September 2003

Renal Disease/Urology

Sheri Ross, DVM

University of Minnesota



I. Chronic Renal Disease: Staging and Diagnosis

Staging

Chronic kidney disease (CKD) is defined as primary renal disease that has persisted for months to years. Chronic kidney disease has been referred to as chronic renal failure, chronic renal insufficiency, etc. These terms are not very useful in categorizing a patient to facilitate treatment and prognosis recommendations. In human nephrology, there is an elaborate staging scheme that facilitates the application of appropriate clinical practice guidelines for diagnosis, prognosis, and treatment. Recently, The International Renal Interest Society (IRIS) has proposed a 4 tier system for staging chronic renal disease in dogs and cats (tables 1, 2 and 3). The specific values used to categorize patients with CKD into these stages are inherently arbitrary, but staging in nonetheless useful for establishing prognosis and managing patients with CKD.

Severity of CKD is classified by the level of renal function. Ideally, the severity of a patient's CKD would be measured using glomerular filtration rate values. Renal function may be more accurately measured using plasma clearances of iohexol, inulin, or other substances excreted exclusively by glomerular filtration. Although it has become much easier to obtain accurate GFR values, technical and economic constraints have limited their routine use. Plasma clearance studies are indicated in at least 3 settings. First, they provide an accurate measure of renal dysfunction in stage 1 patients where serum creatinine determinations are notoriously insensitive. Second, they provide a basis for dosage adjustments for drugs that are potentially toxic and are excreted primarily by the kidneys. Finally, they are an excellent means of assessing progression of CKD.

Serum creatinine concentration has been the most commonly used measure of severity of renal dysfunction and is usually the basis for staging CKD. In order to optimize accuracy of staging of CKD, serum creatinine concentrations used to stage CKD should be evaluated when patient is well hydrated. Multiple measurements are desirable to establish accuracy and stability of renal dysfunction. Because body muscle mass commonly declines as CKD progresses through stages 2 and 3, endogenous production of creatinine from muscle creatine may decline confounding interpretation of serial serum creatinine values.


Table 1: Markers of kidney damage*a

Blood markers: Elevated blood urea nitrogen concentration
Elevated serum creatinine concentration
Hyperphosphatemia
Hyperkalemia or hypokalemia
Metabolic acidosis
Hypoalbuminemia
Urine markers: Impaired urine concentrating ability
Proteinuria
Cylinduria
Renal hematuria
Inappropriate urine pH
Inappropriate urine glucose concentration
Cystinuria
Imaging markers -
abnormalities in kidney:
Size
Shape
Location
Density
Number


* Markers must be confirmed to be of renal origin to be evidence of kidney damage.
a. From Polzin D, et al: Chronic Renal Failure: in Ettinger SG (ed): Textbook of Veterinary Internal Medicine, ed 6. In Press


Table 2: Stages of Canine Chronic Kidney Disease
(From International Renal Interest Society)

Stage 1 (Non-azotemic) Markers of renal disease present
Creatinine <1.4 mg/dl
Proteinuria: Classify - (P/NP/BP)*
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)=
Stage 2 (Mild Renal Azotemia) Markers of renal disease present
Creatinine 1.4 - 2.0 mg/dl
Proteinuria: Classify - (P/NP/BP)
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)
Stage 3 (Moderate Renal Azotemia) Markers of renal disease present
Creatinine 2.1 - 5.0 mg/dl
Proteinuria: Classify - (P/NP/BP)
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)
Stage 4 (Severe Renal Azotemia) Markers of renal disease present
Creatinine > 5.0 mg/dl
Proteinuria: Classify - (P/NP/BP)
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)


* P=proteinuria
= Hc = hypertension with complications
NP = nonproteinuria
Hnc = hypertension with no complications
BP = borderline proteinuria
NH = non-hypertensive
BH = borderline hypertensive
HND = hypertension not determined
a. From International Renal Interest Society


Table 3: Stages of Feline Chronic Kidney Diseasea

Stage 1 (Non-azotemic) Markers of renal disease present
Creatinine <1.6 mg/dl
Proteinuria: Classify - (P/NP/BP)*
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)=
Stage 2 (Mild Renal Azotemia) Markers of renal disease present
Creatinine 1.6 - 2.8 mg/dl
Proteinuria: Classify - (P/NP/BP)
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)
Stage 3 (Moderate Renal Azotemia) Markers of renal disease present
Creatinine 2.9 - 5.0 mg/dl
Proteinuria: Classify - (P/NP/BP)
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)
Stage 4 (Severe Renal Azotemia) Markers of renal disease present
Creatinine > 5.0 mg/dl
Proteinuria: Classify - (P/NP/BP)
Hypertension: Classify - (Hc/Hnc/NH/BH/HND)


* P=proteinuria
= Hc = hypertension with complications
NP = nonproteinuria
Hnc = hypertension with no complications
BP = borderline proteinuria
NH = non-hypertensive
BH = borderline hypertensive
a. From International Renal Interest Society
HND = hypertension not determined


Pathophysiology

The kidneys have 3 basic types of function: 1) excretory, 2) regulatory, and 3) biosynthetic. The excretory function involves elimination of toxins from the body by way of glomerular filtration and tubular secretion. Elimination of urea, creatinine, and other nitrogenous waste products of protein catabolism are excretory functions. Excretory failure is often recognized as azotemia.

The regulatory function of the kidney involves regulation of body fluids, electrolytes and minerals by a combination of glomerular filtration, tubular secretion, and tubular re-absorption. Maintaining fluid, electrolyte and acid-base homeostasis is the basis of the regulatory function. The most obvious clinical evidence of regulatory failure is decreased urine concentrating and diluting capacity manifest as polyuria and polydipsia. Measuring urine-concentrating ability assesses regulatory failure. Urine specific gravity values less than 1.030 in dogs or less than 1.035 in cats should prompt consideration of primary renal failure.

The biosynthetic function of the kidneys involves the formation of a variety of hormones and other chemicals, which have both local and systemic effects. In chronic renal failure (CKD), the most important examples of biosynthetic failure include inadequate formation of erythropoietin and 1,25-dihydroxycholecalciferol. The clinical effect of failure to produce erythropoietin is the hypoproliferative anemia of CKD. The clinical impact of inadequate renal production of 1,25-dihydroxycholecalciferol is development of renal osteodystrophy and renal secondary hyperparathyroidism. It is usually not necessary to demonstrate biosynthetic failure to confirm the diagnosis of primary renal failure, but clinical evidence of biosynthetic failure is useful in confirming the diagnosis of CKD because the chronic absence of these hormones is necessary to produce clinical effects.

Loss of these renal functions results in a narrowing of the physiologic range over which the kidneys are able to adapt. For example, loss of urine concentrating ability (regulatory failure) leads to obligatory increases in water intake. The failing kidneys have impaired ability to adapt to extremes (high or low) in electrolyte intake. This limited ability of the failing kidneys to adapt to variations in intake directly relates to therapeutic plans.


Table 4: Summary Of Physiologic Activities
In Nephrons And Collecting Ducts During Formation Of Urine

Component of Nephron Physiologic Process
Glomerulus Passive formation of ultrafiltrate of plasma devoid of most protein.
Bowman's capsule Collection of glomerular filtrate
Proximal tubule Active Reabsorption of:
Glucose, proteins & amino acids, vitamins, ascorbic acid,
acetoacetate, hydroxybutyrate, uric acid, sodium,
potassium, calcium (� by PTH), phosphate (� by PTH), sulfate, bicarbonate

Passive Reabsorption of:
Chloride, water, urea
Active Secretion of:
Hydrogen ion
Henle's loop Generation of medullary hyperosmolality
Descending limb Passive Reabsorption of:
Water

Passive Secretion of:
Sodium, urea
Thin ascending limb Passive Reabsorption of:
Urea, sodium, impermeable to water
Thick ascending limb Active Reabsorption of:
Chloride, calcium

Passive Reabsorption of:
Sodium, impermeable to water, potassium
Distal tubule Active Reabsorption of:
Sodium (� by aldosterone), calcium, HCO3, small amounts of glucose

Passive Reabsorption of:
Chloride, water (� by ADH)

Active Secretion of:
Hydrogen ion, ammonia, uric acid Passive Secretion of:
Potassium
Collecting ducts Active Reabosorption of:
Sodium (� by aldosterone)

Passive Reabsorption of:
Chloride, water (� by ADH)

Active Secretion of:
Hydrogen ion

Passive Secretion of:
Potassium


Pathophysiology of Progression of CKD

When an insult to the kidney results in nephron loss, the remaining nephrons undergo hypertrophy and hyperfunction to compensate for the acquired renal functional deficits. As CKD advances, kidney function is supported by a diminishing pool of functioning (or hyperfunctioning) nephrons rather than relatively constant numbers of nephrons, each with diminishing function. This concept has important implications for the mechanisms of disease progression in CKD. Clinical studies of patients and experimental studies in animals with chronic renal disease have shown that once the GFR falls below some critical level, there is an inevitable progression to end-stage renal failure, even when the initial disease/cause was removed.

In humans, the rate of decline of GFR in a given individual followed a near-constant linear relationship with time, enabling remarkably accurate predictions of the date at which end-stage renal failure would be reached and renal replacement therapy required. Among patients with diverse renal diseases, the gradient of the GFR-time relationship was a characteristic of individual patients rather than typical of their specific renal diseases.

This observation suggested: 1) that CKD advanced via a programmed course, irrespective of the primary nephropathy, and 2) that the progressive nature of renal disease could be explained by a final common pathway.

Brenner and colleagues formulated a unifying hypothesis for renal disease progression: CKD progression occurs, in general, through focal nephron loss and the responses of surviving units (e.g., glomerular hyperfiltration and hypertrophy), although initially serving to increase single-nephron GFR (SNGFR) and offset the overall loss in clearance, ultimately prove detrimental to the kidney. Over time, glomerulosclerosis and tubular atrophy reduce nephron mass, fueling a self-perpetuating cycle of nephron destruction culminating in uremia (Fig. 1).

Extensive resection of renal mass is followed by proteinuria, systemic hypertension, and the development of focal and segmental glomerulosclerosis and hyalinosis in the remnant kidney. Loss of more than some critical mass (>50% in humans) of the nephron mass initiates the cycle of progressive injury even before signs or symptoms of CKD are apparent.


Figure 1

Scheme depicting the vicious cycle of nephron loss initiated by renal mass ablation. Ang II = angiotensin II; FSGS = focal and segmental glomerulosclerosis; HTN = hypertension. (courtesy of Dr. David Polzin)

Diagnosis of CKD

Diagnosis of primary renal failure is based on demonstrating concurrent excretory and regulatory failure. Detection of inadequate urine concentrating ability (urine specific gravity values less than 1.030 in dogs and less than 1.035 in cats) in an azotemic patient usually confirms the diagnosis of primary renal failure. Other conditions may cause dilute urine associated with prerenal azotemia, but this is unusual and often apparent by examining the case history and other laboratory findings. Note that renal failure patients do not typically have urine specific gravity values less than 1.006. Values below this specific gravity indicate urine-diluting capacity and are usually inconsistent with a diagnosis of primary renal failure.

