CKDD
CKDD
CKDD
Chronic kidney disease (CKD) involves a loss of functional renal tissue due to a
prolonged (≥2 mo), usually progressive, process. Dramatic changes in renal structure
may be seen, although structural and functional changes in the kidney are only loosely
correlated. CKD often smolders for many months or years before it becomes clinically
apparent, and it is invariably irreversible and frequently progressive. Although congenital
disease results in a transient increase in prevalence in animals <3 yr old, the prevalence
increases with advancing age from 5–6 yr. In geriatric populations at referral institutions,
CKD affects as many as 10% of dogs and 35% of cats. The prevalence in the general
small animal population is likely to be lower, perhaps 1%–3%. Several breeds of dogs
and cats are associated with heritable CKD ( see Congenital and Inherited Anomalies of
the Urinary System). There is no apparent breed or sex predisposition for nonheritable
CKD in dogs or cats.
In general, animals in substage AP3 and those in substage AP2 with preexisting target
organ damage (eg, retinal injury or CKD) should be considered candidates for
antihypertensive therapy.
Species-specific antibodies for albumin have led to development of highly specific and
sensitive assays for the detection and measurement of urine albumin concentrations.
Microalbuminuria is defined as a urine protein content that leads to a negative reaction
for the routine urine dipstick and a positive reaction with a species-specific antibody
test. Animals with microalbuminuria frequently exhibit or subsequently develop kidney
disease, systemic inflammatory or metabolic disease, neoplasia, or infectious diseases.
Etiology:
Attempting to identify the primary process causing the kidney disease, especially in
Stages 1 and 2, is important to form a prognosis and treatment plan. Known causes of
CKD include diseases of the macrovascular compartment (eg, systemic hypertension,
coagulopathies, chronic hypoperfusion), microvascular compartment (eg, systemic and
glomerular hypertension, glomerulonephritis, developmental disorders, congenital
collagen defects, amyloidosis), interstitial compartment (eg, pyelonephritis, neoplasia,
obstructive uropathy, allergic and immune-mediated nephritis), and tubular
compartment (eg, tubular reabsorptive defects, chronic low-grade nephrotoxicity,
obstructive uropathy). Many causes of chronic, generalized renal disease are associated
with progressive interstitial fibrosis. The severity of interstitial fibrosis is positively
with progressive interstitial fibrosis. The severity of interstitial fibrosis is positively
correlated with the magnitude of decline of GFR and negatively correlated with the
prognosis. The glomerular, tubulointerstitial, and vascular lesions found in animals with
generalized CKD are often similar, regardless of the initiating cause, particularly in Stage
4. At this point, renal histology may show only marked interstitial fibrosis, which may be
called chronic interstitial nephritis or tubulointerstitial fibrosis. This term describes the
morphologic appearance of kidneys with end-stage chronic disease of any cause.
Because acute kidney injury may progress to a chronic condition, any cause of acute
kidney injury is also a possible cause of CKD.
Clinical Findings:
Generally, no clinical signs are seen as a direct result of disease until ≥75% of nephron
function has been impaired (Stages 3 and 4). Exceptions are chronic kidney diseases
that develop as part of a systemic disease with clinical signs referable to involvement of
other body tissues (eg, systemic lupus erythematosus, systemic hypertension), chronic
kidney diseases accompanied by nephrotic syndrome, or those associated with marked
renal inflammation and capsular swelling leading to flank pain and occasionally to
vomiting. Usually, the earliest clinical signs commonly attributable to renal dysfunction
are polydipsia and polyuria, which are not seen until the function of approximately two-
thirds of the nephrons has been impaired (late Stage 2 or early Stage 3). Further
destruction of renal tissue leads to azotemia without new clinical signs in Stage 2, and
finally to the clinically apparent uremic syndrome in Stage 4. Initially, uremia is
associated with occasional vomiting and lethargy. As the disease progresses within
Stages 3 and 4 throughout months (dogs) to years (cats), anorexia, weight loss,
dehydration, oral ulceration, vomiting, and diarrhea become fully manifest. Loose teeth,
deformable maxilla and mandible, or pathologic fractures may be seen with renal
secondary osteodystrophy ( see Renal Secondary Hyperparathyroidism), but these are
uncommon and generally seen only in young dogs with end-stage congenital renal
disease. Physical examination and imaging studies of animals in Stages 3 and 4 usually
reveal small, irregular kidneys, although normal to large kidneys can be seen in animals
with neoplasms, hydronephrosis, or glomerulonephritis. Mucous membranes are pale in
late Stage 3 and Stage 4, due to the presence of a nonregenerative, normocytic,
normochromic anemia.
