Using urine specific gravity values to localize azotemia in veterinary care

In previous issues of dvm360 (see the dvm360.com/Osborne "The whole story"), we discussed various aspects of urine specific gravity values and their implications on patient health. Here, we discuss urine specific values and localization of azotemia.

Keep in mind that some azotemic cats with primary renal failure retain comparably greater urine concentrating capacity than dogs do. In dogs with progressive disease resulting in primary renal failure, azotemia usually follows loss of the ability to concentrate urine to a specific gravity of at least 1.030. In some cats with primary renal failure, azotemia may precede loss of the ability to concentrate urine to values of 1.040 to 1.045.

Prerenal azotemia

Causes and pathogenesis. Extraurinary diseases may cause varying degrees of alteration in glomerular filtration because of reduced renal blood flow. Inadequate perfusion of normal glomeruli with blood, regardless of cause, may cause prerenal azotemia.

Prerenal azotemia is initially associated with structurally normal kidneys that are capable of quantitatively normal renal function, provided compromised renal perfusion is corrected before the onset of ischemic nephron damage. Progression of prerenal azotemia to intrarenal (primary) renal failure due to persistent ischemia prolongs and reduces the likelihood of complete recovery.

Consider prerenal azotemia if abnormal elevations in blood urea nitrogen (BUN) and creatinine concentrations are associated with adequately concentrated urine (1.035 in dogs; 1.040 in cats) in patients with no specific evidence of generalized glomerular disease. Adequately concentrated urine in association with azotemia indicates that enough functional nephrons are present to prevent primary renal azotemia. Significantly elevated BUN or creatinine concentrations due to primary renal failure cannot be detected in dogs until about 70 to 75 percent of the nephron population is nonfunctional. Elevated urine specific gravity associated with prerenal azotemia probably reflects a compensatory response by the body to combat low perfusion pressure and blood volume by secreting antidiuretic hormone (and possibly other substances) to conserve water filtered through glomeruli. Appropriate volume replacement therapy to restore renal perfusion is typically followed by a dramatic drop in urea and creatinine concentrations to normal in about one to three days.

Another form of potentially reversible prerenal azotemia associated with primary renal disease may develop in patients with glomerulonephropathy and severe hypoalbuminemia. At the level of the glomerulus, hypoalbuminemia enhances the glomerular filtration rate because of reduced colloidal osmotic pressure. However, decreased renal blood flow and glomerular filtration that occur in association with a marked reduction in vascular volume secondary to a reduction in colloidal osmotic pressure result in a proportionate degree of retention of substances normally cleared by the kidneys (e.g., creatinine, urea). These two mechanisms have opposite effects on glomerular filtration. So carefully interpret an abnormal increase in BUN or creatinine concentration (or a reduction in creatinine clearance) in hypoproteinemic nephrotic patients. Azotemia is not indisputable evidence of severe primary glomerular lesions since a component of the azotemia may be associated with a potentially reversible decrease in renal perfusion caused by hypoalbuminemia.

Diagnosis. Diagnosis of prerenal azotemia is based on the following:

> Elevated serum BUN or creatinine concentrations

> Oliguria

> High urine specific gravity (1.035 in dogs; 1.040 in cats) or osmolality

> Detection of underlying cause

> Rapid correction of azotemia after administration of appropriate therapy to restore renal perfusion.

Prognosis. The prognosis of prerenal azotemia depends on reversibility of the primary cause. The prognosis is favorable for renal function if perfusion is rapidly restored. However, complete loss of renal perfusion in excess of two to four hours may result in generalized ischemic renal disease. With the exception of shock, this degree of reduced renal perfusion is uncommon. Thus, the onset of generalized renal disease would be expected to require a longer period of altered renal perfusion.

Postrenal azotemia

Pathogenesis. Diseases that prevent urine excretion may cause postrenal azotemia. The kidneys are structurally normal initially and capable of quantitatively normal function provided the underlying cause is corrected. However, if the underlying cause persists, death from alterations in water, electrolyte, acid-base and endocrine balance, in addition to metabolic waste product accumulation, will occur within a few days. If urine outflow is only partially obstructed, allowing the patient to survive for a longer time, varying degrees of hydronephrosis may subsequently occur.

Causes. Complete urine outflow obstruction (i.e., obstruction in urethra, bladder, or both ureters) for more than 24 hours usually results in postrenal azotemia. Unilateral ureteral occlusion (an example of renal disease) is not associated with azotemia unless generalized disease of the nonobstructed kidney is also present. Azotemia resulting from excretory pathway rupture (usually the bladder) is primarily related to urine absorption from the peritoneal cavity. Unless damaged as a result of hypovolemic shock or trauma secondary to cause of the excretory pathway rupture, the kidneys are structurally and functionally normal.

Diagnosis. A diagnosis of postrenal azotemia is based on the integration of clinical findings. Lesions causing urine outflow obstruction are commonly associated with:

> Elevated serum BUN and creatinine concentrations

> Oliguria or anuria, dysuria and tenesmus

> Obstructive lesions detected by physical examination (e.g., urethral plug, herniated bladder), radiography, ultrasonography, etc.

> Variable urine specific gravity values

Rupture of the excretory pathway is commonly associated with:

> Progressively elevated serum BUN or creatinine concentrations

> Progressive depression, painful abdomen, ascites

> A history of trauma and associated physical examination findings

> Inability to palpate the urinary bladder

> Detection of a modified transudate or exudate by abdominocentesis

> Abnormalities detected by ultrasonography or retrograde contrast (positive or negative) cystography or urethrocystography.