Urine concentrating ability is best described as appropriate, adequate or maximal. Appropriate urine concentration means that the kidneys are responding in a physiologically appropriate response to the stimulus for urine concentration (mediated by antidiuretic hormone - ADH). Adequate urine concentrating ability means the kidneys can concentrate sufficiently to maintain homeostasis (especially relevant to the diagnosis of primary renal failure versus prerenal azotemia). Maximal urine concentration is the concentration of urine which develops under maximum stimulus from ADH.

Serum creatinine concentration (SCr) is the most commonly used test of renal function. Serum urea nitrogen concentration (SUN) is also used for this purpose, but many factors other than renal function influence SUN values. In contrast, SCr values primarily reflect glomerular filtration rate (GFR) and body muscle mass. However, SCr is a very poor index of GFR in that very large changes in GFR produce minimal change in SCr values. It is important to learn how to interpret minor changes in SCr values in the laboratory you usually use in order to enhance detection of early CKD. Serial monitoring of SCr is an effective method of establishing the significance of small increases in SCr values. Alternatively, measurement of GFR may be helpful for establishing early CKD.


Table 5: Characteristic Urine Volumes and Specific Gravity Values
Associated with Different Types of Azotemia in Dogs and Cats(a)

  1. PRERENAL AZOTEMIA
    1. Physiologic oliguria
      • Dogs: USG > 1.030
      • Cats: USG > 1.035 to 1.040

  2. PRIMARY ACUTE ISCHEMIC OR NEPHROTOXIC AZOTEMIA
    1. INITIAL OLIGURIAb
      • Dogs: USG = 1.006 to ~ 1.029
      • Cats: USG = 1.006 to 1.034 - 1.039��
    2. SUBSEQUENT POLYURIC PHASE
      • Dogs: USG = 1.006 to ~ 1.029
      • Cats: USG = 1.006 to ~ 1.034 - 1.039

  3. OBSTRUCTIVE POSTRENAL AZOTEMIA
    1. INITIAL OLIGURIA OR ANURIA
    2. DIURESIS AND POLYURIA FOLLOWING RELIEF OF OBSTRUCTION
    3. URINE SPECIFIC GRAVITY VALUES ARE VARIABLE

  4. PRIMARY CHRONIC AZOTEMIA
    1. POLYURIA
      • Dogs: 1.006 to ~1.029
      • Cats: 1.006 to ~ 1.034 - 1.039c��
    2. TERMINAL OLIGURIC PHASE
      • USG = 1.007 to ~1.013
    3. REVERSIBLE OLIGURIA DUE TO FACTORS INDUCING PRERENAL


(a) From Osborne CA, et al: Pathophysiology of renal disease, renal failure, and uremia, in Ettinger SG (ed): Textbook of Veterinary Internal Medicine, vol 2, ed 2. Philadelphia, WB Saunders Co, 1982, p 1758.
(b) Acute renal failure caused by nephrotoxic drugs often is not associated with an initial phase of oliguria. The term nonoliguric is often used to describe such patients.
(��) Some cats with primary renal azotemia may concentrate urine to 1.045 or higher.


Table 6: Summary of Diagnostic Tests Indicated for Renal Failure Patients


Evaluation Purpose
Blood urea nitrogen Assess degree of azotemia
Serum Creatinine To establish the diagnosis & measure intrinsic renal function
Urinalysis To establish diagnosis & identify renal complications
Urine culture To rule-out urinary tract infection
Complete blood count To detect anemia of renal failure & inflammatory complications
Serum sodium To detect hyponatremia or hypernatremia
Serum potassium To detect hypokalemia or hyperkalemia
Serum total carbon dioxide To assess metabolic acid-base status
Serum chloride Useful in assessing serum tCO2 and Na concentrations
Serum phosphorus To detect hyperphosphatemia
Serum calcium To detect hypercalcemia or hypocalcemia
Serum albumin & total protein concentrations To assess nutritional status
Body weight To assess nutritional status
Protein:creatinine ratio (if proteinuric) To assess magnitude of proteinuria
Blood pressure To evaluate for hypertension
Fundic examination To evaluate for hypertensive retinopathy or other systemic diseases
Survey abdominal radiographs To rule-out urolithiasis, structural lesions, or urinary obstruction
Renal ultrasound To structurally evaluate the kidneys to establish a primary diagnosis
Renal Biopsy To structurally evaluate the kidneys to establish a primary diagnosis


A special note on renal biopsies!

Deciding which patients will benefit from a renal biopsy is difficult. Prior to performing a renal biopsy, the following questions should be asked; 1) Will biopsy influence patient management? 2) Will biopsy provide useful prognostic information? 3) Is the patient at increased risk of biopsy or anesthetic complications? (Medically unstable patients, kidney positions difficult to access by ultrasound, arterial hypertension, or coagulopathy). Always remember that the likelihood of adverse consequences post-biopsy is highly related to the experience of the ultrasonographer and clinician performing the biopsy.

It has been generally believed for years, that inability to identify the causes(s) of renal disease in dogs and cats is, at least in part, a function of our limited ability to detect early renal disease. Once renal disease has progressed to renal insufficiency or failure, it becomes difficult, if not impossible, to identify the inciting disease process using current techniques. Unfortunately, renal biopsies are often performed in patients that have relatively advanced disease. The inability to translate lesions observed in such patients to effective therapy should is not surprising.

Other factors limiting our use of renal biopsies include the lack of: 1) a generally recognized classification scheme for renal biopsies based on light, immunofluorescent and electron microscopic evaluation, and 2) randomized, controlled clinical trials linking biopsy findings to therapeutic outcomes in canine and feline patients.

Probably the most common indications for renal biopsy in dogs and cats include investigation of proteinuric renal diseases, renomegaly (or renal mass), familial renal disease, and acute renal failure. However, clinical benefits of renal biopsy for these patients remains to be established. Presumably, identification of treatable disease or evidence of reversible disease in acute renal failure translates to improved patient care. There appears to be a clear benefit in confirming familial renal disease for genetic counseling.

Although generally safe, there are some relative contraindications for renal biopsy. These include coagulopathy, severe anemia, solitary kidney, uncontrolled systemic hypertension, pyonephrosis, renal abscess, hydronephrosis, and bilateral reduction in kidney size. Potential complications to renal biopsy may include hemorrhage, infection, arteriovenous fistula, renal obstruction (with blood clots), and inadequate biopsy sample. Adequate patient evaluation and experience with renal biopsy reduce these risks.

The clinical value of renal biopsies remains to be established in dogs and cats. It is essential for veterinary nephrologists to develop a standardized classification scheme for renal biopsies, and to apply this system to randomized controlled clinical trials to establish the value of various interventions in managing renal disorders. Epidemiological studies are needed linking biopsy findings to clinical outcomes.

Differentiating Acute from Chronic Renal Failure

The diagnosis of chronic renal failure is based on identifying historical, physical, or laboratory findings, which suggest that renal failure has been present for an extended time. The medical history and physical examination are often the most revealing and reliable clues to chronicity. A history of signs such as polyuria, polydipsia, weight loss, selective appetite, or deteriorating haircoat occurring over several months is strong evidence for CKD. Physical exam findings of poor nutritional status, poor haircoat, small kidneys, or renal osteodystrophy strongly suggest chronicity. Laboratory findings are often not helpful in establishing the diagnosis of chronic renal failure, although the presence of a hypoproliferative anemia may be suggestive of chronicity. Radiology may be useful in establishing kidney size or presence of renal osteodystrophy.

Acute renal failure is often diagnosed by the absence of signs of chronicity. In some instances, the history of a potential renal insult (such as exposure to aminoglycoside therapy or ethylene glycol consumption) is helpful in making a tentative diagnosis of acute renal failure. The patient with acute renal failure may be in good nutritional health because the onset of renal failure is recent. However, for a given level of azotemia, acute renal failure patients may be more clinically affected. Acute renal failure may be non-oliguric or oliguric; detection of normal to increased urine production does not rule-out acute renal failure.


Table 7: Differentiation of Prerenal Azotemia, Intrarenal Azotemia,
Prerenal & Intrarenal, and Postrenal Azotemia(a)


Observation Prerenal * Intrarenal *
Normal hydration
Prerenal &
Intrarenal *
Postrenal *
Blood urea nitrogen
Serum creatinine
Serum phosphorous N, �
Serum calcium N�, N, ��, N, �N
Serum sodium N, (�), (�)�, N, ��, N, �N
Serum potassium NN, �N, �N, �
Serum chloride N�, N, ��, N, �N
Blood bicarbonate �, N�, N�, N�, N
Urine specific gravity 1.030+ dog
1.040+ cat
1.007 to 1.029 dog
1.007 to 1.039 cat
1.007 to 1.029 dog
1.007 to 1.039 cat
Variable
Urine output �, N�, N, ��, N, �� (N, �)
Packed cell volume N, �N, �, (�)N, �, (�)N
Historical polydipsia /
polyuria
0+, (0)+, (0)0, (+)
Historical
oliguria / anuria
+, (0)+, 0+, 0+, (0)
Historical uremic
symptoms
0+, 0+, 00
Debilitation 0+, 0+, 00
Renal osteodystrophy 0+, 0+, 00
Kidney size N�, N, ��, N, �N, �
Response of azotemia
to rehydrartion
with fluids
GoodComparitively poorPartial**Variable**
Response to oliguria
to rehydration
with fluids
DramaticVariablePartial**Variable**

� = increased; N = normal range; � = decreased; 0 = absent; + = present, values in parentheses = atypical.
* Values expected prior to the initiation of therapy. ** Magnitude of response is dependent on magnitude of prerenal component contributing to azotemia.
(a) From Ross SJ, et al: Acute Renal failurein Wingfield W, Raffe M (ed):The Veterinary ICU Book, ed 1.JacksonTeton NewMedia, 2002.


