OVERVIEW OF CHRONIC RENAL FAILURE

Chronic renal failure (CRF) is the most common form of renal disease in dogs and cats, and it is generally considered a progressive and irreversible disease. It is estimated that 1 in 3 elderly cats and 1 in 5 elderly dogs in the United States have CRF.

Flaws in "Traditional" Tests for Renal Function

Medical literature states that urine concentrating ability is impaired when 66% of nephrons are no longer functioning, and that azotemia develops when 75% of nephrons are no longer functioning. Although both of these statements are correct, there are many variables not necessarily related to renal function that can affect urine concentrating ability, as well as BUN and serum creatinine.

It is well known that certain medications, such as corticosteroids and phenobarbital can result in the production of dilute urine in dogs, and furosemide can affect urine concentration in both dogs and cats. In addition, diet can influence urine concentration. It is well known that feeding a dog a protein-restricted diet results in medullary washout and production of dilute urine. In fact, evaluating urine concentration, as well as BUN levels, are two methods for assessing owner compliance while strictly feeding a protein-restricted diet. Non-renal diseases, such as diabetes mellitus, diabetes insipidus, liver failure, etc can also produce a low urine specific gravity. The activities of a dog and its temperament can also influence urine concentration without it being necessarily inappropriate or suggestive of renal dysfunction. Therefore, although it is true that urine concentrating ability is impaired when 66% of nephrons are no longer functioning, finding a dilute urine does not always equate with renal disease.

It is well established that BUN values are influenced by several factors other than glomerular filtration rate (GFR), and that BUN is inferior to creatinine for estimating GFR. Therefore, the main clinical utility of BUN is its use as an indicator of retention of harmful nitrogenous wastes in the body rather than its value for determining renal function.

The serum creatinine concentration is simple to perform, but gives only a crude estimate of GFR. Differences in the rate of creatinine production, relative to diet and muscle mass, may affect this value. For example, it is not uncommon to see serum creatinine concentrations decreasing in dogs and cats with advanced CRF due to muscle wasting and not due to improvement in GFR.

Another important point to keep in mind is while BUN and serum creatinine increase as GFR declines, this relationship is not linear. Large changes in GFR early in renal disease cause only small increases in BUN and serum creatinine, while small changes in GFR in advanced renal disease may be associated with large changes in BUN and serum creatinine. This occurs because the insidious loss of nephrons occurring with CRF is initially accompanied by compensatory hypertrophy of residual functional nephrons so that their single-nephron GFR may more than double. This results in enhanced excretion of nitrogenous wastes, and delays onset of azotemia until more nephrons are lost. Studies with the remnant kidney model of renal failure also indicate that renal mass and nephron numbers are reduced to 10 to 15% of normal at the time when GFR is still 25% of normal because of compensatory hypertrophy of the remaining nephrons. These findings indicate that patients are often worse off in terms of number of functional nephrons than surmised by considering GFR values. This interpretation, as well as the abundance of non-renal influences on urine concentration, BUN and serum creatinine levels, provides a strong argument for pursuing more sensitive methods for evaluating renal function than tests of urine concentration and azotemia currently offer.

More Sensitive Tests for Detecting Renal Dysfunction

Reciprocal of Serum Creatinine versus Time--it has been suggested by some investigators that plotting the reciprocal of the serum creatinine vs time shows a linear decrease in renal function with time, and it is an accurate method of following the progression of renal disease. Other studies have suggested that this method often gives erroneous estimates of rates of progression because a perfect linear correlation between 1/creatinine and GFR does not always occur. Therefore although the reciprocal of serum creatinine vs time is commonly used to assess GFR, the accuracy of this test is in question.

Plasma Clearance Tests--GFRis defined as the mls of plasma that are cleared of a substance/min/kg body weight. Renal clearance assays are therefore used to define GFR by determining the clearance of a plasma-borne solute from urine. The solute should not be protein bound, should be freely filtered across the glomeruli, and neither secreted nor reabsorbed by the renal tubules. The clearance of this solute is proportional to GFR. Inulin and creatinine are well suited for this purpose.