Diagnosis:
In Stages 1 and 2, diagnosis is often missed or made incidentally during imaging studies
In Stages 1 and 2, diagnosis is often missed or made incidentally during imaging studies
or urinalyses conducted for other purposes. In Stages 3 and 4, the BUN, serum
creatinine, and inorganic phosphorus concentrations are increased. Potassium
depletion, due to renal potassium wasting combined with inadequate intake and the
kaliuretic effects of acidosis, is frequently seen in cats and occasionally in dogs.
Hyperkalemia associated with oliguria and anuria may be noted in terminal Stage 4 or
whenever marked prerenal azotemia is concurrent with CKD. Systemic hypertension and
associated complications develop in ~20% of affected cats and dogs and can occur at
any stage. Osteoporosis may be seen radiographically, although this late finding is
generally not helpful for diagnosis.
The urine specific gravity may range from 1.001–1.060 in dogs and 1.005–1.080 in cats,
depending on body needs for water homeostasis; the normal range overlaps the
abnormal or inappropriate range. In animals with dehydration and normal renal function,
urine specific gravity should be >1.030 in dogs and >1.035 in cats. The inability to
produce concentrated urine when challenged by dehydration is an early sign of CKD;
however, dogs with primary glomerular disease, and some cats, may become azotemic
while retaining the ability to concentrate urine to a specific gravity >1.035. Even so,
concentrated urine is rarely seen when the serum creatinine is >4 mg/dL in an animal
with azotemia of renal origin.
The polydipsia and polyuria of CKD must be differentiated from diseases that cause
primary polydipsia (eg, psychogenic polydipsia, hyperthyroidism) or interfere directly
with the urine-concentrating mechanism. This includes conditions that lead to retention
of solute in tubular fluid (eg, diuretic administration, diabetes mellitus), central diabetes
insipidus, and nephrogenic diabetes insipidus (eg, hyperadrenocorticism,
hypercalcemia, pyometra, diseases causing septicemia). Adrenal insufficiency leads to a
urine-concentrating defect and may thus be confused with Stage 2 and 3 renal disease,
because prerenal azotemia may be caused by the vomiting, diarrhea, and polydipsia
associated with hypoadrenocorticism. Hyperkalemia, hyponatremia, and/or reduced
plasma Na+ to K+ ratio helps establish a tentative diagnosis of adrenal insufficiency,
which must be confirmed by hormonal assay(s). Also, animals with hypoadrenocorticism
improve rapidly in response to proper therapy.