Table 8: Typical Similarities and Differences Between Patients with
Acute Primary Renal Failure, Chronic Primary Renal Failure, and
Acute Decompensation of Chronic Primary Renal Failure(a)


   Chronic Acute Acute on Chronic
HISTORY AND PHYSICAL EXAM         
Recent exposure to nephrotoxin or ischemic episode Unlikely Probable Possible
Previously diagnosed renal failure Possible Unusual Usually
Weight loss Chronic due to tissue loss Acute due to fluid loss Tissue and fluid loss
Urine Volume Prolonged polyuria;
potential oliguria
Initial oliguria;
subsequent polyuria
Oliguia preceeded
by prolonged polyuria
Severity of signs for comparable degree of azotemia Less severe due to compensatory adaptations Marked Moderate
RADIOGRAPHS / ULTRASOUND         
Renal size and shape Often decreased; may be normal, increased, or unequal in size Normal to increased Decreased, may be normal or increased. May reveal radiodense uroliths.
Renal Surface Contour Often irreguular Smooth Often irregula
Osteodystrophy Often Absent Often
BLOOD CHEMISTRY         
Serum urea nitrogen Increased Increased Increased
Serum creatinine Increased Increased Increased
Serum Osmolality Increased Increased Increased
Serum phosphorous Increased Increased Increased
Serum calcium Usually normal to decreased; may be increased Variable, dependent on cause Usually normal to decreased; may be increased
Serum potassium Normal if polyuric;
Increased if oliguric
Increased if oliguric;
Normal if polyuric
Normal if polyuric;
Increased if oliguric
Blood bicarbonate (metabolic acidosis) Mild to moderate decrease Moderate to severe decrease Moderate to severe decrease
HEMOGRAM         
PCV and Hb Normal to decreased
(nonregenerative)
May initially be normal or increased; then decreased Normal to decreased
(nonregenerative)
URINALYSIS         
Impaired renal concentrating/diluting ability Yes Yes Yes
Glucosuria Very uncommon Sometimes, primarily with nephrotoxins Uncommon
Pyuria Variable Variable; suggests infectious cause Variable
Crystalluria Uncommon Calcium oxalate with ethylene glycol Uncommon
Proteinuria Variable Variable Variable
Tubular Casts Uncommon Granular casts frequently associated with ischemia and nephrotoxins; white cell casts indicate infectious cause Possible


(a) From Ross SJ, et al: Acute Renal failurein Wingfield W, Raffe M (ed):The Veterinary ICU Book, ed 1.JacksonTeton NewMedia, 2002


II. Managing Patients with CKD


Conservative medical management of CKD consists of supportive and symptomatic therapy designed to correct deficits and excesses in fluid, electrolyte, acid-base, endocrine, and nutritional balance and thereby minimize the clinical and pathophysiological consequences of reduced renal function. goals of conservative medical management of patients with chronic primary renal failure are to: (1) ameliorate clinical signs of uremia, (2) minimize disturbances associated with excesses or losses of electrolytes, vitamins, and minerals, (3) support adequate nutrition by supplying daily protein, calorie, and mineral requirements, and (4) modify progression of renal failure. The components of conservative medical management are summarized in table 1. Conservative medical management is most beneficial when combined with specific therapy directed at correcting the primary cause of renal disease.


Table 1: Conservative Medical Management of
Chronic Renal Failure in Dogs and Cats

Clinical or Laboratory Abnormality Treatment Options
Progression of CKD Diet therapy
Azotemia/uremia Diet therapy
Polyuria and polydipsia Free access to water
Consider diet therapy
Dehydration (prophylaxis) Free access to water
Avoid stress
Canned Food
Supplemental fluid therapy (?)
Metabolic acidosis Therapeutic alkalinization
Anemia of CKD Erythropoietin therapy
Supplemental Iron
Transfusion therapy
Androgen therapy
Hyperphosphatemia Diet therapy
Intestinal phosphate binding agents
Hypocalcemia Oral calcium supplements
Calcitriol therapy
Renal osteodystrophy Minimize hyperphosphatemia
(prophylaxis/ treatment)
Oral calcium supplements
Calcitriol therapy
Systemic hypertension Sodium restriction
Antihypertensive drug therapy
Drug reactions/overdosage Avoid nephrotoxic drugs
Adjust dosages according to renal function
Urinary tract infection Monitor for infection
Antibiotic therapy


Therapy of Hypokalemia and Metabolic Acidosis

Potassium supplementation may be necessary to prevent or correct hypokalemia in some dogs and cats with CKD. Hypokalemia is a relatively frequent complication of renal failure with a reported incidence of 19% in one clinical study of feline renal failure. Although an association between renal failure and development of hypokalemia has been confirmed in cats, the mechanism of hypokalemia has not been established.

Potassium replacement therapy is indicated for cats with hypokalemia, even in absence of clinical signs of hypokalemia. Oral administration is the safest and preferred route of adminstration for potassium replacement therapy. Potassium gluconate is generally regarded as the potassium salt of choice for replacement therapy. Potassium may be administered orally as potassium gluconate in a palatable powder form (Tumil-K, Daniels Pharmaceuticals, Inc.), potassium gluconate elixir (Kaon Elixir, Adria Laboratories, Columbus, OH), or potassium citrate solution (Polycitra-K, Willen Drug, Baltimore, MD). Depending on the size of the cat and severity of hypokalemia, potassium gluconate is given initially at a dose of 2 to 6 mEq per cat per day. Potassium dosage should thereafter be adjusted based on the clinical response of the patient and serum potassium determinations performed during the initial phase of therapy.

Serum potassium concentrations should be monitored every 24 to 48 hours during the initial phase of therapy. Serum potassium concentrations should be monitored every 7 to 14 days during the maintenance phase of therapy. Routine supplementation of all cats with CKD has been recommended, regardless of serum potassium concentrations. The goal of such therapy is to prevent or correct hypokalemia-induced renal dysfunction. The safety and efficacy of this approach has not been evaluated. Diets that are acidifying and restricted in magnesium content may promote hypokalemia, and should therefore generally be avoided in cats with CKD. Potassium depletion and metabolic acidosis may promote potentially fatal reductions in plasma taurine concentrations in cats.

Alkalinizing agents should be administered when necessary to correct the metabolic acidosis of CKD. Because even mildly reduced plasma bicarbonate concentrations may promote some of the adverse effects of chronic metabolic acidosis, oral alkalinization therapy is probably indicated when serum bicarbonate concentration declines to 17 meq/l or below (total CO2 concentrations of 18 meq/l or below). Oral sodium bicarbonate is the most commonly used alkalinizing agent for patients with metabolic acidosis of CKD. The suggested initial dose of sodium bicarbonate is 8 to 12 mg/kg body weight given every 8 to 12 hours. A solution containing approximately 84 mg of sodium bicarbonate per ml (1 meq/ml) of solution can be prepared by adding 2.5 ounces of sodium bicarbonate to 1 quart of water (84 mg added to 1 liter of water). This solution may be stored capped and refrigerated for several months. This solution may be administered at a starting dose of 1 to 1.5 ml per 10 kg of body weight. The solution may be administered orally by syringe or mixed with the food.

Potassium citrate is a useful alkalinizing agent that limits sodium intake and provides supplemental potassium. Potassium citrate may be administered orally at a dosage of 40 to 60 mg/kg every 12 hours. Alkalinizing agents should be given in several smaller doses rather than a single large dose to minimize fluctuations in blood pH. The patient's response to alkalinization therapy should be determined by measuring blood bicarbonate or serum (plasma) total CO2 concentrations 10 to 14 days after initiating therapy. Ideally, blood should be collected just prior to administration of the drug. Dosage of alkalinizing agents should be adjusted so that blood bicarbonate (or serum total CO2) concentrations are maintained between 18 and 24 meq/l.

Treatment of Calcium and Phosphorus Imbalances

Most dogs and cats with CKD benefit from therapy designed to minimize calcium and phosphorus imbalances. The objectives of management of abnormal divalent ion metabolism in CKD are to: 1) maintain serum levels of calcium and phosphorus as close to normal as possible, 2) prevent or suppress excessive secretion of parathyroid hormone (PTH), 3) prevent or ameliorate renal osteodystrophy, 4) prevent or reverse extraskeletal mineralization, and 5) limit progressive renal dysfunction. Calcium and phosphate balance in patients with renal failure may be improved or corrected by limiting phosphate intake and providing adequate quantities of dietary calcium and metabolically active forms of vitamin D.

Limiting dietary intake of phosphate and, if necessary, administering intestinal phosphate binding agents should minimize phosphate retention and hyperphosphatemia. The ultimate goal of therapy is to prevent or minimize renal secondary hyperparathyroidism and its various adverse consequences. Dietary phosphate restriction is an important and effective first step toward normalizing phosphate balance because it may normalize serum phosphate concentrations in mild to moderate CKD, and it reduces the quantity of phosphate that must be bound by intestinal phosphate binding agents if their use becomes necessary. Serum phosphate concentrations should be determined after the patient has been consuming the phosphate-restricted diet for about 2 to 4 weeks. Samples obtained for determinations of serum phosphate concentration should be collected after a 12-hour fast to avoid postprandial effects.) Phosphate binding agents should be used in conjunction with dietary phosphate restriction when dietary therapy alone fails to reduce serum phosphate concentrations to within the normal range.

Intestinal phosphate binding agents render ingested phosphate and the phosphate contained in saliva, bile, and intestinal juices unabsorbable. Because the primary goal is limiting absorption of phosphate contained in the diet, administration of phosphate binding agents should be timed to coincide with feeding. These agents are best administered with or mixed into the food, or just prior to each meal. Currently available phosphate binding agents include aluminum-based and calcium-based compounds. Aluminum-containing intestinal phosphate binding agents include aluminum hydroxide, aluminum carbonate, and aluminum oxide. Although quite effective for binding phosphate, an important disadvantage of long-term use of aluminum-containing antacids in humans with CKD has been development of aluminum toxicity. The potential for toxicity of aluminum salts in dogs and cats has been confirmed, but clinical evidence of toxic accumulation of aluminum has not been reported in these species.

Calcium salts such as calcium acetate, calcium carbonate, or calcium citrate may be highly effective as phosphate binding agents. Calcium-based phosphate-binding agents do not entail the risk of aluminum toxicity that accompanies use of aluminum-based phosphate-binding agents. Unfortunately, calcium-based products may promote clinically significant hypercalcemia; therefore, it is necessary to carefully monitor serum calcium concentrations intermittently when using these drugs. Calcium acetate is the most effective calcium-based phosphate-binding agent as well as the agent least likely to induce hypercalcemia because it releases the least amount of calcium compared to the amount of phosphate it binds. It is particularly important that calcium-based phosphate-binding agents be administered with meals both to enhance the effectiveness of phosphate binding and to minimize absorption of calcium and the risk of hypercalcemia. Administration of calcium-based phosphorus binding agents between meals promotes absorption of calcium and increases the risk of inducing hypercalcemia

Dosage of phosphate binding agents should be individualized so that serum phosphate concentrations are normalized. It has been suggested that a dose of approximately 100 mg/kg/day divided into two or three doses is an appropriate starting dose for aluminum or calcium based phosphate binding agents when serum phosphorus concentration exceeds 6.0 mg/dl. The effect of therapy should be monitored by serial evaluation of serum phosphate concentrations at about 10 to 14 day intervals. Dosage should be increased until serum phosphate concentrations are reduced to or near normal. Dosage of calcium-based phosphate binding agents should be decreased if serum calcium concentrations exceed normal limits; additional aluminum-based agents should be used in these patients if hyperphosphatemia persists. Thereafter, serum calcium and phosphate concentrations should be monitored every 4 to 6 weeks or as needed.