1.  Inulin or isotope clearance is considered the "gold standard" for estimating GFR. However, performing an insulin clearance is labor intensive, requires continuous infusion of inulin and arduous laboratory measurements, making this technique impractical for routine use in clinical practice.

2.  Radionuclides and nuclear imaging techniques may be an alternative method for calculating GFR. However, due to the need for specialized equipment and handling of radioactive materials, the use of this test is primarily limited to veterinary teaching hospitals and therefore this test is also impractical for routine use in clinical practice.
Less precise alternatives include endogenous or exogenous creatinine clearance. Both exogenous and endogenous creatinine clearance tests require that urine be collected in exactly defined time intervals. Accurately performed timed urine collections require intermittent catheterization of the urinary bladder, are labor intensive and stressful and slightly invasive for the patient.

3.  The endogenous creatinine clearance test is not suitable for detecting slight degrees of dysfunction because noncreatinine chromogens constitute a large percentage of plasma chromogens and lead to underestimation of renal function. Another criticism of the endogenous creatinine clearance test is the considerable variability inherent in this measurement.

4.  The exogenous creatinine clearance obviates the problems with noncreatinine chromogens. However, creatinine clearance may not accurately estimate GFR in heavily proteinuric patients because of tubular secretion of creatinine.

Alternative Test for Detecting Renal Dysfunction in Clinical Practice

Until recently, diagnosing early (pre-azotemic) renal disease in dogs and cats was primarily limited to renal clearance tests, such as inulin or creatinine clearance. The inability to readily assess renal function in a practical way often posed a dilemma for clinicians with patients whose only finding was a low urine specific gravity. As a result, detection of early (pre-azotemic) renal disease was often missed. In addition, assessing renal function in patients with azotemic renal failure also had inherent limitations, and relying solely on serum creatinine and BUN levels was fraught with its own set of problems.

Iohexol Clearance Test

Recently, this renal clearance test has been developed for use in dogs and cats, and it iseasy to perform, doesn't require any specialized equipment or collection of urine, and therefore is practical for routine use in clinical practice. The relative ease in performing plasma or serum clearance procedures, compared to urinary clearance procedures, also makes this test attractive.

Iohexol (Omnipaque®) is a low osmolar, nonionic, iodinated radiographic contrast medium used for radiographic procedures in both human and veterinary medicine. By measuring the plasma or serum disappearance of iodine following a single intravenous dose of iohexol, GFR can be estimated. [see end of section for complete protocol for performing iohexol clearance]

Iohexol clearance was compared to urinary clearance of exogenous creatinine in 10 dogs with normal renal function, and in 12 dogs with surgically reduced renal mass (Finco, 2001). Plasma was analyzed for iohexol by 3 assay methods: chemical, high-performance liquid chromatolography (HPLC), and inductively coupled plasma emission spectroscopy (ICP). Results showed significant correlation between iohexol clearance and urinary clearance of exogenous creatinine using all three of the assay methods (chemical R² = 0.90; HPLC R² = 0.96; and ICP R² = 0.96). The investigators concluded that iohexol clearance is a reliable marker of GFR in the dog.

Iohexol clearance was also recently evaluated in cats (Miyamoto K, 2001). Four renal-intact and 6 partially nephrectomized adult cats were evaluated in this study. Iohexol clearance results were compared to (exogenous) urinary clearance of creatinine. Correlation between iohexol clearance and (exogenous) urinary clearance of creatinine for all cats was high (r = 0.951). Therefore, just like in dogs, iohexol clearance in cats provides a reliable estimation of GFR.

Suggested indications for iohexol clearance include:

1.  Determining if renal insufficiency is responsible for clinical signs or laboratory abnormalities observed in patients with equivocal evidence of renal dysfunction (i.e., polyuria in nonazotemic animals),

2.  Identifying occult renal dysfunction prior to procedures or therapy which may be detrimental to renal function,

3.  Monitoring changes in renal function after initiating therapy,

4.  Optimize dosing schedules for drugs eliminated by glomerular filtration in patients with renal dysfunction.

Although uncommon, as with any procedure where radiographic contrast material is being administered intravenously, potential adverse reactions to iohexol can occur and include anaphylaxis, arrhythmias, hypotension, acute renal failure, nausea and vomiting. Incidentally, one 10 year old male castrated Sheltie dog involved with an ongoing clinical study of CRF had a history of having a mild adverse reaction (vomited) to a different radiographic contrast agent administered for an excretory urogram. We administered diphenhydramine intramuscularly to the dog prior to each time we administered iohexol, and never had any adverse reactions. Therefore, although the potential for adverse reactions exists and clients need to be counseled on this, the frequency of adverse reactions associated with this procedure are infrequent.

