Update on chronic renal failure (Proceedings)

The definition of kidney disease includes any structural or functional change of the kidneys. The kidneys are uniquely susceptible to injury due to the large quantity of blood filtered for each cardiac cycle (20-25% of cardiac output), regional differences in blood supply within the kidney, and a high rate of metabolic activity of renal tubular cells. Disease and failure can occur acutely or chronically.

Although renal disease and renal failure are common, diagnosing the kidney disease can be challenging due to limitations of testing and difficulty interpreting test results. Diagnostic mainstays include clinical findings, serum biochemical profile, and urinalysis. Structural renal changes can precede loss of function; therefore thorough physical examination is imperative, and imaging studies such as radiography and abdominal ultrasound can be utilized to evaluate structural changes. Important clinical questions to answer include whether the disease is acute or chronic, whether there is an underlying cause of disease such as urinary infection or obstruction, and whether any negative prognostic indicators such as proteinuria or hypertension exist.

The first and most important step in diagnosing renal disease is based upon obtaining a complete history and performing a thorough physical examination. If the initial patient survey identifies an impaired hemodynamic state, emergency therapy and stabilization should be achieved prior to lengthy client interview. If the history reveals the possibility of exposure to toxins such as ethylene glycol, emergency induction of emesis and administration of an antidote that might prevent renal failure should be considered. Historical and physical examination findings, such as evidence and duration of polydipsia and polyuria and renal size and shape changes can aid the clinician to determine whether renal disease is acute or chronic. Determination of acute or chronic disease is imperative for guiding therapeutic and prognostic information with the client. Findings that can be used to differentiate acute from chronic kidney disease are outlined in Table 1.

Table 1: Differentiating Acute from Chronic Renal Failure

Acute renal failure presentation Chronic renal failure presentation

History of possible toxin exposure or predisposing event.

Smooth, normal to enlarged kidneys

Severe symptoms for degree of dysfunction

Normal body condition

No anemia

Elevated serum potassium

Severe metabolic acidosis

History of chronic polyuria/polydipsia, weight loss, prior diagnosis of renal insufficiency.

Small irregular kidneys

Mild signs for degree for dysfunction

Poor body condition

Nonregenerative anemia

Low serum potassium

Less severe metabolic acidosis

Osteodystrophy

A staging scheme for chronic kidney disease, based upon similar schemes used in human medicine, has been developed for use in dogs and cats by the International Renal Interest Society and approved for use by the Society of Veterinary Nephrology and Urology. (Table 2) This scheme assigns 4 grades of severity of chronic kidney disease based upon presence of certain clinical and biochemical findings. Proteinuria and hypertension are identified as independent factors for each stage of disease since each of these findings can worsen the long-term prognosis no matter the stage of disease at diagnosis.

As is evident by reviewing the criteria, it is not necessary for a cat to be azotemic to be diagnosed with chronic kidney disease since stage 1 includes animals with normal biochemical findings. This scheme provides clinical framework to identify the severity of disease, and has been applied in a number of research settings to determine survival differences between stages and to prospectively evaluate therapeutic interventions such as diet in animals with naturally occurring renal disease.

The mainstays of confirming a diagnosis of kidney disease remain serum biochemical analysis and urinalysis. Urea nitrogen and creatinine provide an indication of renal function; however the complete profile also allows for evaluation of electrolyte and protein changes that occur as a result of kidney disease, and sometimes provides clues to the underlying cause of disease.

Urea nitrogen is a useful marker of changes in renal filtration. This small molecule (MW 60) is produced in the liver as a by-product of protein metabolism, freely filtered at the level of the glomerulus, and is about 50% reabsorbed in the renal tubules under normal tubular flow conditions. It is an important osmole in establishing renal medullary concentration. In dehydration or hypovolemia causing impaired renal blood flow, an increase in BUN is seen that is commonly referred to as “pre-renal azotemia”. Likewise, urinary obstruction beyond the level of the kidneys (ureters, urethra) or urine leakage into the peritoneal cavity or soft tissue will cause an elevation in BUN known as “post-renal azotemia”. Intrinsic renal failure causes “renal azotemia”, which is typically differentiated from the other two forms by identification of concurrent isosthenuria and ruling out postrenal azotemia.  