Intestinal malabsorption of calcium is common in CKD, but can be overcome by increasing dietary calcium intake. Because increasing calcium intake may elevate serum calcium concentration and thereby reduce serum PTH activity, calcium supplementation may play an important role in preventing or ameliorating renal osteodystrophy and systemic toxicities resulting from hyperparathyroidism. The optimum time for initiating calcium supplementation during the course of CKD is uncertain. In any case, the increased risk of inducing extraskeletal mineralization attending calcium supplementation dictates that it should generally be withheld at least until serum phosphate concentration are normalized by other therapeutic means.

Oral calcium supplementation should be considered in patients with hypocalcemia; clinical, radiographic, or histologic evidence of renal osteodystrophy; or patients with inadequate dietary calcium intake. Oral administration of a variety of calcium salts may be used to improve calcium balance. Calcium carbonate may be the preferred calcium salt in many patients with CKD because it contains a high fraction of calcium and is inexpensive, tasteless, and usually well tolerated. Initially, calcium carbonate should be administered at a dose of 100 mg/kg/day. In order to maximize calcium absorption, calcium salts should be given in small quantities throughout the day. Administration of one or two large doses is likely to be substantially less effective and more likely to induce complications such as gastrointestinal side-effects. Administration of calcium carbonate with meals that contain large quantities of phosphate should be avoided because it will limit calcium absorption because of the phosphate-binding effect.

Vitamin D supplementation may be considered for dogs and cats with proven renal secondary hyperparathyroidism. In mild renal failure, calcitriol deficiency results predominantly from the inhibitory effects of phosphate retention on renal 1a-hydroxylase activity. As renal failure progresses, loss of viable renal tubular cells limits calcitriol synthetic capacity. Therefore, over time, phosphate restriction alone may fail to prevent renal secondary hyperparathyroidism, necessitating vitamin D supplementation for complete PTH suppression.

Although potentially beneficial in CKD patients, vitamin D therapy must be undertaken with great caution because hypercalcemia is a frequent and potentially serious complication of vitamin D therapy. Vitamin D therapy does not directly impair renal function, but sustained vitamin D-induced hypercalcemia can result in reversible or irreversible reduction in GFR. Hypercalcemia reportedly occurs in 30% to 57% of humans treated with 1,25-dihydroxycholecalciferol. Chew and colleagues reported that hypercalcemia was an uncommon side-effect in dogs with CKD when calcitriol was administered at low dosages. However, hypercalcemia was reported to occur when calcitriol therapy was combined with calcium-containing phosphate binding agents. Because hyperphosphatemia enhances the tendency for vitamin D therapy to promote renal mineralization and injury, serum phosphate concentration must be normalized before initiating vitamin D therapy. In general, patients should not receive vitamin D therapy unless serum calcium and phosphate concentrations will be carefully monitored throughout treatment.

Vitamin D may be administered as calcitriol, 1a-hydroxyvitamin D, or 25-hydroxyvitamin D (calcidiol). Calcitriol (Rocaltrol Capsules, 0.25 mcg and 0.50 mcg; Roche Laboratories, Nutley, NJ) rapidly and effectively suppresses renal secondary hyperparathyroidism in dogs and humans. An important advantage of calcitriol therapy in CKD is that it does not require renal activation for maximum efficacy. Dogs and cats appear to require lower dosages of calcitriol than those recommended for humans (on a per weight basis). Nagode and colleagues have recommended a dosage of 1.5 to 3.5 ng/kg body weight per day given orally to dogs with CKD. Preliminary findings suggest similar doses may be effective in cats with CKD as well. Brown and colleagues have recommended a dosage of 6.6 ng/kg given orally once daily. In our current studies, we have found this dose to be somewhat high. Vitamin D therapy may enhance intestinal absorption of calcium and phosphorus and therefore should not be given with meals.

Serum calcium concentrations must be monitored during therapy with calcitriol to prevent hypercalcemia. Hypercalcemia may develop at any point during therapy with calcitriol. Calcitriol's rapid onset (about 1 day) and short duration of action (half-life less than 1 day) permits rapid control of unwanted hypercalcemia, but early detection of hypercalcemia is indicated to limit the extent of renal injury. The recommended endpoint of calcitriol therapy is normalization of PTH activity.


Table 2: Guidelines for Monitoring Patients with Chronic Renal Failure


Test Purpose
History To assess response to therapy; to ascertain compliance with recommendations and owner-perceived problems with therapy; to detect communication problems with the client; to detect new problems or complica-tions
Physical examination To detect new problems or complications; to assess hydration; to assess nutritional status and well-being of the animal
Body weight To assess nutritional and hydration status
Serum creatinine conc. To assess severity and progression of renal dysfunction; to detect concomitant prerenal and postrenal azotemia
SUN concentration To assess compliance with dietary recommendations; to detect concomitant prerenal and postrenal azotemia
Urinalysis To detect urinary tract infection; to detect changes in urine sediment or urine chemistries which may suggest active or changing renal lesions which may warrant specific therapy or changes in therapy
Serum phosphorus conc. To determine success of dietary phosphorus restriction and to adjust dosages of intestinal phosphate binders
Serum calcium conc. To assess need for and to adjust dosage of calcium supplements and vitamin D
Serum albumin conc. To assess nutritional status; important for monitoring impact of urinary protein loss in patients with glomerulopathies; neces-sary for interpretation of serum calcium values and assess influence on protein-bound drugs
Total CO2 or blood gas analysis To assess need for alkalinization therapy; necessary for adjusting dosage of alkalinization therapy
PCV or CBC To assess response to therapy for anemia; may also be useful for assessing nutritional status
Urine culture Indicated: (1) if urinalysis supports possible UTI, (2) to confirm that previously detected and treated UTI have been successfully eradicated, (3) as routine part of follow-up studies in patients with recurrent UTI and CKD.
Abdominal radiographs (cats) To evaluate presence, size and movement of nephroliths and/or ureteroliths.


GLOMERULAR DISEASE

Treatment of glomerular disease may involve elimination of diseases initiating the condition, immunomodulation, or therapy designed to minimize ongoing progressive injury to the glomerulus. Elimination of diseases responsible for development of immunological disturbances and glomerular disease may halt progression of glomerular disease or induce its resolution. For this reason, it is important to attempt to identify infectious and non-infectious agents in dogs and cats suspected of having immune-complex GN. Although elimination of antigens is the most logical and seemingly safest therapeutic approach to GN, it is limited in many instances by the obscurity of the antigenic source, the fact that more than one antigen may be involved, and/or identification of an antigenic source that is currently impossible to eliminate.

Corticosteroids and immunosuppressive drugs (particularly cyclophosphamide, chlorambucil, cyclosporine A, and others) have been used for treating patients with glomerulonephritis (GN) with the expectation that they will suppress formation of immune-complexes, and ameliorate the glomerular inflammatory reaction initiated by antigen-antibody-complement reactions. One theoretical basis for use of these drugs is that patients with GN have a hyperactive immune system leading to formation of immune-complexes. However, naturally occurring immune-complex GN is not consistently associated with a hyperactive immune system. To the contrary, at least some patients with immune-complex disease may have suppressed immune systems. Therefore, administration of immunosuppressive agents to patients with GN resulting from circulating immune complexes may be harmful. However, this line of reasoning may not be valid when immune complexes are formed in situ.

Several recent studies in dogs with glomerular diseases have confirmed that corticosteroids promote proteinuria. Since proteinuria has been linked to progressive renal injury, corticosteroids should be used with great caution in dogs with renal disease. The only randomized, controlled clinical trial designed to evaluate immunosuppressive therapy in dogs with GN found no significant advantage of cyclosporin compared to placebo.

Because proteinuria may promote progressive renal injury, reducing proteinuria is a logical therapeutic goal. Administration of angiotensin converting enzyme (ACE) inhibitors reduces the magnitude of proteinuria in humans with various renal diseases. A recent randomized, controlled clinical trial comparing enalapril therapy to a placebo supports an antiproteinuric and potential renoprotective role for ACE inhibitors in dogs. Data available to date have failed to verify an antiproteinuric effect of benazepril in cats.

Studies have shown that high dietary protein intake may have an adverse effect on the magnitude of proteinuria and hypoalbuminemia in humans. Reducing dietary protein intake in humans with nephrotic syndrome limits proteinuria while stabilizing protein nutrition. Studies examining the effects of dietary protein intake on proteinuria in dogs have yielded mixed results. It is cautiously recommended that protein intake be limited in dogs and cats with moderate to severe proteinuria. Response to protein restriction should be monitored. If protein restriction reduces proteinuria and does not adversely affect renal function or serum albumin concentration, therapy should be continued. Continued monitoring of renal function, proteinuria, and serum albumin concentration is recommended. In addition, body weight and subjective assessments of protein nutrition such as muscle mass and hair coat condition should also be monitored. Diet therapy has been shown to prolong survival in dogs with renal failure.

Anticoagulant (heparin, coumadin) and anti-platelet (aspirin, indomethacin, dipyridamole, and others) therapy have been used for treatment of GN in humans because of the apparent role of the coagulation system in development of glomerular lesions. Intraglomerular coagulation and fibrin deposition appears to play a role in many glomerulonephritidies. There is also evidence from both experimental GN and spontaneous human GN that platelets may be involved in mediating or amplifying glomerular injury by: 1) promoting proliferation of glomerular mesangial and endothelial cells, and 2) by increasing vascular permeability, thereby facilitating glomerular localization of circulating immune complexes. Platelets may also promote proteinuria through glomerular localization of platelet-derived cationic secretory proteins leading to loss of glomerular fixed anionic charge and enhanced glomerular capillary permeability.

Platelets can induce inflammation and release chemotactic and mitogenic substances. Platelet turnover has been found to be increased in several forms of GN. Furthermore, a positive correlation has been reported between intraglomerular-cell proliferation and increased platelet consumption. Evidence supporting a link between increased platelet destruction, proliferation of mesangial cells, and glomerular inflammation is based on observations that platelet-derived factors stimulate proliferation and migration of arteriolar smooth muscle cells and are chemotactic for monocytes and neutrophils.

Although studies in dogs with experimental glomerulonephritis suggest a possible role for thromboxane synthetase inhibitors in managing glomerular disease in dogs, efficacy and safety of anti-platelet agents and anticoagulants have not been clinically evaluated in dogs and cats with spontaneous GN. However, in humans, combination therapy with dipyridamole and aspirin was associated with significant hemorrhagic complications. Pending results of controlled clinical trials documenting the safety and efficacy of these drugs in treatment of canine and feline GN, treatment with this class of drugs should probably be limited to administration of low doses of aspirin.