In summary, iohexol clearance is a reliable and simple method for accurately assessing GFR in both dogs and cats. It is hoped that as veterinarians begin using this test more routinely in patients with polyuria/ polydipsia, that more patients will be diagnosed with renal disease prior to development of azotemia. This will also increase our understanding of the progression of spontaneous CRF and allow assessment of dietary management of this disease. In addition, it is hoped that this test replaces almost all water deprivation tests being performed in these same patients. Although administering iohexol to dogs and cats has the potential to be associated with an adverse reaction, the risks of performing this test are much less than the risks of performing an inappropriately conducted water deprivation test, and the iohexol clearance test likely yields more useful results than the water deprivation test.

PROTOCOL FOR ESTIMATION OF GFR IN DOGS AND CATS BY SERUM IOHEXOL CLEARANCE

[from Kruger JM, Braselton E, Becker T, et al. Proc 16^th ACVIM Forum, page 657, 1998]

1.  Patient should be well hydrated and fasted for 12 hours prior to the iohexol clearance study (water is okay and recommended).

2.  Record an accurate body weight in kilograms.

3.  Place an intravenous catheter and flush with sterile saline to ensure patency prior to administration of iohexol.

4.  If concerned about an adverse reaction to Iohexol, pretreat the patient with diphenhydramine.

5.  Administer a single dose of iohexol (150 to 300 mg/kg) as a rapid intravenous bolus and record time administered to the nearest minute. Iohexol is relatively expensive, especially if you are using it in a large dog. Therefore severity of azotemia may impact what dose of iohexol is used:

a.  With mild azotemia, it is best to choose 300 mg I/kg dose of iohexol to ensure enough iohexol will remain in the blood to be detected by the assays used to measure it.

b.  With moderate to severe azotemia, it is perfectly acceptable to use 300 mg/kg dose of iohexol. However, because renal clearance of iohexol is impaired, a lower dose (150 mg/kg) of iohexol can often be used.

6.  After administering the intravenous dose of iohexol, blood is collected in a clot tube at 2, 3, and 4 hours after iohexol injection. It is VERY important to record the times samples were collected to the nearest minute.

7.  Allow blood sample to clot and transfer serum (1.2 ml or more) into a plastic vial appropriately labeled. Serum samples may be refrigerated or frozen.

8.  Ship chilled or frozen serum samples to appropriate laboratory, being certain to include the exact dose of iohexol administered (mg iodine/kg body weight), the exact time of iohexol administration, and the exact time samples were collected [see table below]. Send samples in to Michigan State.

9.  GFR will be reported in ml/min/kg body weight.

Example of Table Used For Iohexol Clearance

SUPPORTIVE CARE FOR CRF

Despite all the controversy, dietary therapy continues to be a mainstay in the management of dogs and cats with CRF. In addition to appropriate dietary therapy, it is important not to overlook symptomatic and supportive care.

Although we have some newer options available for managing dogs and cats with CRF, such as hemodialysis and renal transplantation, in our desire to make our patients better, it is very important not to overlook some of the basic therapeutic options available. For example, it is important not to overlookongoing causes of renal injury that are potentially amenable to treatment, such as pyelonephritis, hypertension, renal obstruction, nephrotoxic drugs, and mineral and electrolyte abnormalities, such as hypercalcemia, hyperphosphatemia, and hypokalemia (cats). Some of the more basic therapeutic options will be briefly discussed, as well as a few of the newer therapeutic options.

