF
Dietary management
The benefits of dietary modification in CRF have been well
documented. Protein, when metabolized, gives rise to uremic toxins that
the failing kidneys cannot properly excrete. By reducing the amount of
protein in the diet, azotemia is lessened, and this helps ameliorate
clinical signs such as weight loss, poor appetite, vomiting, and
lethargy. In the past, choices were very limited with regard to these
diets for cats. Fortunately, several companies now manufacture palatable
feline “kidney failure diets” that are restricted in protein as well as
phosphorus and sodium.
Much controversy has been generated as to whether dietary protein
restriction can actually slow the progression of kidney disease in cats.
Several studies in recent years, however, have confirmed that dietary
modification can have a significant impact on mortality in cats. Cats
with naturally occurring renal failure that were fed a veterinary renal
diet lived considerably longer (median survival 633 days) than those cat
that did not receive (or refused to eat) these diets (median survival
264 days).3 Another study compared 23 cats fed a maintenance
food with 22 cats fed a prescription diet designed for renal failure.
Cats fed the maintenance food had a significantly greater number
of uremic episodes compared to cats fed the renal diet.
Throughout the duration of the 2 year study, none of the cats fed
the renal diet died from kidney-related causes, whereas five cats in the
maintenance group died from renal causes.7 These data led the
authors to recommend feeding a renal diet to cats with CRF early in the
course of disease, i.e. when their serum creatinine level exceeds 2 mg/dL.
More recently, a retrospective study compared 175 cats with kidney
failure fed maintenance diets with 146 cats fed a special diet designed
for renal failure. Survival time for cats on the conventional diet was 7
months, compared to 16 months for those fed the prescription diets.8
These studies confirm that cats that consume a prescription “kidney
failure diet” have increased survival and good quality of life compared
to cats that do not (or will not) eat this type of diet. Many
manufacturers, for example, The Hill’s Company (Topeka,
Kansas), Iams Company (Dayton,
Ohio), Royal Canin Company (St. Charles, Missouri), and Purina Company (St. Louis, Missouri),
now offer these kinds of diets. Whether or not one particular brand
offers more benefit than another remains to be determined.
Monitoring potassium
Hypokalemia is a common finding in feline CRF. It is unclear
whether hypokalemia is a cause of CRF, a consequence of CRF, or both.9
Most instances of hypokalemia are mild, with no apparent clinical signs.
Marked hypokalemia, however, can lead to general muscle weakness.
In more severe cases, cats can develop hypokalemic polymyopathy
which, if misdiagnosed, can lead to paralysis of the respiratory muscles
and death by respiratory arrest if aggressive potassium supplementation
is not undertaken. Potassium
depletion and hypokalemia in cats with CRF may result from inadequate
consumption of potassium, dietary issues, enhanced renal loss of
potassium, or a combination of these factors.10
Hypokalemia contributes to the progression of kidney failure.2
In many cats with CRF and hypokalemia, kidney function improves when low
potassium levels are restored to normal using oral or parenteral
potassium therapy, suggesting that hypokalemia may induce a reversible
reduction in glomerular filtration rate.9,10 Potassium
supplements (usually in the form of potassium gluconate) are currently
available in a variety of palatable forms (oral liquids, granules to be
added to food, and flavored ointments), increasing the likelihood of
successful administration in cats who tend to be finicky or difficult to
medicate.
Vitamins and omega-3 fatty acids
Cats with diseased kidneys have difficulty conserving water
soluble vitamins5,
given the excessive amount of urine that is
produced by the failing kidneys every day.
Cats with chronic renal failure, therefore, should receive a
daily multivitamin. 4
In human patients with CRF, increased free radical production and
antioxidant depletion may play a role in progression of the disease11,
and supplementation of the diet with antioxidants such as vitamins A, C,
and E has been shown to reduce oxidative stress in humans with CKD.12
A recent study in which cats with CRF were fed a prescription
diet designed for renal failure that was supplemented with additional
vitamin E (742 mg/kg), Vitamin C (84 mg/kg) and beta-carotene (2.1
mg/kg) showed a significant reduction of oxidative DNA damage in cats
with spontaneous CRF.13
Prescription diets that are designed for cats with renal failure
are restricted in protein, phosphorus and sodium. Recently,
manufacturers have been adding a larger proportion of omega-3 fatty
acids to these diets, based on studies showing evidence of beneficial
effects these fatty acids have in dogs14, and presumably
cats, with chronic renal failure.
