Etiology

Antibiotics such as aminoglycosides, tetracycline, and sulfa drugs are known to be nephrotoxic. Neomycin, gentamicin, amikacin, and other aminoglycosides can cause renal tubular damage in cattle and other species. Tetracycline, and perhaps the vehicles used in certain injectable forms of tetracycline, may contribute to renal tubular nephrosis. Propylene glycol and polyvinylpyrrolidone vehicles are used in many oxytetracycline hydrochloride preparations, and these vehicles may cause hemodynamically mediated reduced renal perfusion, thereby accentuating any basic nephrotoxicity of the antibiotic itself. Sulfa preparations possess the ability to damage kidney tubules and precipitate in the renal tubules. Most antibiotic nephrotoxicity occurs as a result of two factors that deserve emphasis:

Overuse of calcium salts has also, on rare occasions, caused renal tubular nephrosis. In some instances, recumbent cattle received inordinate amounts of calcium solutions as therapy for suspected hypocalcemia.

Nephrosis also may result from physiologic progression of minor renal ischemia associated with septic conditions, gastrointestinal diseases, and other problems that reduce renal perfusion and glomerular filtration rate (GFR). Early manifestations of renal ischemia include renal infarcts and papillary necrosis. These conditions are much more common in dehydrated cattle than most veterinarians realize but are relatively benign if the cow’s primary disease and dehydration status are treated. When severe renal ischemia occurs, widespread reduction in renal perfusion results in further organic necrosis of tubulointerstitial renal tissue. Acute renal failure is possible in this instance and would be indicated by azotemia and isosthenuria, despite severe dehydration in the patient.

Reduced renal perfusion also is a possible result of overuse of NSAIDs in cattle. Drugs such as phenylbutazone and flunixin meglumine are potent inhibitors of prostaglandin synthesis within many tissues, including the kidney. Renal prostaglandins are “cytoprotective” because they help maintain renal perfusion through small vessels during times of hypotension or dehydration. Loss of this protective effect occurs when NSAIDs have reduced the production of renal prostaglandins. Therefore the kidneys are more susceptible to ischemic damage. Although renal papillary necrosis frequently is associated with the use of NSAIDs, minor (infarction) or major (tubular nephrosis) renal organic disease also may occur. Once again, the use of NSAIDs in dehydrated patients increases the risk of nephrotoxicity. The risk of toxicity can be further exacerbated by hypoalbuminemia such as occurs with acute gastrointestinal diseases because more of the NSAID being administered will be non–protein bound and therefore pharmacologically active drug. Therefore reduction of the dosage or total avoidance of these drugs, unless concomitant fluid therapy restores renal perfusion, should be practiced when devising therapy for a dehydrated patient.

Other nephrotoxins include the heavy metals (i.e., lead, mercury, and arsenic) and plant toxicities, such as oxalates, oak, and pigweed, that occur in some parts of the United States. Toxicities may involve several animals within a group, thus raising an index of suspicion regarding a toxic etiology. Oak poisoning most commonly affects heifers at pasture, with acorns being ingested in the fall and oak buds in the spring.

Clinical Signs

Cattle affected with toxic nephrosis usually have nonspecific signs, including depression, anorexia that varies from mild to absolute, dehydration, and potentially recumbency. Cattle with drug-related nephropathies usually have more blatant lesions in other body systems, such as septic mastitis, septic metritis, abomasal disorders, diarrhea, pneumonia, and so forth. Therefore coexisting or primary diseases may mask the existence of nephrosis. Polyuria may be present in some, but certainly not all, calves and cattle with nephrosis. When present, this sign is helpful because an obviously dehydrated animal is observed to void grossly dilute urine frequently. Rectal palpation may suggest enlargement of the left kidney.

In nephrosis associated with ingestion of heavy metals, neurologic signs (lead, arsenic) or gastrointestinal signs (lead, arsenic, and mercury) may be present and raises suspicion of intoxication. In plant toxicities, an absence of historical evidence of previous antibiotic or NSAID use, as well as absence of obvious infectious diseases, may lead to suspicion of plant poisoning. In many such plant toxicities, however, diagnosis must be assisted by clinical pathology and necropsy.