Table 3: Diagnostic Evaluation of Patients with Progressive or Marked Proteinuria


  1. Medical history and physical examination
  2. Urinalysis (including urine sediment examination)
  3. Quantitative measure of magnitude of proteinuria (Usual method is urine protein:creatinine ratio)
  4. Serum total protein, albumin, and globulin concentrations
  5. Renal function tests
    1. Serum urea nitrogen
    2. Serum creatinine concentration
    3. Consider endogenous Ccr for nonazotemic patients
  6. Serum cholesterol concentration
  7. Complete blood count (including cytologic examination of blood cells)
  8. Serum (or plasma) electrolyte and acid-base profile
    1. Sodium, potassium, and chloride concentrations
    2. Bicarbonate or total CO2 concentrations
    3. Calcium and phosphorus concentrations
  9. Serum alanine aminotransferase, alkaline phosphatase, amylase and lipase activities
  10. Blood pressure determination to rule out systemic hypertension
  11. Consider:
    1. Freezing aliquots of serum (or plasma) and urine for additional diagnostic determinations which may be desired later (e.g. titers against infectious agents, toxicological studies, etc.).
    2. Survey radiographs of thorax and abdomen to identify/localize infectious, inflammatory, or neoplastic processes
    3. Abdominal ultrasonography to evaluate kidneys and to identify/localize infectious, inflammatory, or neoplastic processes
    4. Rule out immune-mediated diseases:
      1. FANA
      2. Coomb's test
      3. LE prep
      4. Joint taps
      5. Serum protein electrophoresis
      6. Others?
    5. Fundic examination - R/O hypertensive lesions, infectious diseases
    6. Screening for infectious diseases:
      1. Bacterial endocarditis - Blood cultures, echocardiogram
      2. Cats: Rule out FeLV and FIV
      3. Rule out Dirofilariasis
      4. Rule out appropriate infectious disease (e.g. Ehrlichiosis, Rocky Mountain Spotted Fever, Borelliosis, etc.)
    7. Rule out hyperadrenocorticism
    8. Coagulation - particularly Antithrombin III and fibrinogen levels
    9. Renal biopsy to identify morphologic lesion
      1. Light microscopy
      2. Immunofluorescence/electron microscopy


III. Dietary Modifications in Renal Failure

Diet therapy remains the cornerstone of therapy for CKD because it addresses the four primary goals of treatment of CKD by: (1) ameliorating signs of uremia; (2) minimizing deficits and excesses of fluids, electrolytes, minerals, and acid-base; (3) promoting optimum nutrition; and (4) retarding progression of CKD. Modifying diets to minimize deficits and excesses of metabolites associated with generalized renal dysfunction is not an all-or-none phenomenon. Best results are achieved when diet therapy is combined with other components of conservative medical management. Re-evaluation of patients at regular intervals is necessary to accurately assess response to therapy and achieve optimum therapeutic response.

Diet therapy for patients with CKD has traditionally meant reducing dietary protein content. The rationale for restricting protein intake of patients with CKD is based on the premise that controlled reduction of nonessential proteins will result in decreased production of nitrogenous wastes with consequent amelioration of clinical signs.

Dietary constituents other than protein should be modified to optimize the benefits of diet therapy. For example, dietary content of electrolytes and minerals which require renal excretion should generally be reduced in patients with CKD (e.g. phosphorus, sodium, magnesium, hydrogen ions). Dietary supplementation may be necessary or useful for some minerals and electrolytes (e.g. potassium and calcium). Although the principal benefit ascribed to dietary therapy in patients with CKD has been amelioration of clinical signs of uremia due to reduced retention of nitrogenous waste products, diet therapy may also benefit renal failure patients in other ways:
  1. Diet therapy may influence progression of renal failure.
    1. Protein restriction may minimize spontaneous, progressive renal damage in patients with CKD by modifying renal hemodynamics or compensatory renal growth.
    2. Dietary phosphorus restriction appears to slow progression of experimentally induced canine CKD.
    3. Other dietary factors which may influence progression of chronic renal failure include: dietary lipid content and composition, sodium intake, total calorie intake, the acidifying nature of the diet, and potassium content.
  2. Because proteinaceous foods are a major dietary source of phosphorus, dietary protein restriction is associated with a simultaneous reduction in phosphorus intake with potential amelioration of renal secondary hyperparathyroidism.
  3. Severity of polyuria and polydipsia is usually moderated when renal failure patients are fed reduced protein diets.
  4. Moderate protein restriction may reduce the severity of anemia of CKD.
  5. Because hydrogen ions are a by-product of protein catabolism, protein restriction may minimize metabolic acidosis.
The decision as to when to intervene with dietary therapy in patients with CKD is based, in part, to the severity of renal dysfunction and the goals of dietary therapy. There is little controversy as to the value of reduced protein diets in dogs with overt clinical signs of uremia when fed normal or high protein diets. The therapeutic value of dietary protein restriction for dogs and cats with early or mild renal failure is less clear.

Dogs with CKD should initially be fed a diet designed for dogs with renal failure or its nutritional equivalent. The limited evidence indicates cats with CKD should initially be fed a diet designed for cats with renal failure or its nutritional equivalent. At this point there is insufficient evidence to state at which point a cat should be started on a low protein diet. If started early in the disease, (creatinine 2.0-4.0) the cat may experience protein malnutrition, as cats tend to live for quite some time with their renal disease. However, there is one study that showed that cats with advanced renal failure do clinically better on a reduced protein and reduced phosphorous diet. Note that diets designed for dogs with renal failure do not contain sufficient protein for cats and therefore must not be fed to normal cats or cats with renal failure. Diets designed for cats with renal failure contain too much protein to be considered appropriate for dogs with renal failure. Because of the intrinsic variability of protein requirements of normal dogs and cats and the probable varied influence of uremia on protein requirements of uremic dogs and cats, dietary protein should be adjusted to meet individual patient needs. Sufficient calories should be provided to maintain a normal, stable body weight. Supplementing B-complex vitamins may be considered for dogs and cats with CKD, particularly during periods of reduced food consumption.

Protein intake is typically limited in diets designed for dogs and cats with CKD to ameliorate clinical signs of uremia. While the ideal quantity of protein to feed dogs and cats with CKD remains unresolved, there is a general consensus of opinion, that reducing protein intake ameliorates clinical signs of uremia in CKD and is therefore indicated for stage 3 CKD. Blood urea nitrogen can be used as a crude measure of compliance with dietary recommendations because it declines as dietary protein intake is reduced. While not generally regarded as an important uremic toxin, BUN is a surrogate marker for retained non-protein nitrogenous waste products and often correlates better with clinical signs than serum creatinine concentration.

The concept of reducing dietary protein intake in CKD patients that do not have clinical signs of uremia has been questioned. Limiting protein intake has been advocated for these patients in order to slow progression of CKD. This suggestion derives from studies in rats indicating that dietary protein restriction limits glomerular hyperfiltration and hypertension and slows the spontaneous decline in kidney function that follows reduction in kidney mass. Studies in humans have supported the concept that protein restriction slow progression of CKD, albeit this effect may be small In contrast, multiple studies have failed to confirm a beneficial role for protein restriction in limiting progression of CKD in dogs or cats. However, when not excessive, limiting protein intake has not been proven to have any adverse effects and it may be easier to initiate prior to the onset of clinical signs of uremia. In addition, protein restriction may delay onset of clinical signs of uremia as renal disease progresses. While a role for protein restriction in slowing progression of canine and feline CKD has not been entirely excluded, available evidence fails to support a recommendation for or against protein restriction in this group of patients.

Renal diets are limited in phosphorus content in order to limit phosphorus retention, hyperphosphatemia, renal secondary hyperparathyroidism, and progression of renal disease. Phosphate balance results largely from the interaction between dietary intake and renal excretion. Ingested phosphate is cleared from blood by glomerular filtration, and then total excretion is adjusted by modifying proximal tubular reabsorption. As renal function declines, renal tubular reabsorption of phosphorus declines (increasing renal excretion) in an attempt to compensate for the reduction in glomerular filtration, thereby maintaining phosphorus balance. However, if phosphorus intake continues unabated, the renal adaptive capacity soon becomes overwhelmed and phosphorus retention and hyperphosphatemia develop.

While phosphorus retention and hyperphosphatemia probably do not cause clinical signs, they may promote renal mineralization and a progressive decline in renal function. Dietary phosphorus restriction has been shown to enhance survival and a slow decline in renal function in dogs with induced renal failure. In cats, dietary phosphorus restriction has been shown to limit renal mineralization.

Available evidence supports a recommendation for dietary phosphate restriction for dogs and cats in stage 2 and 3 CKD. Because protein is a major source for phosphate, it is usually necessary to limit dietary protein in order to limit diet phosphate content.

Dietary supplementation with omega-3 PUFA have been shown to be beneficial in dogs with induced CKD. Compared to dogs fed diets high in saturated fats or omega-6 PUFA, dogs consuming a diet supplemented with omega-3 PUFA had lower mortality, better renal function, fewer renal lesions, less proteinuria, and lower cholesterol levels. In dogs fed the omega-3 PUFA diet, renal function actually increased and remained above baseline over 20 months of study. Lesions of glomerulosclerosis, tubulointerstitial fibrosis, and interstitial inflammatory cell infiltrates were also diminished in dogs fed the omega-3 PUFA diet.

A variety of effects attributed to omega-3 PUFA supplementation may have contributed to the favorable renal effects observed, including their tendency to reduce hypercholesterolemia, suppress inflammation or coagulation (by interfering with the production of proinflammatory, procoagulant prostanoids, thromboxanes, and/or leukotrienes), lower blood pressure, favorably influence renal hemodynamics, provide antioxidant effects, or limit intrarenal calcification. A subsequent study supported possible roles for altered lipid metabolism, glomerular hypertension and hypertrophy, and urinary eicosanoid metabolism in the beneficial renal effects of omega-3 PUFA.

Clinical trial evidence supporting use of renal diets in dogs with chronic renal failure


We have recently completed a randomized, controlled clinical trial designed to address the question of effectiveness of manufactured renal diets. Essentially, we asked whether there were clinically important benefits to recommending a diet change from a typical canine maintenance diet to a "renal diet" in dogs with spontaneously occurring chronic renal failure. Other than being randomly assigned to either the renal diet or the maintenance diet, dogs were managed in an identical manner with respect to other treatment interventions. Thirty-eight dogs were enrolled in this 2-year study.

We found that compared to dogs fed the maintenance diet, dogs fed the renal diet had reduced incidences of uremic crises, renal mortality and all-cause mortality. The relative risk of an uremic crisis occurring was reduced by 72% among dogs fed the renal diet. The median symptom-free interval among dogs fed the renal diet was 615 days, but only 252 days among dogs fed the maintenance diet. Dogs fed the renal diet had a median survival time of 594 days, while dogs fed the maintenance diet had a median survival time of only 188 days. Renal-related death was the primary caused for enhanced early mortality among dogs fed the maintenance diet. These benefits applied equally well to dogs with serum creatinine values less than 3.0 mg/dl (265 ?mol/L). The relative risk of an uremic crisis occurring was reduced by 74% among dogs with mild renal failure fed the renal diet. The median symptom-free interval among dogs with mild renal failure fed the renal diet was 615 days, but only 461 days among dogs fed the maintenance diet. In addition, renal function declined more slowly in dogs fed the renal diet.