While it has been shown that and cats 3,7,8 fed
prescription diets designed for renal failure live longer and have
improved quality of life than cats fed a conventional diet, it is not
possible to say which single nutrient alteration (or combination of
alterations) is responsible for the benefit. In a retrospective study
that evaluated the median survival time of cats fed a variety of “renal
failure diets” vs. maintenance diets, not only did the cats fed the
modified diets live longer (median survival: 7 months vs. 16 months),
the diet associated with the longest survival time (23 months) had
particularly high levels of eicosapentaenoic acid.8 The ideal
ratio of omega-6: omega-3 fatty acids in diets designed for renal
failure has yet to be determined.
Controlling excessive urinary protein loss
In humans, proteinuria is a risk factor for the progression of
chronic renal failure, and controlling proteinuria has been shown to
increase survival times in humans with CRF.
A recent study has shown that the severity of proteinuria is
related to survival in cats with chronic renal failure.15
When the kidneys start to fail and nephrons are lost, hemodynamic
adaptations occur in some of the remaining nephrons, causing increased
single nephron GFR, glomerular plasma flow, and increased hydraulic
pressure across the glomerulus.16
Angiotensin converting enzyme (ACE) catalyzes the
generation of angiotensin-II from angiotensin-I within the kidney,
causing vasoconstriction of glomerular arterioles. The efferent
arteriole is preferentially constricted.
Vasoconstriction of the efferent arteriole increases
intraglomerular capillary pressure.
Initially, this is adaptive, allowing for maintenance of
excretory function and total kidney GFR.
Ongoing intraglomerular hypertension, however, is ultimately
maladaptive, leading to increased trafficking of macromolecules into the
mesangium, resulting in proliferation of mesangial cells and increased
production of mesangial matrix, i.e. glomerulosclerosis, resulting in
further kidney damage.
Measuring the intraglomerular pressure is not possible in a
clinical setting, however, proteinuria can be an indicator of elevated
glomerular pressure. Proteinuria can be detected and quantified by
determining the urine protein/creatinine ratio (UPC). In cats, a UPC ≥
0.5 is indicative of persistent renal proteinuria.17
In a study that looked at the relationship between survival time
and proteinuria in cats with CRF, the UPC was shown to be a significant
predictor of survival time.
Median survival time for cats with a UPC < 0.43 was 766 days compared to
only 281 days for cats with UPC > 0.43. 15 Although cats with
chronic renal failure typically have low concentrations of protein in
their urine, the degree of proteinuria is of prognostic significance.
ACE inhibitors are ideally suited to treat elevated
intraglomerular pressure because they selectively dilate the efferent
arteriole of the glomerulus.
The ACE inhibitor benazepril has
been shown to prolong survival time and reduce proteinuria in a large
clinical trial in humans 18
and to have beneficial hemodynamic effects (normalization of glomerular
hypertension with maintained or increased glomerular filtration rate) in
a model of CRF in cats.19 Benazepril has been studied
in cats. A clinical trial of
201 cats with CRF showed that cats that received benazepril had improved
appetite, quality of life, weight gain, and longer lifespan,
particularly those cats whose renal failure was deemed severe (401 day
survival, compared to 126 days for cats that received placebo). 20
Benazepril appears to decrease proteinuria, and in doing so increases
survival times and slows progression of renal disease in cats diagnosed
with CRF. Veterinarians
should view the results of this study cautiously, however, as the
results have not been published in a peer-reviewed veterinary journal.
Phosphorus restriction, Renal Secondary Hyperparathyroidism, and
Calcitriol
Renal secondary hyperparathyroidism occurs when the parathyroid
glands secrete excessive parathyroid hormone as a result of chronic
renal failure. This is due
to several factors, the primary factor being an impaired ability of cats
with CRF to synthesize calcitriol.
The kidneys are responsible for the final step in the synthesis
of calcitriol from its precursor, 25-hydroxyvitamin D.
As the kidneys fail, there are fewer healthy proximal tubule
cells with the enzyme system necessary to catalyze this synthesis.
Another contributing factor is the inhibition of calcitriol synthesis
due to rising phosphorus levels.
Phosphorus inhibits the enzyme system involved in the synthesis
of calcitriol.
Phosphorus is filtered from the bloodstream by the kidneys. When
the kidneys begin to fail, the phosphorus levels begin to rise. When
serum phosphorus levels are high, phosphorus can combine with calcium in
the bloodstream. This is
known as the law of mass action.