Clinical Pathology and Diagnosis

The diagnosis is linked primarily to clinical pathology data and history. Renal failure will be documented by a urine specific gravity in the isosthenuric range (,1.022) despite obvious dehydration. RBCs, WBCs, granular casts, and proteinuria usually are confirmed by urinalysis in acute nephrosis. Azotemia is present and characterized by elevations of serum urea nitrogen and creatinine. Specific causes may be suggested by the history (i.e., previous use of aminoglycosides, NSAIDs) or merely suspected (severe dehydration in a patient with salmonellosis). Serum chemistry often confirms hypochloremia, which may be more severe than that seen with intestinal obstruction, hypokalemia, hyponatremia, hypocalcemia, hyperphosphatemia, and hypermagnesemia.

Renal biopsy is the most definitive means of diagnosis and can be accomplished by percutaneous biopsy of the left kidney, which is pushed during rectal examination into the right paralumbar fossa, or either kidney can be biopsied from the right with ultrasound guidance. A Tru-Cut biopsy needle (Baxter Health Care, Deerfield, Il.) is used for this procedure. Evaluation of a coagulation panel may be indicated before biopsy because some renal diseases of cattle have been associated with a bleeding diathesis.

Ultrasound study of the kidney may be a helpful ancillary procedure if available.

Treatment

Therapy must attempt to reestablish renal function and to correct primary disorders that may have contributed to nephrosis. Previous use of nephrotoxic drugs should be discontinued and other potentially nephrotoxic drugs avoided in the therapy.

Aggressive fluid therapy to ensure adequate renal perfusion and accomplish diuresis is the primary therapeutic goal. IV fluids that are balanced to address associated electrolyte or acid-base abnormalities must be tailored to the individual patient. Because hypochloremia, hypokalemia, and hyponatremia usually are present, physiologic sodium chloride with supplemental KCl added at 20 to 40 mEq/L is frequently used. Unless the patient is anuric, large volumes of IV fluids are required to address existing dehydration, allow for anticipated fluid losses, and establish diuresis. If an adult patient is anuric or oliguric following an initial 20 to 40 L of IV fluids, 250 to 500 mg of furosemide may be administered IV one or more times at 15- to 30-minute intervals in an effort to initiate diuresis. Failure to produce urine in the face of high volume fluid therapy alongside diuretic administration should be taken as a negative prognostic sign. Repeated bladder evaluation by rectal palpation or ultrasonography to confirm urine production and accumulation may be a useful monitoring technique. Patients that are severely hypoproteinemic, produce inadequate urine despite large volume fluid administration, or show evidence of dependent edema may need additional monitoring for an increasing central venous pressure. A 500-kg cow that is azotemic, isosthenuric, and 10% dehydrated requires 50 L of fluids simply to counteract her existing dehydration. Therefore she may require a total of 80 to 100 L during the first 24 hours of therapy to establish adequate diuresis.

Judicious IV calcium or subcutaneous (SQ) calcium borogluconate should be utilized in those patients that are hypocalcemic. A low percentage of dextrose may be added to the basic fluids by adding 1 L of 50% dextrose to each 20 L of saline/KCl if desired.

Although adult cows with renal failure resulting from nephrosis seldom become hyperkalemic, calves that have acute diarrhea and metabolic acidosis may be hyperkalemic. Therefore initial fluid therapy should be formulated based on the individual patient’s acid-base and electrolyte status. Acidotic, hyperkalemic patients should receive IV saline, dextrose (half-strength physiologic saline solution [PSS] mixed equally with 2.5% dextrose), and supplemental NaHCO₃. Salmonellosis patients (either calves or cows) with secondary tubular nephrosis may be acidotic and require bicarbonate therapy if balanced crystalloid administration does not correct the acidosis. Oliguric or anuric patients also may require 20 L of 10% dextrose solution in addition to furosemide to instigate osmotic diuresis. Anuria that is unresponsive to fluid diuresis and furosemide therapy may also necessitate dopamine (3 to 5 μg/kg/min) and/or dobutamine (2 to 5 μg/kg/min) in 5% dextrose if all other therapy fails. Other potential treatments include mannitol, norepinephrine, vasopressin, and aminophylline.

