Current concepts for management of chronic renal failure in dogs: early diagnosis and supportive care (Proceedings)

Flaws in Traditional Tests for Renal Function

Urine concentrating ability is impaired when 66% of nephrons are no longer functioning, and azotemia develops when 75% of nephrons are no longer functioning. However, many variables not related to renal function can affect urine concentrating ability, blood urea nitrogen (BUN) and serum creatinine (SCr). In addition, the relationship between GFR and BUN, SCr is not linear. Early in renal disease, large decreases in GFR cause only small increases in BUN and SCr, while in advanced renal disease, small changes in GFR result in large changes in BUN and SCr. 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, resulting in enhanced excretion of nitrogenous wastes and delay of onset of azotemia until more nephrons are lost. These findings indicate that patients are often worse off in terms of number of functional nephrons than surmised by considering BUN and SCr values. This interpretation and the abundance of non-renal influences on urine concentration, BUN and SCr, provides a strong argument for pursuing more sensitive methods for evaluating renal function

More Sensitive Tests for Detecting Renal Dysfunction

Reciprocal of Serum Creatinine (1/SCr) versus Time

It has been suggested by some investigators that plotting the 1/SCr vs time shows a linear decrease in renal function with time, and it is an accurate method of following 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/SCr and GFR does not always occur. Therefore although the 1/SCr vs time is commonly used to assess GFR, the accuracy of this test is in question.

Plasma Clearance Tests

GFR is defined as mls of plasma that are cleared of a substance/min/kg BW. Renal clearance assays are used to define GFR by determining clearance of a plasma-borne solute from urine. Examples include:

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

2. Radionucleides and nuclear imaging techniques is an alternative method for calculating GFR. However, specialized equipment and handling of radioactive materials is required, and therefore use of this test is primarily limited to research settings, and it is impractical for routine use in clinical practice.

3. Less precise alternatives include endogenous or exogenous creatinine clearance. Both of these tests require accurately performed timed urine collections. This entails intermittent catheterization of the urinary bladder, is labor intensive and stressful and slightly invasive for the patient.

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 has inherent limitations, and relying solely on SCr and BUN levels was fraught with its own set of problems.

Iohexol Clearance Test

This test has been recently developed for use in dogs and cats. It is easy 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 of performing 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 disappearance of iodine in serum following a single IV dose of iohexol, GFR can be estimated [see end of notes for the protocol for performing iohexol clearance].

Comparison of Iohexol Clearance and Urinary clearance of Exogenous Creatinine

In both healthy dogs and dogs with surgically reduced renal mass (Finco, 2001) showed that iohexol clearance is a reliable marker of GFR in dogs. Iohexol clearance is also a reliable marker of GRF in cats (Miyamoto K, 2001). As with any procedure where radiographic contrast material is being administered IV, potential adverse reactions to iohexol can occur and include anaphylaxis, arrhythmias, hypotension, acute renal failure, nausea and vomiting. Patients can be pre-treated with diphenhydramine IM to try to reduce the likelihood of an adverse reaction occurring. Although potential for adverse reactions exists and clients need to be counseled on this, the frequency of appears infrequent.

It is hoped that as veterinarians begin using this test more routinely in patients with polyuria/polydypsia, more patients will be diagnosed with renal disease prior to development of azotemia. 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.

Supportive Care for Dogs and Cats with Chronic Renal Failure

Although some newer options, such as hemodialysis and renal transplantation, are available for managing dogs and cats with CRF, it is very important not to overlook some basic therapeutic options. For example, it is important not to overlook ongoing causes of renal injury that are potentially amenable to treatment, such as pyelonephritis, hypertension, renal obstruction, nephrotoxic drugs, and mineral and electrolyte abnormalities.

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 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 with CRF, 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 a strongly acidic, bicarbonate-free urine. In healthy patients, 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. 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 which reduces the amount of net acid excreted. 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 protein catabolism and renal osteodystrophy and activation of the alternative complement pathway in patients with CRF. 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. The dose of sodium bicarbonate and potassium citrate for dogs and cats are:

Hypertension

Hypertension is a well-recognized complication of CRF in both dogs and cats. The most profound clinical effect of hypertension in cats is hypertensive retinopathy. Jacob et al (2002) reported that systemic hypertension is a risk factor for rapid progression of renal failure, a greater magnitude of proteinuria, and decreased survival time among dogs with spontaneous CRF. Based on results from this clinical study, the frequency and magnitude of hypertension in dogs with spontaneous CRF appears to be greater than that in dogs following induced renal failure model. This raises concerns about clinical applicability of this model. 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, it is presumed that the effects on renal function and survival times in cats will be similar.

The general consensus of the definition of hypertension in dogs is a systolic blood pressures (bp) >160 mm Hg. The Hypertension Consensus Group report in 2002 classified risks associated with systolic blood pressure in cats. The consensus was a systolic bp < 150 mm Hg was associated with minimal risk; systolic bp of 150-159 mm Hg was associated with low risk; a systolic bp of 160-179 mm Hg was associated with moderate risk; and a systolic bp of>180 mm Hg was associated with severe risk.

ACE inhibitors

Such as enalopril and benazopril, 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. 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-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 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. It is recommended to be more proactive in treatment of this problem in dogs and cats 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:

Other Symptomatic and Supportive Therapies

Other symptomatic and support therapies are available. Unfortunately, there is not enough time to discuss all of them.

Protocol For Estimation Of Gfr In Dogs And Cats By Serum Iohexol Clearance

[From Kruger JM, Braselton E, Becker T, Et Al. Proc 16th ACVIM Forum, Page 657, 1998]

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

2. Record an accurate body weight in kilograms. Place an intravenous catheter and flush with sterile saline to ensure patency prior to administration of iohexol. If concerned about an adverse reaction to Iohexol, pretreat patient with diphenhydramine.

3. 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/kg dose of iohexol to ensure enough iohexol will remaiin 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.

4. 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.

5. Allow blood sample to clot and transfer serum (0.4 ml or more) into a plastic vial appropriately labeled. Serum samples may be refrigerated or frozen.

6. 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].

7. Send to Michigan State. GFR will be reported in ml/min/kg body weight.

Example of Table Used For Iohexol Clearance