The formation and deposition of calcium phosphate in the soft
tissues, including the kidneys, can cause further renal damage.
Serum phosphorus levels in excess
of 7 or 8 mg/dL will decrease the serum ionized calcium level
approximately 0.1 mg/dL, which is enough to stimulate PTH secretion.
This is yet another factor in which hyperphosphatemia promotes
the development of renal secondary hyperparathyroidism.
Calcitriol plays a role in maintaining normal levels of calcium
in the bloodstream, since calcitriol is necessary for the intestines to
properly absorb dietary calcium.
As the kidneys fail and become incapable of producing adequate
amounts of calcitriol, the serum calcium level begins to fall. To
maintain adequate levels of calcium in the bloodstream, the parathyroid
glands release PTH, restoring and maintaining normal calcium levels.
Although production of PTH is physiologically appropriate,
excessive amounts of PTH are toxic to the kidneys and other organs.
Toxic effects of PTH on the brain likely contribute to the depression
and stupor seen in cats with renal failure.21 In experimental
animals, excessive PTH also slows nerve conduction, contributes to the
anemia often seen with CRF, and enhances the progression of kidney
failure.21 This likely
occurs in cats as well.
Calcitriol is the natural, biologically active form of Vitamin D.
When administered to animals with renal secondary hyperparathyroidism,
calcitriol causes a reduction in PTH production by the parathyroid
glands. 18 Reducing PTH levels through control of dietary
phosphorus intake has been shown to improve survival in cats3
with CRF. Although data demonstrating improved survival as a result of
administration of calcitriol to cats with CRF is lacking, calcitriol has
many direct beneficial effects in uremic animals independent of its
PTH-lowering properties21, and administration of calcitriol
to supplement cats in the early stages of chronic renal disease appears
safe, effective, and advisable. 22
Limiting phosphorus consumption appears to slow the progression
of CRF in humans and dogs, and there is evidence that dietary phosphorus
restriction also limits renal injury in cats with CRF.3
Prescription diets designed for cats with kidney failure contain
reduced levels of phosphorus. However, the level may not be restricted
enough to prevent hyperphosphatemia. Orally administered phosphorus
binders, such as aluminum salts (e.g. aluminum hydroxide) and calcium
salts (e.g. calcium carbonate) are the most commonly used phosphate
binders. Aluminum salts have been removed from the human market over
concern for aluminum toxicity.
Sevelamer hydrocholoride (Renalgel) is an organic polymer that is
a non-calcium, non-aluminum containing compound that binds phosphorus in
the intestinal tract. It has been used safely in cats, but has the
potential to bind vitamins in the intestinal tract. Animals receiving
this drug should receive a vitamin supplement as a precaution. Lanthanum
carbonate (Fosrenol) is a new intestinal phosphate binder in human
medicine that does not contain calcium or aluminum. Reports of its
clinical use in dogs or cats are lacking.
Epakitin (Vetoquinol USA,
Buena
NJ) is a phosphate binder
consisting of calcium carbonate and chitosan. Most cats dislike the
taste of liquid phosphorus binders, and the tablets are often difficult
to administer due to their large size. Epakitin is a palatable powder
that can be mixed into canned food. Because
they are calcium-based, there is some concern that the use of calcium
salts could raise the blood calcium level, especially if given in
conjunction with calcitriol.
Phosphorus binders are most effective when given at the time of feeding
or shortly thereafter (within 2 hours).
Traditionally, phosphorus restriction was initiated when high
phosphorus levels were detected on blood tests.
However, phosphorus restriction may have benefit when initiated
before the onset of overtly high levels of phosphorus, because renal
secondary hyperparathyroidism occurs before serum phosphorus
concentrations exceed the normal range, and because fasting serum
phosphorus concentration may not accurately reflect overall phosphorus
metabolism.10
Return of serum phosphorus to normal levels does not guarantee that PTH
levels will return to normal, since phosphorus restriction is effective
only in those animals that have an adequate number of healthy proximal
tubule cells to synthesize calcitriol once the inhibitory effects of
excessive phosphorus are controlled.
For those patients whose PTH levels remain high despite a
seemingly well-controlled phosphorus level, administration of calcitriol
may be necessary to control PTH levels.
Calcitriol should not be given to cats until hyperphosphatemia
has been controlled. If the
Ca x P product exceeds 70, or if the serum phosphorus remains higher
than 6.0 mg/dl, calcitriol should not be administered, as soft tissue
mineralization, including renal mineralization, is a risk.