Once diuresis is established, fluid therapy is adjusted to maintain diuresis and assist renal excretion of wastes. Serum urea nitrogen and creatinine initially should be monitored each day to establish a trend. The length of treatment varies from a few days to 2 weeks in most cases. The prognosis is guarded until normal renal function is reestablished. The more prolonged the azotemia, the more likely the patient is to develop chronic renal failure. Initially the clinician must proceed with therapy in the hope that nephrosis is acute and reversible. The exact degree of renal damage is impossible to assess initially. Response to therapy and the results of renal biopsies, once available, afford the best means of prognosis.

If a potential nephrotoxic drug must be used to treat a primary condition, reduced dosages and monitoring of blood levels, if available, are essential to continued usage.

Etiology

In cattle, bacterial pyelonephritis has been attributed to ascending infection of the urinary tract by Escherichia coli or Corynebacterium renale (Figure 10-3). At least three C. renale serotypes exist as normal flora of the caudal portion of the reproductive tract of female cattle and the sheath of male cattle. Unlike most gram-positive organisms, C. renale possesses pili that promote attachment to and colonization of the urinary tract mucosa. Conditions that provide physical or chemical damage to the mucosa in the lower portion of the urinary tract such as dystocia, bladder paralysis, or catheterization may predispose the cow to pyelonephritis as a result of C. renale ascending infection from the urinary bladder to the ureters and kidneys. C. renale causes a humoral antibody response when renal infection develops but not when infection is limited to the bladder. Because routine catheterization of cattle to assess urinary ketones has been abandoned, pyelonephritis caused by C. renale is seen less frequently, whereas pyelonephritis caused by gram-negative organisms is seen more frequently. Pyelonephritis as a result of E. coli infection has a similar pathogenesis to pyelonephritis caused by C. renale in that ascending infection from the lower urinary tract occurs following damage to the caudal portion of the reproductive tract.

Figure 10-3 Gram stain of the urine from a cow with C. renale pyelonephritis.

Clinical Signs

Acute primary pyelonephritis causes fever of 103.5 to 105.5° F (39.72 to 40.83° C), anorexia, and a precipitous decrease in milk production. Some cows with acute pyelonephritis have colic manifested by kicking at the abdomen, restlessness, and treading. Signs of colic usually are associated with renal or ureteral inflammation and pain, but urinary obstruction caused by blood clots blocking urine outflow from a kidney (ureter) or bladder (urethral) also may contribute to colic (Figure 10-4). Further agitation, such as swishing of the tail, may be observed if the affected cow also has cystitis as a precursor lesion of pyelonephritis. Stranguria, polyuria, an arched stance, gross hematuria (Figures 10-4 and 10-5), blood clots, fibrin, or pyuria also are observed in some patients with C. renale infection. Acute pyelonephritis should be considered as a differential for acute colic in postparturient cattle. Consequently left kidney and ureter palpation per rectum should be mandatory components of the physical examination of any sick cow with signs of colic.

Figure 10-4 Large blood clot protruding from the vulva of a 3-year-old Holstein with acute pyelonephritis. The visible clot was part of a larger clot occluding the urethra, causing the animal to show signs of colic.

Figure 10-5 Hematuria and pyuria in a bull with C. renale pyelonephritis.

Chronic pyelonephritis is associated with weight loss, poor hair coat, anorexia, poor production, diarrhea, polyuria, anemia, stranguria and gross urine abnormalities. Lordosis and stretching out may be apparent in some cows affected with chronic pyelonephritis because of renal pain.

Latent or subclinical pyelonephritis may exist in cattle with multiple medical problems, especially during the first few months of lactation. Cattle with concurrent abomasal displacement, metritis, mastitis, or cattle that had dystocia may develop pyelonephritis that is “masked” by more obvious signs in other systems. Only through screening urine and subsequent urinalysis will the condition be confirmed. Specific physical signs of pyelonephritis in these instances are minimal unless, on rectal palpation, the left kidney is large, painful, and has indistinct lobulations, thereby increasing the possibility of pyelonephritis.