Metabolic Acidosis

In 1994, Dr. Tim Allen wrote an article entitled "Metabolic Acidosis--The Hidden Assassin of Chronic Renal Failure." In this article, he discusses some of the adverse consequences of metabolic acidosis in patients with CRF. Although metabolic acidosis has the potential to cause detrimental effects in patients with CRF and it is very easy to treat, this problem is often ignored. We often underestimate the impact that metabolic acidosis can have on patients withCRF, and at least in veterinary medicine, it appears that metabolic acidosis tends to be undertreated in patients with CRF.

The normal response of the kidney to an acid load is to excrete strongly acidic, bicarbonate-free urine. In normal subjects, the total capacity to excrete hydrogen ions by renal tubular cells is only partially utilized, implying a secretory acid excretion reserve exists. However, in patients with CRF, this reserve is saturated and can result in systemic metabolic acidosis.

Acidosis can result from:

1.  Failure to reabsorb filtered bicarbonate,

2.  Failure to buffer sufficient buffer to excrete the daily load of acid, or

3.  Failure to acidify the urine.

The acidification process is an integrated function that occurs at several nephron segments. A major part of excreted acid is carried by ammonia, which is synthesized by the kidney. Protein catabolism provides a source of glutamine, which is a substance for renal ammoniagenesis. As renal disease progresses, the amount of ammonia produced per nephron is increased. However, because the number of surviving nephrons is decreased, the total amount of ammonia produced is reduced. This decreases the amount of net acid excreted. The progressive decrease in renal ammoniagenesis in CRF is one of the main causes of metabolic acidosis observed with CRF.

Progressive loss of lean body mass and bone disease are not uncommon in patients with CRF. Although the pathophysiology of these changes is complex, chronic metabolic acidosis plays a pivotal role in the pathophysiology of protein catabolism and renal osteodystrophy.

Metabolic acidosis stimulates or contributes to the following effects on protein catabolism:

1.  Severe catabolism of endogenous proteins

2.  Exacerbation of azotemia

3.  Negative nitrogen balance,

4.  Decreased muscle protein, muscle wasting, and loss of lean body mass

Inadequately controlled metabolic acidosis also contributes to renal osteodystrophy. Some of the deleterious effects of metabolic acidosis that contributes to the development of renal osteodystrophy are:

1.  Increased sensitivity of bone to parathyroid hormone

2.  Inhibition of vitamin D₃ 1-alpha-hydroxylation

Patients with CRF tend to excrete less acid than they produce metabolically. Since this positive acid balance occurs despite a constant level of bicarbonate, an extrarenal nonbicarbonate buffer must neutralize endogenous acid. Bone serves this function in the acidosis of CRF. Balance studies have shown that positive acid balance is accompanied by a comparable degree of negative calcium balance. Retained acid is neutralized by calcium carbonate in bone, thus protecting serum bicarbonate levels. Accordingly, acidosis can contribute to renal osteodystrophy by more than one mechanism.

The effects of increased ammonia production per nephron were evaluated in rats with partial nephrectomies by administering sodium bicarbonate (Nath, 1985). Dietary supplementation with sodium bicarbonate was shown to:

1.  Lower tissue ammonia concentrations

2.  Reduce peritubular deposition of complement components

3.  Diminish functional and structural tubulo-interstitial lesions

Another important point to keep in mind is that ammonia activates the alternative complement pathway by the reaction of ammonia with the 3^rd component of complement, culminating in deposition of complement proteins and initiation of complement-mediated cellular infiltration and tissue injury. These effects further impair tubular function and may promote a self-perpetuating cycle of adaptation and injury. As a result, correcting metabolic acidosis has the potential to not only slow down the progression of CRF, but it also has the potential to minimize protein catabolism and renal osteodystrophy.

Metabolic acidosis can be easily corrected by administration of either sodium bicarbonate or potassium citrate. In cats with CRF, it may be preferable to use potassium citrate because of the apparent association between metabolic acidosis and negative potassium balance, however, it is important to monitor serum potassium levels, as well as serum bicarbonate or total carbon dioxide concentrations.