Treatment:
With appropriate therapy, animals can survive for long periods with only a small fraction
of functional renal tissue, perhaps 5%–8% in dogs and cats. Recommended treatment
varies with the stage of the disease. In Stages 1 and 2, animals usually have minimal
clinical abnormalities. Efforts to identify and treat the primary cause of the disease
should be thorough. The identification and supportive treatment of developing
complications (eg, systemic hypertension, potassium homeostasis disorders, metabolic
acidosis, bacterial urinary tract infection) should be aggressively pursued. The systemic
hypertension seen in ~20% of animals with CKD may be seen at any stage and is not
effectively controlled by feeding a low-salt diet. The usual antihypertensive medications
for blood pressure substages AP2 and AP3 ( see Table: Substages of Chronic Kidney
Disease Based on Arterial Blood Pressure (AP) Measurements and Risk of Target Organ
Damage) are a calcium-channel blocker such as amlodipine besylate (0.25–0.5
mg/kg/day, PO) or an angiotensin-converting enzyme (ACE) inhibitor such as enalapril or
benazepril (0.5 mg/kg, once daily in cats and bid in dogs) or an angiotensin-receptor
blocker (ARB) such as telmisartan (1 mg/kg, once daily in cats and bid in dogs). If an
ACE inhibitor is used in conjunction with a renal diet, potassium should be carefully
monitored. Hyperkalemia may develop, particularly in Stage 4, and dietary change or
dosage adjustment should be considered if serum potassium exceeds 6.5 mEq/L. While
ACE inhibitors (or ARBs) and calcium-channel blockers may be administered together, a
calcium-channel blocker is usually recommended as initial therapy in cats and an ACE
inhibitor (or ARB) in dogs. In addition to providing a continuous supply of fresh drinking
water and encouraging (and documenting) adequate dietary intake, body condition
scoring should be used routinely to assess adequacy of intake. Animals in this stage
should be fed standard, commercially available maintenance diets, unless they are
markedly proteinuric (see below). All affected animals should be reevaluated every 6–12
markedly proteinuric (see below). All affected animals should be reevaluated every 6–12
mo, or sooner if problems develop.
In Stages 2 and 3, the principles for management of complications are the same, except
that the animal should be evaluated every 3–6 mo. These evaluations should include
hematology, serum biochemistries, and urinalysis. Because dogs and cats with CKD are
prone to development of bacterial urinary tract infections, urine culture should be
performed annually and any time urinalysis suggests infection. The progressive nature
of this disease produces a vicious cycle of progressive renal destruction. Measures that
may slow this progression include dietary phosphorus restriction, dietary fish oil
supplementation, antihypertensive agents (for hypertensive dogs and cats), and
administration of ACE inhibitors or ARBs (proteinuria substage P; see Table: Substages
of Chronic Kidney Disease Based on Proteinuria). Dietary restriction of phosphate and
acid load is essential in this stage, and specialized diets for management of kidney
disease should be fed. Potassium citrate or sodium bicarbonate, given PO, may be
indicated if the animal is severely acidotic (plasma bicarbonate <15 mEq/L) or remains
acidotic 2–3 wk after diet change. If dietary restriction of phosphorus is unsuccessful in
maintaining a normal level of serum phosphorus within 2–3 mo, phosphate-binding gels
containing calcium acetate, calcium carbonate, calcium carbonate plus chitosan,
lanthanum carbonate, or aluminum hydroxide should be administered with meals to
achieve the desired effect. There is also a clear rationale for the inclusion of dietary n-3
polyunsaturated fatty acids in these stages.
In late Stage 3 and Stage 4, all of the principles of managing the preceding stages
apply, except that the animal should be evaluated every 1–3 mo. Dietary restriction of
protein may relieve some of the signs of uremia. High-quality protein (eg, egg protein)
should be fed at a level of 2–2.8 g/kg/day for dogs and 2.8–3.8 g/kg/day for cats.
Commercial diets formulated for cats and dogs with CKD generally meet this
recommendation. Administration of a proton pump inhibitor such as omeprazole (0.5–1
mg/kg/day, PO) or an H2-receptor antagonist such as famotidine (5 mg/kg, PO, tid-qid)
decreases gastric acidity and vomiting. Anabolic steroids, such as oxymethalone or
nandrolone, have been administered to stimulate RBC production in anemic animals, but
this is not effective.
Because not all animals with acute kidney injury (AKI) will be identifed or exhibit
azotemia, AKI has replaced the older term, acute renal failure. Animals with AKI are most
often presented to the veterinarian when a sudden, major insult damages the kidneys.
The principal causes are toxins (eg, ethylene glycol, aminoglycoside antibiotics,
hypercalcemia, hemoglobinuria, melamine-cyanuric acid, grapes or raisins, NSAIDs),
ischemia (eg, embolic showers from disseminated intravascular coagulation or severe
prolonged hypoperfusion), and infection (eg, leptospirosis, borreliosis).