This study provides strong evidence supporting the value of dietary intervention in dogs with chronic renal failure, regardless of the severity of their disease. In order to optimize success with renal diets, therapeutic diets should be initiated slowly over at least several days to several weeks, depending on patient acceptance and response. Metabolic causes for poor appetite should be addressed, including dehydration, uremic gastritis, anemia, acidosis, hypokalemia, hyperparathyroidism, and others. Suboptimal acceptance of therapeutic diets most often results from failure to introduce the diet appropriately and failure to attend to treatable complications of renal failure.

Clinical trial evidence supporting use of renal diets in cats with chronic renal failure.

The effectiveness of diet therapy in cats has been tested in a prospective study comparing a renal diet characterized by protein and phosphorus restriction to no diet change. Cats that would not accept the renal diet, either due to pet or owner issues, continued to eat their regular diet. This study was neither randomized nor blinded, but yielded results similar to those observed in the canine study. Cats fed the renal diet (mean survival time = 633 days) survived substantially longer than cats that continued to consume their regular diet (mean survival time = 264 days). Plasma urea nitrogen, phosphorus, and parathyroid hormone concentrations were reduced in cats that consumed the renal diet.

We are currently finishing a double-blinded, randomized, controlled clinical trial designed to evaluate the effectiveness of a commercial renal diet vs. a maintenance diet in cats with stage 2, naturally occurring chronic renal failure.Statistical analysis of the data has not been completed to date. Interestingly, most of the cats have had minimal or no progression of their renal disease at this early stage of the disease.

Indications for Diet Therapy


Current data supports a recommendation for diet therapy in dogs and cats in stage 2 and 3 CKD. The value of diet therapy in stage 1 CKD has not been established; therefore there is no evidence to support a recommendation for or against diet therapy in stage 1 CKD.

In the past, criteria for timing of dietary intervention in dogs and cats with naturally occurring CKD have been based on empirical observations. An often-cited guideline has been to initiate dietary therapy when serum creatinine exceeds 2.5 mg/dl or the SUN exceeds 60-80 mg/dl. More recently, one investigator recommended a staged approach whereby dietary phosphorus restriction and omega-3 PUFA dietary supplementation be implemented in stage 2 CKD with dietary protein restriction recommended only in stage 3 CKD. However, the clinical trial data available to date have demonstrated a benefit of dietary intervention in both stage 2 and stage 3 CKD.

Managing Anorexia in CKD


Malnutrition is usually detected clinically as weight loss, declining values for serum albumin concentration (or total plasma protein), anemia, and subjective evidence of decreased muscle mass. Reduced values for serum urea nitrogen may also indicate inappetence and malnutrition. An ideal method for evaluating nutritional status has not yet been devised, and the methods suggested here are relatively insensitive for detecting early malnutrition.

Malnutrition in patients with CKD usually results from inadequate food intake rather than deficiencies in diet formulation, although diets exceptionally restricted in protein content have been reported to promote protein malnutrition. Most current manufactured diets designed for CKD patients appear to contain sufficient protein to sustain adequate nutrition when consumed in appropriate quantities.

When food intake is less than optimal, we recommend a step-wise approach designed to facilitate adequate food intake. The first step is to assure that metabolic causes for decreased appetite have been corrected. Common metabolic derangements that may promote anorexia include prerenal azotemia due to dehydration, dietary indiscretion, or gastrointestinal hemorrhage, acidosis, hypokalemia, anemia, and drug-associated anorexia. Some antibiotics and enalapril are particularly prone toward inducing anorexia, but increased levels of any drug normally excreted by the kidneys should be suspected of potentially promoting anorexia in patients with CKD. Inappetence also appears to be an occasional complication of urinary tract infection.

Once metabolic causes for anorexia have been excluded or corrected, therapy for uremic gastroenteritis should be initiated. This recommendation assumes that nausea and gastrointestinal distress may be the cause for anorexia even in patients that are not vomiting. Some veterinarians recommend initiating this therapy at the time that CKD patients are transitioned to renal diets to facilitate acceptance of the diet change. Therapy for uremic gastroenteritis includes administration of an H2 antagonist, either alone or combined with antiemetics. The H2 antagonist famotidine (Pepcid�) may be administered at a dosage of 0.5 to 1.0 mg/kg orally every 24 hours. Alternatively, the H2 antagonist ranitidine (Zantac�) is administered at a dosage of 1 to 2 mg/kg orally every 12 to 24 hours. Since they are partially excreted by the kidneys, dosage adjustments may be necessary with prolonged usage or in patients with marked reduction in renal function. Famotidine has the advantage of being available over-the-counter in a particularly convenient dose size for smaller animals and may be effective with once daily dosing. Ranitidine may cause false-positive urine protein readings on Multistix�.

The antiemetic most commonly recommended for patients with CKD is metoclopramide (Reglan�). It is administered orally or subcutaneously at a dose of 0.1 to 0.4 mg/kg every 8 hours. The kidneys excrete metoclopramide, and dosage should be reduced by 50% in advanced renal failure. The selective serotonin antagonists dolesatron (0.3 to 0.6 mg/kg orally or slow intravenously, once daily) or ondansetron (0.6 to 1.0 mg/kg orally or intravenously every 12 hours) are powerful antiemetics that can be used in addition to metoclopramide if necessary.

If therapy with histamine blocking agents and antiemetics fails to restore normal appetite, tube feeding should be considered. Nasogastric feeding with liquid diets may be used short-term to support nutrition and restore appetite; however, for long-term nutritional support, the clinician should consider placing a percutaneous gastrostomy (PEG) tube. Long-term PEG tube feeding is useful for maintaining nutrition as well as hydration. In our hands, patients with PEG tubes have had extended periods of good quality of life. In addition, some patients begin eating again after a period of nutritional support using PEG tubes.

It has also been suggested that limiting dietary protein intake may induce protein malnutrition. However, currently available data does not support this view. Currently manufactured renal diets do not lead to protein malnutrition. The sum effect of these voiced concerns about protein restriction has been confusion over when diet therapy is appropriate.

Although the principal controversies in diet therapy largely surround the issue of protein restriction, current manufactured diets designed for use in dogs with chronic renal failure include multiple modifications designed to enhance their therapeutic efficacy. These enhancements are designed to ameliorate signs of CKD, maintain optimum nutrition, and minimize progression of renal failure. Enhanced omega 3: omega 6 polyunsaturated fatty acid (PUFA) ratios and reduced dietary phosphorus content have been shown to be efficacious in canine models of chronic renal failure. Reducing dietary protein and sodium content, increasing caloric density of the diet and increased fiber content have been justified on the basis of "pathophysiologic rationale."


Table 12: Typical modifications characteristic of renal diets

Dietary Component Change from typical maintenance diets
Protein quantity Reduced
Protein quality Increased
Phosphorus Reduced
Sodium Reduced
Fatty acids Enhanced omega 3:omega 6 PUFA ratio
Caloric density Enhanced
Fiber Enhanced


IV. Acute Renal Failure ...
The Joy of Success, The Agony of Defeat

Abnormalities in renal function constitute a major problem in both veterinary and human intensive care units. Acute renal failure (ARF) is defined as an abrupt decrease in renal function leading to the accumulation of nitrogenous wastes such as urea nitrogen and creatinine. Acute renal failure (ARF) is an important contributing factor to morbidity and mortality in the critical care setting. Patients usually either present with established renal disease, or they are at risk of developing acute renal disease while they are critically ill in the intensive care unit. Patients in the latter group, often develop renal disease in a step-wise fashion following sequential renal insults including hypovolemia, hypotension, heart disease, pro-thrombotic states, nephrotoxic drugs, and infection. Careful monitoring and management of the patients in this group is crucial in preventing the development of ARF.

Classically, ARF is dived into three stages. The first, or initiation phase may last from hours to days and is the period of time during which the kidneys are exposed to ischemic, toxic or otherwise noxious stimuli. The second, or maintenance represents the period of time during which tubular lesions occur and nephron dysfunction is evident. The length of this phase will vary with the etiology. The third, or recovery stage is usually marked by diuresis as the resorptive function of the kidney is still impaired. The tubules will slowly repair if the basement membrane has been left intact, and nephron function will improve.

Identification of either a prerenal or postrenal cause of ARF makes the initiation of a specific therapy possible. If, however, these two categories can be ruled out, then an intrarenal cause can be implicated. The renal parenchymal causes of ARF are usually subdivided into those primarily affecting the glomeruli, the intrarenal vasculature, or the renal interstitium. The term acute tubular necrosis denotes another broad category of intrinsic renal failure that cannot be attributed to glomerular, vascular, or interstitial causes.

The characteristic tubular injury in acute tubular necrosis (ATN) represents a nonspecific response than can be seen with a variety of renal insults, including renal ischemia and exposure to exogenous or endogenous nephrotoxins. The net effect is a rapid decline in renal function. There are two major histiologic changes that take place in ATN: 1) tubular necrosis with sloughing of the epithelial cells and 2) occlusion of the tubular lumina by casts and by cellular debris

In addition of the tubular obstruction, two other factors appear to contribute to the development of renal failure in ATN: backleak of filtrate across the damaged tubular epithelia and a primary reduction in glomerular filtration. The decrease in glomerular filtration results both from arteriolar vasoconstriction and from mesangial contraction. The decline in renal function in ATN has a variable onset. It typically, begins abruptly following a hypotensive episode, rhabdomyolysis, or the administration of a radiocontrast media. In comparison, when aminoglycosides are the cause, the onset is more insidious, with the first rise in creatinine being at seven or more days.

Special Considerations for patients with pre-existing renal disease

Management of animals with CKD must focus on two primary goals. The first is to ensure that the remaining functional renal tissue is preserved. The second is to help prevent the development of secondary pathologic derangements. Patients with decreased renal reserve are more susceptible to hypoperfusion injury, more likely to develop acute tubular necrosis and less likely to recover from an acute insult. Patients with CKD cannot compensate for hypovolemia or hypotension leaving them at great risk for further acute reductions in GFR. The development of acute on chronic renal failure is a fairly common occurrence in the intensive care setting and most often develops from the additive effects of multiple small hypotensive, ischemic, or nephrotoxic insults in addition to the pre-existing renal disease.