The limitations of BUN as a diagnostic test for renal failure include situations in which both non-renal elevations and decreases can occur. Since BUN is produced in the liver, an animal with liver failure can have a lack of production. An overabundance of a dietary protein source, such as upper gastrointestinal ulceration with bleeding and melena, can cause an overproduction of BUN and non-renal elevation. In conditions of rapid tubular flow such as chronic polyuria and polydipsia, BUN can become low secondary due to inadequate time for reabsorption.

Creatinine (MW 115) is a byproduct of muscle breakdown that is freely filtered at the glomerulus and neither reabsorbed nor secreted by the tubules. Therefore, it is viewed as a more sensitive marker for renal disease, although is subject to pre-renal and post-renal elevation similar to BUN. Animals that are markedly muscle wasted can have lower than expected creatinine. Some technical challenges exist when measuring creatinine. The presence of non-creatinine chromagens in serum can cause an elevation in creatinine in any given individual, making comparisons between animals difficult.

Additionally, different laboratories have widely variable reference ranges. Despite these limitations, creatinine is a very good diagnostic test to evaluate progression of disease in any given individual, since body composition in the individual patient does not usually change dramatically. Even if a value remains within a laboratory reference range, an elevation of creatinine compared to a previous sample most likely represents a decline in glomerular filtration rate (GFR), which is the true marker of renal function. Likewise, relatively small incremental increases in creatinine represent significant decreases in GFR in the individual.

Electrolytes that are important for evaluation of the patient with renal failure include phosphorous, potassium, sodium, chloride, bicarbonate, and calcium. Phosphorous is managed similarly to BUN by the kidneys, and an increase indicates a reduction in glomerular filtration. Since phosphorous is an intracellular anion, severe muscle trauma, muscle reperfusion, or tumor lysis syndrome can cause an increase that is not due to renal failure. Phosphorous elevation is not useful in determining whether the azotemia is acute or chronic since either situation can cause hyperphosphatemia. Potassium can be either low from potassium wasting with renal disease (more commonly seen in cats), or elevated with acute oliguric/ anuric or end-stage chronic renal failure. Hyperkalemia can become life-threatening and require emergency treatment to lower potassium and protect against myocardial toxicity pending resolution of the underlying cause. Hyponatremia can occur in animals with polyuric acute renal failure if there are significant fluid losses from the kidneys and resultant hypovolemia stimulates antidiuretic hormone to reclaim free water. Metabolic acidosis frequently occurs with renal failure and can cause low bicarbonate. Longstanding or marked acidemia can cause renal injury and failure. Mild hypercalcemia or hypocalcemia can also occur with various presentations of renal failure.

Urinalysis provides important clues in the diagnosis of renal disease. Evaluation of specific gravity prior to fluid administration is the best method to determine renal concentrating ability in the dehydrated animal.  Although urine specific gravity following the onset of acute renal failure will remain isosthenuric for several weeks and is of no prognostic significance, the urine sediment parameters listed above can be useful to monitor for hospital acquired infection from an indwelling catheter, or for renal injury. Cats have a greater capacity to maintain some renal concentrating ability than do dogs as kidney function is deteriorating. Although some cats can maintain concentrating ability, the urine specific gravity is typically marginally concentrated (Urine specific gravity 1.040) and does not increase during episodes of dehydration.

Hypertension can occur in cats with acute or chronic renal disease, and persistent hypotension can exacerbate renal injury. Blood pressure should be evaluated in every cat with kidney disease, and normalized with medical management if outside of the reference range. A number of techniques to measure blood pressure and to institute and monitor therapy have been described in the literature.

Treatment Considerations for Feline Renal Failure

Treatment strategies for acute or chronic renal failure are aimed at correcting hypovolemia, restoring and maintaining hydration, monitoring hydration status and urine output to appropriately calculate fluid plan, and managing non-renal manifestations of uremia. In general, acute renal failure demands more intensive therapy than chronic renal failure in the short term.