Because of variability, the urine specific gravity of patients with postrenal azotemia is not relied on to the same degree for assessing renal function as it is in patients with primary renal and prerenal azotemia.

Prognosis associated with obstructive lesions. If the patient has total obstruction to urine outflow for three to six days, death from uremia will occur caused by alteration of fluid, acid-base, electrolyte, nutrient and endocrine balance, as well as accumulation of metabolic waste products. Death usually occurs before significant hydronephrosis has time to develop. The prognosis is favorable if the obstructive lesion or lesions are rapidly removed. The long-term prognosis depends on the reversibility of the underlying cause.

Prognosis associated with excretory pathway rupture. If a persistent rent in the excretory pathway results in progressive azotemia, the patient will likely die if the rent is not repaired. The prognosis for recovery of adequate renal function is favorable if the rent is repaired or heals. The long-term prognosis depends on the reversibility of the underlying cause.

Primary intrarenal azotemia

Pathogenesis. Intrarenal azotemic renal failure may be caused by many disease processes that destroy about three-fourths or more of the parenchyma of both kidneys. Depending on the disease's biologic behavior, primary renal failure associated with intrarenal azotemia may be reversible or irreversible and acute or chronic. Chronic irreversible azotemic renal failure is usually slowly progressive.

Diagnosis. In dogs, at least two-thirds of the nephron mass must be impaired if a dehydrated patient has impaired ability to concentrate urine. Total loss of ability to concentrate and dilute urine does not always occur as a sudden event but often develops gradually. Thus, a urine specific gravity between 1.007 to 1.029 in dogs or 1.007 to 1.039 in cats associated with clinical dehydration or azotemia is indicative of intrarenal azotemia. Total inability of the nephrons to concentrate or dilute urine (so-called fixation of specific gravity or isosthenuria) results in the formation of urine that is similar to that of glomerular filtrate (approximately 1.008 to 1.012).

If a hydrated patient has elevated BUN and creatinine concentrations and an impaired ability to concentrate or dilute urine, likely at least three-fourths of the functional capacity of the nephron mass has become impaired.

More definitive studies (e.g., ultrasonography, radiography, biopsy, exploratory surgery) are required to establish the underlying cause of primary azotemic renal failure. When formulating a prognosis and therapy, recall that the uremic signs are not directly caused by renal lesions but are related to varying degrees of fluid, acid-base, electrolyte and nutrient imbalances; vitamin and endocrine alterations; and retention of waste products of protein catabolism that develop as a result of nephron dysfunction caused by an underlying disease (Table 1).

Table 1

Azotemia associated with glomerulotubular imbalance. In some patients with primary renal failure caused by generalized glomerular disease, abnormally elevated BUN or creatinine concentrations may occur in association with varying degrees of urine concentration. Be sure not to overinterpret the absolute value of the urine specific gravity in such patients, since it may be slightly elevated by the effect of protein. Adding 40 mg protein/100 ml of urine will increase the urine specific gravity by about 0.001.

The renal lesion must be characterized by glomerular damage that is sufficiently severe to impair renal clearance of urea and creatinine but that has not yet induced enough ischemic atrophy and necrosis or renal tubular cells to prevent varying degrees of urine concentration. Thus, glomerular filtrate that is formed may be concentrated to such a degree that prerenal azotemia is initially considered. However, this group of patients may be differentiated from patients with prerenal azotemia by failure of a search for one of the extrarenal causes of poor perfusion, by persistent proteinuria and by persistent azotemia despite restoration of vascular volume and perfusion with appropriate therapy.

Combinations of azotemia

Pathogenesis. Severely diseased kidneys have impaired ability to compensate for stresses imposed by disease states, dietary indiscretion and changes in environment. In patients with previously compensated primary renal disease, uremic crises are commonly precipitated or complicated by a variety of concomitant extrarenal factors.

Extrarenal mechanisms that may be associated with uremic crises include the following:

> Factors that accelerate endogenous protein catabolism increase the quantity of metabolic by-products in the body since the kidneys are incapable of excreting them. Protein by-products contribute significantly to the production of uremic signs in patients with renal failure.

> Stress states (fever, infection, change of environment) are associated with glucocorticoid release from the adrenal glands.

> Glucocorticoids stimulate conversion of proteins to carbohydrates (gluconeogenesis) and, thus, increase the quantity of protein waste products in the body.

> Abnormalities that decrease renal perfusion (i.e., decreased water consumption, vomiting, diarrhea) cause prerenal uremia.

> Nephrotoxic drugs in a patient with chronic renal failure may precipitate an acute uremic crisis by damaging nephrons.

Diagnosis. Combinations of causes of azotemia should be considered based on:

> A previous history of compensated primary renal failure

> Detection of primary extrarenal disease processes as well as generalized renal disease

> Detection of clinical dehydration—dehydration associated with azotemia and impaired urine concentration is reliable evidence that a portion of the azotemia is prerenal in origin.

> How the patient responds to therapy—uremic crises precipitated by reversible extrarenal disorders may rapidly respond to supportive and symptomatic therapy (rapid and significant reduction in the magnitude of azotemia). Uremic crises caused by progressive irreversible destruction of nephrons usually respond slower (a marginal reduction in the magnitude of azotemia).

Prognosis. Withhold formulating a prognosis until the magnitude of azotemia is reassessed after correcting the prerenal or postrenal components of azotemia.

Dr. Carl A. Osborne is the director of the Minnesota Urolith Center and a professor at the College of Veterinary Medicine at the University of Minnesota. Dr. Eugene Nwaokorie is pursuing a PhD at the University of Minnesota.