Table 1: Standard Operating Procedure for Therapy of an Acute Uremic Crisisa


  1. Acute Renal Failure
    1. Establish baseline data prior to treatment and initiate flow sheet.
    2. Place an intravenous catheter aseptically and rehydrate the patient with appropriate fluid (percentage of dehydration x body weight in kilograms = liters of fluid). Use caution; do not overhydrate patients.
    3. Correct life threatening electrolyte and acid-base disturbances; hyperkalemia, metabolic acidosis, hypocalcemia.
    4. Following correction of dehydration and hypotension determine if patient is oliguric or nonoliguric.
    5. Ensure adequate fluid balance and maintain mean arterial pressure above 60 mmHg.
    6. If persistently oliguric when rehydrated, place indwelling urinary catheter and monitor urine production.
  2. If Oliguric
    1. Attempt to convert oliguria to non-oliguria.
      1. Furosemide
        • Consider furosemide at 2-4 mg /Kg IV. If diuresis does not occur within 30-60 minutes, the dose may be doubled and given again.
        • Alternatively may try a constant rate infusion of 0.5 - 1.0 mg/kg/hour. (May want to consider a "loading dose" of 2 mg/Kg IV bolus) Caution: furosemide should only be used in patients that have been rehydrated and should not be used in patients receiving aminoglycoside therapy. If no response within 3 hours, discontinue.
      2. Dopamine
        • Consider low dose dopamine (2-5�g/Kg/min) as a constant rate infusion in 0.9% sodium chloride.
        • At dosages above 5�g/Kg/min dopamine will exert some vasoconstrictive effects as well and above 10�g/Kg/min vasoconstrictive effects predominate. Ventricular arrhythmias and tachycardias may result at high doses or rapid
        • If no improvement in urine output within 6 hours, the dopamine should be discontinued.
        • Dopamine should not be used concurrently with metochlopramide as the actions of these two drugs antagonize each other.
        • It has recently been demonstrated that cats do not have renal dopamine receptors as do dogs and humans, but anecdotally diuresis is still possible.
      3. Combination Therapy of Dopamine and Furosemide
        • Some clinicians prefer a combination of furosemide and dopamine after the patient has been rehydrated.
        • Typically dopamine is infused at 2-5�g/Kg/hr in addition to furosemide given at 0.5 - 1.0 mg/Kg/hr as a constant rate infusion or as hourly boluses.
      4. Mannitol (20% to 25% solution)
        • 0.25g to 0.5g/Kg body weight (IV) over 5 minutes
        • If significant diuresis develops, repeat every 4-6 hours the first day.
        • If diuresis does not ensue, do not repeat as vascular overload may result.
        • Discontinue diuretics if no effect within 1 (mannitol) to 6 (furosemide, dopamine or both) hrs.
    2. If patient becomes non-oliguric, see section C, Non-oliguria.
    3. If patient fails to become non-oliguric, two options are available:
      • Peritoneal dialysis or hemodialysis.
      • Conservative management of fluid and electrolyte balance and uremic symptoms.
    4. Maintenance of fluid and electrolyte balance.
      • Serial monitoring as needed: body weight, urine output, fluid intake, clinical hydration status, blood pressure, venous blood gas, packed cell volume, total plasma proteins, blood urea nitrogen, serum creatinine, Na+, K+, and Cl- concentrations complete blood count, urinalysis, serum Ca+2, PO4-3.
      • Balance fluid intake with losses (total fluid intake should equal insensible losses plus urine output).
      • Attempt to maintain stable body weight (anorexic animals lose approximately 0.1 kg to 0.3 kg per 1000 calories required per day).
      • Probably desirable to maintain animals in a state of very slight overhydration (estimate 1% to 3% of body weight and monitor very carefully).
      • Reassess therapy if fluid, electrolyte, or acid-base disturbances persist.
    5. Control uremic manifestations.
  3. Nonoliguria
    1. Provide adequate fluid therapy, anticipate diuresis.
    2. Correct life threatening electrolyte disturbances; hyperkalemia, metabolic acidosis, hypocalcemia.
    3. Fluid, electrolyte, and acid-base disturbances may be managed as above for oliguric patients. Serial monitoring as needed: complete blood count, urinalysis, serum creatinine, serum Ca+2, PO4-3, and HCO3- (or total CO2) concentrations
    4. Electrolyte and acid-base disorders may be less severe, therefore monitoring may be needed less often except for daily monitoring of body weight, urine output, fluid intake, clinical hydration status, packed cell volume, total plasma proteins, and blood urea nitrogen and creatinine.
    5. Control of uremic manifestations.


(a) From Ross SJ, et al: Acute Renal failurein Wingfield W, Raffe M (ed):The Veterinary ICU Book, ed 1.JacksonTeton NewMedia, 2002

Parameters to Monitor�

Urine Output

Quantitative measurements of the patients' urine should be performed via a sterile, closed indwelling catheter system. Normal urine production for an euvolemic , normotensive dog or cat is 1-2 ml/kg/hr. It is essential that the animal is hydrated and has a blood pressure in excess of 60mmHg in order to correctly interpret the urine production. A urine production of < 0.25 - 0.5 ml/kg/hr is suggestive of acute oligouric renal failure and should prompt vigilent monitoring of the patient. A normal or increased urine production dose not imply normal renal function, as it may represent polyuric renal failure. Excessive urine production is also a classic sign of overhydration.

Hydration status

CKD patients often present in a state of dehydration. The renal related polyuria and gastrointestinal losses from vomiting and diarreha must be compensated for by increased water intake (polydipsia) in order to remain normally hydrated. As CKD progresses and the patient becomes more nauseated, he/she may drink less, or may consume an adequate amount of water that is subsequently lost through vomiting, contributing to the dehydration. The body weight is an important parameter to monitor as it indicates subtle changes in water balance. Amount of urine produced, skin turgor, mucous membrane moisture, hemoconcentration and CVP's are other parameters that should be monitored closely for hydration status.


Table 2 : Do's and Don'ts of fluid therapy(a)


Do
  1. Carefully formulate the prescription for fluid therapy including: 1) rehydration, 2) maintenance, 3) replacement of insensible losses, and 4) replacement of ongoing losses. Assess dehydration from skin turgor, capillary refill time, pulse rate and quality, pulmonary auscultation, packed cell volume, total plasma solids and central venous pressure if available. Remember that the assessment of dehydration is an estimate only, therefore the patient's hydration status should be frequently reevaluated.
  2. Estimate the volume of fluid needed to correct the dehydration according to the following: Volume (ml) of fluid needed = % dehydration x body weight (kg) x 1000.
  3. Estimate the maintenance fluid requirement for a dog or cat with a normal urine production using the normogram (table????) In an oliguric patient, an estimate of maintenance fluid requirement is determined by adding the insensible fluid losses(respiratory and GI) and the amount of urine produced. This volume is adjusted as needed (usually every 4 hours) based upon hydration status (body weight, urine output, etc.)
  4. Weigh the patient at least twice daily using an accurate scale. A rapid loss or gain of 1 Kg corresponds to a deficit or excess of 1L of fluid.
  5. Serially monitor the patients' serum creatinine, potassium, tCO2, serum urea nitrogen, packed cell volume, and total plasma proteins. Adjust the prescription for fluid therapy to minimize excesses and deficits.
  6. Frequently monitor the patient for signs of fluid overload (serous nasal/occular discharge, venous distention, pulmonary crackles., etc. )
Don't
  1. Forget that obese animals may appear well hydrated based on skin turgor as the adipose tissue will add resiliency to the skin, and cachectic animals may appear dehydrated when in fact they have simply lost elasticity in their skin.
  2. Forget that the pretreatment packed cell volume and total plasma proteins of an anemic, hypoproteinemic, dehydrated patient may appear to be normal.
  3. Administer subcutaneous medications to an animal that is >10% dehydrated as the accompanying vasoconstriction will prevent adequate absorption.
  4. Overhydrate the patient in an attempt to initiate diuresis. (table 9)
  5. Fluid overload an animal with hyopoalbumemia, as the decreased oncotic pressure will lead to interstitial edema.
  6. Forget that during the recovery phase, patients may become polyuric. Maintenance fluid requirements for a hydrated polyuric animal should be equal to the urine output plus insensible and ongoing losses.
  7. Don't initiate pharmacologic diuresis until dehydration has been corrected.

(a) From Ross SJ, et al: Acute Renal failurein Wingfield W, Raffe M (ed):The Veterinary ICU Book, ed 1.JacksonTeton NewMedia, 2002

Urinalysis

Urinalysis is one of the first, and easiest, tests that can be done on the patient with suspected renal disease. It can provide both diagnostic information as well as prognostic information about the patient. A dipstick positive for protein (3+, 4+) suggests intrinsic renal disease with glomerular damage. Prerenal azotemia, obstruction, and acute tubular necrosis tend to be associated with less proteinurea (trace-2+) than a glomerular lesion. A dipstick positive for blood indicates the presence of RBC's (> 5/HPF). If no RBC's are present, then there may be either myoglobin or hemoglobin present in the urine. In most cases the most significant amount of information is obtained from the urinalysis comes from the examination of the sediment of a centrifuged urine sample. In patients with prerenal azotemia, the sediment usually lacks cells, casts, and cellular debris. Similarly, postrenal causes of ARF tend to be associated with a benign sediment. The presence of RBC's and red cell casts is characteristic of a glomerular lesion. WBC's and white cell casts are seen in acute interstitial nephritis. The finding of eosinophils in a Wright-stained urine sediment has been suggested as indicating a drug-induced acute interstitial nephritis (this is not a specific finding as eosinophils can be present in other disease states).

Serum Urea Nitrogen and Serum Creatinine:

Creatinine is formed from the breakdown of muscle creatinine and is proportional to the muscle mass. It should be stable from day to day. The creatinine concentration is a function of the amount of creatinine entering the blood from muscle, its volume of distribution, and its rate of excretion. Since the first two are usually constant, ant changes in the serum creatinine level would usually be a result of a change in the GFR. Abrupt cessation of glomerular filtration causes the serum creatinine to rise by 1-3 mg/dl daily. The BUN also rises with renal dysfunction but is influenced by extrarenal factors as well. Increased protein intake, catabolism, GI bleeding, and many other factors will effect BUN.

The two important points to remember about elevations of serum creatinine and BUN are: First, they are late signs of renal dysfunction because GFR may need to be reduced by as much as 75% before elevations reach abnormal amounts. Second, many non-renal variables affect both these levels. Generally, a serum BUN to creatinine ration of greater than 20 suggests prerenal azotemia rather than ATN, which is associated with a ratio of 10, although this value is subject to significant variation.

Blood Pressure
Hypertension is common in end-stage renal disease and may be due to the release of renin by the diseased kidney or increased intravascular fluid volume secondary to abnormal renal handling of salt and water. The hypertension produces cardiac hypertrophy and, on occasion, congestive heart failure. A mean arterial pressure < 60 mg/Hg will result in oliguria due to decreased renal perfusion and a decreased GFR. This is a correctable form of pre-renal failure if detected and treated early with volume replacement and pressure support. Blood pressure should be measured every 4-8 hours depending on the severity of the initial hypotension and the urine output.