Diagnosis

Diagnosis of pyelonephritis is made by combining the clinical signs, rectal palpation findings, vaginal palpation findings, and urinalysis. Fever usually is present in acute pyelonephritis but may be absent in chronic pyelonephritis. Urinalysis abnormalities such as RBCs, WBCs, protein, and bacteria may be present in both cystitis and pyelonephritis. However, cystitis does not usually lead to systemic illness, and the ureters would not be enlarged (as one or both are in pyelonephritis) as determined by palpation per vagina or per rectum. Vaginal palpation remains an essential aid to diagnosis because it allows detection of unilateral or bilateral ureteral enlargement that is too subtle to be detected per rectum.

Rectal palpation may reveal enlargement of the left kidney in unilateral left kidney infection or bilateral infections. Normal lobations of the kidney may be lost; the kidney may feel “mushy”; and there may be a pronounced arterial pulsation. Rectal palpation is not helpful to diagnosis in right kidney infections unless the infection is very chronic with massive enlargement of the right kidney. Ultrasonography is another helpful ancillary aid to diagnosis and may reveal valuable prognostic information (see video clips 20 and 21).

Other laboratory tests may be performed in valuable cattle or when a diagnosis is not definitive. Hypoalbuminemia is present in most pyelonephritis patients and is more severe in chronic pyelonephritis. Proteinuria appears to be very significant in pyelonephritis and occurs in most cases. Serum globulin values may be higher (.5.0 g/dl) if infection has been chronic. Generally a period of 10 to 14 days of renal infection is necessary to elevate globulin values, and adult cattle tend to have higher globulin levels than calves with chronic infection.

Gross examination of the urine may be diagnostic in acute cases in which fibrin, blood clots, and pus are apparent in voided urine. Some cows with acute pyelonephritis will suffer severe renal hemorrhage that may obstruct the ureter or urethra, thus leading to intermittent or continuous urinary blockage. On occasion blood clots may be so substantial as to fill and occlude the bladder and urethra. Cattle with less obvious urinary abnormalities will have positive blood and protein reactions on reagent test strips, and urinalysis will confirm the presence of RBCs, WBCs, protein, and bacteria. Routine use of multiple test reagent strips to screen urine during the routine physical examination is an excellent means to detect pyelonephritis and other urinary tract diseases.

Urine culture is the most important laboratory aid because it allows identification of the causative organisms and more importantly the sensitivity of the causative organism to antibiotics. Previous treatment with antibiotics by the owner may interfere with in vitro growth. Therefore antibiotics should be discontinued for 24 to 48 hours before culture of the urine. Urine for culture should be obtained using catheterization or a midstream voided sample to avoid contamination, and a colony count should be requested. Colony counts (.10³/ml on a catheterized sample or .10⁴/ml on a midstream voided sample) are often necessary to determine the infectious organism(s).

Azotemia is cause for prognostic concern and may indicate prerenal conditions such as dehydration, bilateral pyelonephritis with subsequent renal failure, or postrenal urinary obstruction. Postrenal obstruction usually is obvious following the physical examination and rectal examination. Prerenal azotemia should be suspected if the animal is very dehydrated but is capable of concentrating urine to a specific gravity .1.022. Prerenal azotemia also should respond to rehydration using oral or IV fluids. Most cattle with pyelonephritis that also are azotemic have bilateral disease and renal failure (Figure 10-6). These usually are chronic infections and also have elevated globulin levels, hypoalbuminemia, inability to concentrate urine, and may have electrolyte abnormalities such as hypochloremia, hyponatremia, hypokalemia, and hypocalcemia. Therefore cattle with bilateral pyelonephritis and azotemia have a guarded prognosis.

Figure 10-6 Necropsy view of kidney with severe pyelonephritis caused by C. renale in a Holstein cow that died from the disease. Both kidneys appeared similar.

(Photo courtesy Dr. John M. King.)

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