Clinical Findings:
Mild AKI often goes unrecognized; severe initial or repeated bouts may lead to CKD.
Most often, AKI is recognized in advanced stages and is characterized clinically by
anorexia, depression, dehydration, oral ulceration, vomiting and/or diarrhea, or oliguria.
Physical examination findings often reveal dehydration but otherwise are usually not
remarkable, although pain is occasionally elicited on palpation of the kidneys, which may
be normal in size to slightly enlarged.
Diagnosis:
A history of hypotension, shock, or recent exposure to known nephrotoxins in an animal
A history of hypotension, shock, or recent exposure to known nephrotoxins in an animal
with sudden-onset uremia is the typical clinical picture of an animal with acute kidney
disease. The presence of poorly concentrated urine (specific gravity 1.007–1.030)
despite dehydration and/or azotemia suggests renal dysfunction. Differentiating
between chronic and acute kidney disease (and establishing a specific cause in acute
kidney disease) is important, because the prognosis and specific therapy may differ.
Animals with AKI usually have a compatible history and other urinalysis abnormalities;
marked cylindruria is a frequent and definitive finding. Other urinalysis findings may
include the presence of a large number of renal epithelial cells and leukocytes in the
urine sediment, glucosuria, crystalluria, enzymuria, and/or
myoglobinuria/hemoglobinuria. Animals with AKI generally have increased serum urea
nitrogen, creatinine, and inorganic phosphorus concentrations and metabolic acidosis.
Oliguria or anuria after rehydration, which is often associated with hyperkalemia, is a
poor prognostic sign; in contrast, polyuric animals have a better prognosis, although
they may become hypokalemic. The kidneys are typically normal in size and shape and
an anemia is often, but not always, absent—findings that may help differentiate acute
from chronic kidney disease.
After injury, the kidney has considerable potential for functional regeneration through
the process of compensatory hypertrophy and adaptive hyperfunction. In animals with
CKD, it is likely that most of this regenerative process has occurred before the initial
diagnosis. In contrast, animals with AKI have considerably more potential for
improvement of renal function, if they can be sustained through a uremic episode. The
duration of the uremic episode may be substantial with some nephrotoxins (eg, 1–3 wk
with aminoglycoside antibiotics and 4–8 wk with ethylene glycol). A renal biopsy may be
of value in assessment of the severity, extent, cause, and potential reversibility of the
disease.
As a disease process, AKI is a spectrum, and the International Renal Interest Society
recommends that patients with AKI be categorized primarily on the basis of serum
creatinine. Animals with Grade I AKI have nonazotemic AKI (serum creatinine ≤1.6
mg/dL). Animals with Grades II–V AKI exhibit varying degrees of azotemia, with serum
creatinine levels of 1.7–2.5 mg/dL in Grade II, 2.6–5 mg/dL in Grade III, 5.1–10 mg/dL in
Grade IV, and >10 mg/dL in Grade V.
Treatment:
Severe AKI that necessitates medical intervention is a serious condition, with a survival
Severe AKI that necessitates medical intervention is a serious condition, with a survival
rate of ~50%. If the cause is known, specific therapy should be instituted, eg, 4-
methylpyrazole or ethanol for ethylene glycol toxicity in dogs ( see Ethylene Glycol
Toxicosis). Fluid therapy is indicated for all dehydrated and inappetant animals. A
polyionic fluid such as lactated Ringer’s solution is satisfactory unless hyperkalemia is
present, in which case normal saline is recommended. Sodium bicarbonate may be
cautiously added to the fluids to correct acidosis.
A second therapeutic option, rather than the aggressive measures discussed above, is
to proceed directly to fluid therapy with polyionic solutions while waiting for renal
to proceed directly to fluid therapy with polyionic solutions while waiting for renal
regeneration. Again, feeding tube placement for parenteral nutrition should be
implemented in anorectic animals with marked azotemia. Peritoneal dialysis or
hemodialysis may be necessary if none of the above measures restores urine
production.