Electrolytes

The two electrolytes that are most commonly affected by renal disease are sodium and potassium. These electrolytes may increase or decrease depending on the type, severity, and duration of the renal disease. As the number of functioning nephrons declines, the kidneys become unable to maintain Na balance in the face of the usual fluctuations in salt intake. If salt intake exceeds the excretory capacity of the remaining nephron, ECFV expansion, edema, and hypertension will result. Therefore, Na intake restriction is often necessary. It should be noted that with advancing CKD and the inability of the kidney to dilute the urine and excrete excess water, the serum Na+ level may be lower than normal (hyponatremia) despite a significant degree of Na+ retention.

Most animals in renal failure are able to regulate their sodium concentrations and loose equal amounts of sodium and free water. Hypernatremia may occur either via free water loss, or iatrogenically from the adminstration of high sodium containing fluids or sodium bicarbonate long term. Serum sodium concentrations should be measured at least daily in the ICU setting to ensure that the patient does not become hypernatremic or hyponatremic as a result of fluid therapy.

Hyperkalemia is more often encountered in patients with a lower urinary tract obstruction than in patients with primary renal disease. However, patients with severe oliguria or anuria may develop hyperkalemia due to a failure of excretion. Hyperkalemia may also occur during aggressive fluid therapy with potassium containing fluids in a patient with a decreased GFR. Acute hyperkalemia is poorly tolerated, especially when ARF is associated with extensive tissue damage (crush injuries, tumor lysis, and rhabdomyolysis). The clinical symptoms correlate with the serum K+ level and range from harmless peaking of the T wave of the ECG to ventricular fibrillation and cardiac arrest. Consequently, this complication must be addressed on emergent basis.

Hypokalemia is more commonly associated with polyuric renal failure due to excessive urinary losses of potassium, especially in cats. Other contributing factors may be inadequate oral intake of potassium due to complete or partial anorexia or aggressive rehydration with potassium deficient fluids. Potassium may be a result of, or contribute to renal disease. A systemic decrease in potassium levels will alter the hemodynamics in the systemic vasculature and will decrease the GFR further impairing renal function. Potassium levels should be monitored closely in the intensive care setting, especially in patients with oliguric or anuric renal disease. Potassium levels should be interpreted along with the acid base status of the patient to have a more accurate idea of the total potassium stores in the body. The goals of potassium replacement therapy should be to maintain a normal serum potassium. This is usually achieved via potassium enriched IV fluids in hospital and may require long-term therapy with oral potassium supplements.

Central venous Pressure

The central venous pressure (CVP) is the pressure at the level of the cranial vena cava. It is important that the zero mark of the manometer is level with the right atrium of the patient. The patient should be in the same position for each reading for consistency and to allow for the interpretation of trends. Normal CVP readings should be approximately 0-5 cm H2O, however, a single reading is rarely accurate and more attention should be devoted to trends in a specific patient.

The CVP is an indicator of hytdration status, cardiac function and vascular compliance. An elevation in CVP is commonly seen in animals with heart disease. In the absence of heart disease, the CVP is an excellent monitoring tool when administering fluids as an increase in the CVP could indicate overhydration. In ARF the CVP will rise in an oligouric patient who is being overhydrated and should be monitored every 4 - 6 hours

Acid - Base

In renal insufficiency, the kidneys have an impaired ability to excrete the organic acids that are produced during everyday metabolic processes. In addition, the ability of the kidney to resorb bicarbonate from the filtrate is impaired. The inevitable consequence of these impairments is the development of metabolic acidosis. To some extent the acidosis may be buffered by mobilization of minerals from the bone thus contributing to renal osteodystrophy.

A venous blood gas should be obtained at the time of presentation of the renal patient to the intensive care unit, and repeated as necessary to ensure that the blood pH and blood bicarbonate level stay within a safe range. Mild acidosis (pH 7.30 to 7.35) usually requires no therapy. However, chronic metabolic acidosis (pH < 7.3) is usually associated with a plasma CO2 content < 15 mmol/L and symptoms of anorexia, exaggerated protein catabolism and renal osteodystrophy. Sodium bicarbonate should be administered in increasing doses until symptoms are relieved (CO2 content about 20 mmol/L) or until evidence of Na overloading prevents further therapy.

Coagulopathy

The association of altered hemostasis and uremia has long been recognized, as well as the fairly high morbidity associated with such events. The pathogenesis of bleeding disorders is multifactorial and no single explanation is enough to clarify such a complex and confusing matter. It is widely accepted that the primary mechanisms involve alterations in platelet-vessel wall interaction as well as platelet-platelet interaction due to the uremia. Since it reflects the endothelial integrity, platelet number, platelet function and hematocrit, the bleeding time is the best indicator of the alterations found in uremic patients. The reduced red cell mass seems to be involved in the genesis of the bleeding tendencies since it allows less time for the platelets to be in contact with the vessel wall. It is further demonstrated by the fact that the mere correction of the hematocrit levels (by the use of rHuEPO ) tends to normalize the bleeding time. The blood cells also enhance platelet function by releasing ADP and by inactivating PGI2 (an inhibitor of platelet aggregation).

Gastrointestinal

Nausea, vomiting, and anorexia are extremely common in advanced renal failure. Ulcerative stomatitis, erosive gastritis, and uremic colitis may cause gastrointestinal bleeding. Patients in the intensive care setting should be monitored for melena, decreasing PCV, and a disproportionate increase in BUN relative to creatinine. All of these parameters may indicate gastrointestinal bleeding. Standard therapy usually includes a H2 receptor antagonist to decrease the amount of stomach acid produced.

Pharmacologic Considerations

Renal insufficiency can markedly alter one or more of the pharmacokinetic parameters of a drug including oral bioavailability, volume of distribution, drug binding to plasma proteins, and most importantly the rates of metabolism and excretion, i.e., drug clearance. To minimize drug toxicity and maximize therapeutic benefits, it is often necessary to adjust drug dosage in proportion to the degree of renal insufficiency.

A drug will most likely require dose adjustment in renal disease if:
  1. A substantial fraction (> 40%) of the rug dose is excreted by the kidney either unchanged or as an active (or toxic) metabolites.
  2. The drug or its active metabolite has a narrow therapeutic window such that drug accumulation cannot be tolerated.
  3. The kidney is a major site for the inactivation of the drug. This applies mainly to peptides like insulin, glucagon, PTH, and imipenem.
  4. There is a significant drop in the binding of the drug to plasma proteins. For instance, a decrease in the protein binding from 99 to 95% results in a fourfold rise in the unbound, active drug concentration.
Dose adjustment may involve one or a combination of the following measures:
  1. Extension of the dosing interval.
  2. Reduction of the maintenance dose.
  3. Administration of a loading dose.
  4. Monitoring serum drug levels.
Reduced elimination of a drug prolongs its half life (t1/2) as well as the time required for the serum level to reach a steady state (4 times t1/2). Therefore, whenever it is clinically desirable to rapidly achieve a therapeutic steady state level a loading dose should administered.

To maintain a therapeutic level and, at the same time, avoid drug accumulation and toxicity in a patient with reduced renal function, the clinician must consider reducing the size of the maintenance dose or the dosing frequency or both. In general, this reduction should also be proportional to the degree of renal impairment but should also take into account adaptive or compensatory changes in the metabolism and excretion of the drug through non-renal routes.

Nutritional Management of Acute Renal Failure

Animals in an intensive care setting are often unable or unwilling to consume adequate calories to meet their nutritional needs. Endogenous protein catabolism may be minimized by providing sufficient carbohydrate and fat to meet energy requirements. Provision of nutrition to patients with acute renal failure will help to preserve lean body mass, and provide a substrate for tissue repair.

Body weight is the most commonly used method of nutritional assessment, however, it is also the most crude. Body weight may vary significantly with fluid losses and excesses in ARF patients. However, a baseline weight on a normally hydrated patient may be used as a baseline. In general an anorexic animals will lose 0.3 - 0.5 kg per 1000 Kcal required per day. Body condition scoring also provides a means of roughly monitoring a patient's nutritional status. However, body condition scoring is subject to interoperator variation and relatively large changes in body composition / mass are required to alter scoring. Bioelectrical impedence analysis is an accurate, non-invasive, repeatable and easy method of obtaining accurate measurements of total body water, fat free mass, and ECF volume. These values may be serially monitored to assess both nutritional and hydration status in patients with ARF. Although relatively new in veterinary medicine, the accuracy and simplicity of this method is bound to make it a popular method in the near future.

Patients with ARF are often in a catabolic state and may have a metabolic acidosis which may contribute to the catabolism of protein in the body, thereby, exacerbating azotemia, hyperkalemia, hyperphosphatemia and loss of lean body mass. Protein calorie malnutrition has many negative effects, such as impaired wound / tissue repair, impaired immune function resulting in an increased incidence of infection, and a decrease in muscle strength.

Every effort should be made to encourage the oral intake of calories. A highly palatable diet should be offered to increase patient compliance. It must also be emphasized that when offering a diet to an ill animal, it should be a diet that is unrelated to the proposed long term diet of the patient. This will help prevent the development of food adversion to the preferred theraputic diet.

If vomiting is not a major problem and the animals is alert enough to avoid aspiration of vomited stomach contents, a nasoesophageal tube may be placed to assist with the maintenance of nutrition as well as hydration. Most patients tolerate short term used of nasoesophageal tubes readily, and there are commercially available liquid renal diets for veterinary patients that are easily administered via a nasoesophageal tube. A percutaneous gastrostomy tube (PEG tube) is often considered for the long term management of the inappetant animal, or for animals that require supplementary hydration and/or medications. PEG tubes are usually well tolerated by the patient and are usually large enough that a blenderized, strained mixture of a canned prescription renal diet may be fed. When oral intake is not possible due to protracted vomiting or a moribund state, parentral nutrition should be employed to provide the daily caloric requirements for the patient until oral nutrition is possible.

Prognosis and Outcome

The prognosis for animals with acute renal failure is dependent on the underlying cause, the extent of renal injury, concomitant disease or organ failure, age and response to therapy. A retrospective study completed by Dr. Vaden in 1997 demonstrated that 56% of dogs disgnosed with acute renal failure at a university referral hospital were euthanatized or died before discharge, and over half of the surviving dogs developed some degree of chronic renal failure. In a previous retrospective study by Dr. Berhend, the mortality of dogs with hospital acquired acute renal failure was 62%. Mortality rates for dogs with confirmed ethylene glycol intoxication have been reported to be as high as 100%, while mortality rate for animals with infectious causes of ARF such as Leptosirosis are generally much lower. These percentages have improved considerably with increased use of peritoneal and hemodialysis, although availability currently limits the use of these treatment modalities.

© 2003 - Sheri Ross, DVM - All rights reserved