Long term, acute renal failure may result in chronic renal failure that will require ongoing therapy, or may result in functionally normal kidneys. Chronic renal failure does not resolve, and requires ongoing therapy to control clinical signs. Severity of acute renal failure varies among individuals, however the renal recovery phase continues for several weeks following injury. For that reason, cats experiencing acute renal failure should be protected against further exacerbation of existing renal injury by avoiding dehydration or hypovolemia during or after hospitalization.

Goals of fluid therapy include volume resuscitation, rehydration, and diuresis. Fluid therapy should be initiated with an isotonic sodium-based, electrolyte solution (replacement crystalloid solution). Types of replacement crystalloid solutions include 0.9% sodium chloride (NaCl), lactated Ringer's solution, or Normosol-R or Plasma-Lyte 148® (the latter three all contain bicarbonate precursors to help to correct metabolic acidosis). Patient evaluation should include identification of hypovolemia and assessment of hydration status.

Hypovolemia should be corrected by administration of intravenous crystalloid and/or colloid fluids. In patients that are euvolemic, fluid dose should be calculated to include maintenance fluid needs, dehydration, and contemporary losses from vomiting or diarrhea. Timely evaluation of hydration status is imperative to avoid overhydration, especially with oliguria or anuria. Serial body weight measurement provides a simple, effective means of assessing fluid and hydration status.

Uremia may cause vomiting, anorexia, weight loss, oral ulcers, and gastric ulcers. Ancillary therapy includes gastric acid reduction with an H2 receptor blocker like ranitidine or famotidine. Since these drugs are renally excreted, treatment interval should be lengthened, or dose reduced. If vomiting is persistent, anti-emetic therapy is warranted. Maintenance of appropriate nutrition is important; however sick patients with renal failure will be unlikely to accept a diet change to a “kidney-type” diet. If there is no appetite, a feeding tube should be considered. Renal diets have been shown to delay the onset of uremic crises and death in cats with kidney failure. If phosphorous remains elevated following rehydration and the patient is eating, oral phosphate binders may be administered.

A veterinary phosphate binder, Epakitin® is a combination of calcium carbonate and chtiosan that effectively binds dietary phosphorous. It is sold as a powder form that mixes with food and is well accepted. Azodyl® is a bacteria that utilizes nitrogenous waste in the gut as energy, thereby trapping uremic waste products. Oral ulcers should be rinsed daily with an antiseptic solution an astringent solution. If renal failure is the result of bacterial infection (pyelonephritis, leptospirosis), appropriate antibiotic therapy is necessary. If hypercalcemia caused acute renal failure, specific treatment may be indicated.

Table 2: Stages of Canine and Feline Chronic Kidney Disease (From Ettinger and Feldman, 6th Edition

Stages of chronic kidney disease  

Non-azotemic

Clinical signs: PU/PD, or from proteinuria or hypertension

Positive markers of renal disease

Creatinine < 1.4 mg/dl (<1.6 mg/dl, cats)

Classify proteinuria

Classify hypertension

Mild renal azotemia

Clinical signs: PU/PD, or from proteinuria or hypertension

Positive markers of renal disease

Creatinine 1.4 – 2.0 mg/dl (1.6 – 2.8 mg/dl, cats)

Classify proteinuria

Classify hypertension

Moderate renal azotemia

Clinical signs from renal disease, but not uremic from treatment

Positive markers of renal disease

Creatinine 2.1 – 5.0 mg/dl (2.9 – 5.0 mg/dl, cats)

Classify proteinuria

Classify hypertension

Severe renal azotemia

Clinical signs from uremia

Positive markers of renal disease

Creatinine >5.0 mg/dl (cats and dogs)

Classify proteinuria

Classify hypertension Proteinuria classification: Proteinuric, Non-proteinuric, Borderline proteinuric   Hypertension classification: Hypertension with complications, Hypertensive without complications, Non-hypertensive, Undetermined blood pressure