Fluid therapy
While there are ways to encourage additional water intake in the
home setting (e.g., feeding canned food rather than dry food, adding
water or broth to the food), the fluid intake for cats with CRF is often
inadequate, and some cats require subcutaneous fluid administration.
Most cats tolerate this well, and clients can easily be taught how to
perform this procedure. Fluids are initially administered every day, and
may be tapered to every other day or even less frequently, depending on
how the cat is feeling at home. There is no consensus among
veterinarians regarding when subcutaneous fluid therapy should be
initiated in any given feline patient. In the author’s experience, cats
are clinically more sensitive to changes in hydration status compared to
dogs and will often show dramatic improvement in appetite and activity
when given subcutaneous fluids, with no clear correlation to their level
of azotemia.
Controlling high blood pressure
High blood pressure is seen in almost 20% of cats with CRF
presenting to primary care facilities23.
In referral practices, the incidence has been reported to be as
high as 65%.24 CRF, perfusion pressure in remnant glomeruli
tends to be increased.
Increased systemic blood pressure may be transmitted to the glomeruli,
causing further damage. Hypertension can also cause damage to the brain,
eyes, and heart if uncontrolled.
High blood pressure is a major risk factor for the progression of
chronic renal failure in humans and rats, and evidence has shown this to
be true for dogs25 , and presumably for cats as well.
Cats with CRF should have their blood pressure evaluated.
Hypertension in cats is defined as an indirect systolic pressure greater
than 160 or 170 mm Hg, and a diastolic blood pressure greater than 100
mm Hg.26,24
If hypertension is detected, treatment with amlodipine is
recommended. Hypertensive cats need life-long therapy to keep their
blood pressure under control.
Nausea and vomiting.
Gastrin is a digestive hormone that causes the stomach to produce
acid. The kidneys are responsible for excreting much of the gastrin
produced in the body. As the kidneys fail, gastrin levels begin to rise,
the degree of hypergastrinemia increasing with the severity of the renal
insufficiency.6 This results in increased gastric acidity,
nausea, vomiting, poor appetite, and possible gastric ulceration and
justifies the use of appropriate treatments, such as histamine-2
receptor antagonists or proton pump inhibitors to suppress gastric acid
secretion. Cimetidine, ranitidine, and famotidine are effective at
decreasing gastric acidity in cats. Famotidine may offer an advantage in
that it may be administered only once daily, compared to the others. For
cats suspected of having gastric ulcers, sucralfate helps form a
protective coating over the ulcer, reducing symptoms such as pain,
nausea, and vomiting. The use of a compounding pharmacy may be
necessary, as sucralfate tablets cannot be divided accurately to achieve
the proper dose for most cats.
Anemia
As the kidneys fail, they produce inadequate amounts of
erythropoietin, and many cats with CRF become progressively anemic.
Anemia contributes to the lethargy and poor appetite seen in cats with
CRF. Recombinant human erythropoietin, when given to cats dramatically
reverses the anemia. However, because the hormone is not of feline
origin, approximately 25% of cats will develop antibodies against it.
These antibodies not only bind the human erythropoietin being
administered, but will also bind whatever remaining feline
erythropoietin is present. Cats develop sudden, severe anemia as a
result, and become transfusion dependent.
It is usually at this point that owners elect euthanasia.
Intraintestinal Bacteriotherapy (“Enteric Dialysis”)
The concept of “enteric dialysis” is based on the premise
that the intestinal wall functions as a semi-permeable membrane; solutes
that are in high concentration in the bloodstream readily diffuse from
plasma into the intestinal lumen.
The use of live bacteria that catabolize uremic solutes in the
gut when ingested would create a gradient favorable for the uremic
toxins to diffuse from the plasma into the gut. Azodyl® (Vetoquinol
USA, Buena, NJ)
is a recently introduced nutritional supplement that contains the
bacteria Enterococcus thermophilus,
Bifidobacterium longum, and
Lactobacillus acidophilus, in
capsule form, for this purpose. However, there are no controlled
clinical trials of the use of these probiotics for azotemia and chronic
renal failure in cats.
Conclusion
Many advances have been achieved regarding the treatment of
chronic renal failure. Although CRF is not curable, cats can
live for many years after diagnosis if treated appropriately.
Updated 6/21/11
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Dr. Plotnick's Blog Posts:
Chronic Renal Failure (CRF) ,
kidneys
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