If serum bicarbonate or total carbon dioxide concentrations are below the normal range, the dose of sodium bicarbonate and potassium citrate for dogs and cats are as follows:

Hypertension

Hypertension has become a well-recognized complication of CRF in both dogs and cats. The most profound clinical effects of hypertension in cats seems to be hypertensive retinopathy with retinal detachment, hemorrhage and blindness.

Jacob et al (2002) reported that systemic hypertension is a risk factor for rapid progression of renal failure and decreased survival time among dogs with spontaneous CRF. In this study, hypertension was also associated with a greater magnitude of proteinuria. Based on results from this clinical study in dogs with spontaneous CRF, the frequency and magnitude of hypertension in dogs with spontaneous CRF appears to be greater than that which develops in dogs following the renal ligation model of induced renal failure. This raises the concerns about the clinical applicability of this model. In addition, while induced models of CRF have failed to provide evidence for progression of CRF in cats, clinical studies generally confirm the progressive nature of spontaneous CRF in cats. The effects of systemic hypertension on progression of renal failure and survival times in cats with CRF have not been reported yet. Nonetheless, ocular lesions in cats with systemic hypertension are known to occur. Therefore, there is no reason at this time not to presume that systemic hypertension has similar effects on renal function and survival times in cats as in dogs.

Although many opinions exist regarding the definition of hypertension in dogs, the general consensus is that dogs with systolic blood pressures >160 mm Hg are hypertensive.

The Hypertension Consensus Group in 2002 classified risks associated with systolic blood pressure in cats. The consensus was as follows:

ACE inhibitors, such as enalapril and benazepril, currently appear to be the drugs of choice for managing hypertension in dogs. ACE inhibitors were found be superior to calcium channel blockers for renoprotective effects in dogs with induced diabetes mellitus, and they reduce proteinuria and slow development of lesions in dogs with reduced renal mass. The beneficial effects associated with administration of ACE inhibitors to dogs with hypertension may be due, in part, to hemodynamic effects, but these effects may also be due to other unidentified effects distinct from hemodynamic ones.

Amlodipine, a calcium channel antagonist, currently appears to be the drug of choice for managing hypertension in cats. It has been shown to be effective for lowering blood pressure in at least one clinical trial (Snyder, 1998). In contrast, ACE inhibitors and ß-blocking drugs do not appear as effective in lowering blood pressure in cats.

Uremic Gastritis

Uremic gastritis is characterized by glandular atrophy, edema of the lamina propria, mast cell infiltration, fibroplasia, mineralization, and submucosal arteritis. Clinically, as the severity of azotemia worsens, uremic signs of vomiting, nausea, and anorexia develop. Although some of these clinical signs may be the result of uremic toxins on the medullary emetic chemoreceptor trigger zone (CRT), uremic gastritis may also contribute to these problems.

Cats with CRF have been shown to have increased serum gastrin concentrations, which contribute to the pathogenesis of uremic gastritis. Although vomiting is a frequent, but inconsistent finding in uremic dogs, many cats with uremic gastritis may show only partial to complete anorexia as the clinical signs rather than vomiting. Besides anorexia and vomiting, uremic gastritis may also result in gastrointestinal bleeding. Unfortunately, uremic gastritis is often not addressed by veterinarians until a dog is vomiting or a cat is anorexic, and it is recommended to be more proactive in our treatment of this problem to lesson the likelihood that clinical signs will develop.

A general recommendation is to administer an H2 receptor antagonist, such as ranitidine or famotidine to patients with CRF once serum creatinine levels are above 3.0 mg/dl and prior to the onset of any clinical signs. In the United States, ranitidine and famotidine can be purchased by a client without a prescription.

Recommended dosages are as follows:

Other Symptomatic and Supportive Care

Many other symptomatic and support therapies are available as well. Unfortunately, there is not enough time to discuss all of them. Some of these other therapies include:

1.  Potassium supplementation (primarily cats)

2.  Treatment of anemia with erythropoietin and iron supplement

3.  Phosphate binders for hyperphosphatemia

4.  Calcitriol therapy for elevated levels of PTH

5.  Antiemetic therapy for nausea

6.  Fluid supplementation by feeding a canned diet, adding water to the diet, or subcutaneous fluids

7.  Nutritional support using enteral feeding tubes

References

References are available upon request.