How I approach – the dog with azotemia

Introduction

The main purpose of the kidneys is to rid the body of nitrogenous waste products and products of muscle metabolism (e.g., urea and creatinine) while maintaining appropriate water, electrolyte and acid/base homeostasis. Consequently, when the kidneys are not functioning properly, a buildup of these products occurs, alongside water, electrolyte and acid/base derangements. The identification of increased urea and/or creatinine in the blood that occurs secondary to decreased renal excretion is termed azotemia (1). When identified, azotemia should prompt one to ask why renal elimination is not occurring properly, but to further understand azotemia and to answer this question, we must first understand how renal elimination of waste products occurs and where things can go awry.

Renal function

In order for normal renal elimination of any substance to occur, the substance must be presented to the functional unit of the kidney, the nephron (Figure 1), where it can be filtered out of the bloodstream across the glomerulus and into the tubular filtrate (2). From there it can then be excreted unchanged in urine, or altered by the renal tubules (reabsorbed or actively secreted). Nitrogenous waste products are freely filtered by the glomerulus, meaning so long as these substances can make it to the glomerulus, they should be removed from the bloodstream at an appropriate rate. There are approximately 500,000 nephrons per kidney in a healthy dog that allow for the formation of tubular filtrate (3). These functional units all converge via a system of collecting ducts that drain the filtrate into the renal pelvis, where it then travels down the ureters and into the urinary bladder. Here the urine, containing waste products and other constituents, are actively voided out of the body through the urethra. If normal function is inhibited at any point along this pathway, from nephron to urethra, decreased renal elimination and azotemia can occur.

It is important to remember that elevations in urea and creatinine are not 100% specific for renal disease – i.e., urea and creatinine can be elevated for both renal and extrarenal causes – so we must rule out extrarenal causes before diagnosing a patient with azotemia. To understand the extrarenal causes, a brief review of urea and creatinine physiology is necessary: 

• Urea is produced in the liver from ammonia, which is a byproduct of protein metabolism (1). Therefore, the rate of urea production greatly depends on liver function as well as protein catabolism and digestion of protein in the small intestine. Urea is freely filtered at the glomerulus and is passively reabsorbed in the renal tubules, at an amount determined by tubular flow rate (2). With this knowledge we can then understand that abnormalities in urea levels can be related to decreased renal function, but they can also be from extrarenal causes, such as impaired liver function, increased protein catabolism, or protein digestion. 
• Creatinine is a normal product of muscle metabolism, and as such can be increased or decreased in relation to increased or decreased muscle mass, respectively (1). Creatinine is also freely filtered by the glomerulus, but is not reabsorbed in the renal tubules (2). Again, this allows us to understand that elevations in creatinine can be related to decreased renal function, but can also be from extrarenal causes, such as a significant increase in muscle mass. 

Azotemia categorization

In the approach to canine azotemia we should consider the three main types: prerenal, renal, and post-renal azotemia. These categories allow us to understand where along the pathway normal renal function is inhibited, and will narrow our differential list. A combination of clinical examination findings, along with ancillary diagnostics, allows us to distinguish between the main causes of azotemia. 

Prerenal azotemia overview

Prerenal azotemia refers to the buildup of nitrogenous waste products that results from decreased renal perfusion (4). This commonly occurs as a result of a circulatory disturbance such as dehydration, hypovolemia, or hypotension (Table 1). As a result of altered renal blood flow, less nitrogenous waste products are presented to the glomerulus, and therefore less nitrogenous waste is filtered from the bloodstream. In most cases, dogs with exclusively prerenal azotemia can be identified via physical examination and urinalysis. These patients often have changes on physical exam consistent with dehydration or hypovolemia, cardiac murmurs or arrhythmias, that can increase our suspicion of a prerenal cause for the azotemia. Furthermore, urinalysis will often demonstrate concentrated urine (USG >1.030) (4) without additional evidence of glomerular or tubular dysfunction such as proteinuria, glucosuria (in the absence of hyperglycemia) and casts. These patients will often have resolution of their azotemia following fluid therapy to address the decreased renal perfusion. 

 

Table 1. Causes of prerenal azotemia.

 

 

Renal azotemia overview

Renal azotemia refers to the buildup of nitrogenous waste products that results from decreased glomerular filtration rate due to decreased functional renal mass (4). A number of etiologies can lead to renal azotemia (Table 2). It is important to remember that azotemia is not 100% sensitive for renal damage; a significant drop in glomerular filtration rate occurs before significant increases in urea and creatinine develop in early kidney disease. In fact, approximately 75% or more of the patient’s nephron mass must be lost before renal azotemia occurs (4). With this knowledge, it is easy to understand that significant renal damage can be present before azotemia is identified on laboratory work. Because the ability to concentrate urine also relies on the functional nephron, specifically the tubules and collecting ducts, patients with renal azotemia will have a USG <1.030. Deficits in urine concentrating ability are seen when only 66% of functioning nephrons are lost, and therefore are often present before azotemia itself (5). Commonly, the USG of a dog with renal azotemia is isosthenuric, (1.008-1.012), meaning the kidneys are neither diluting nor concentrating the filtrate. In addition to minimally concentrated urine, urinalysis may show other markers of glomerular or tubular injury, such as proteinuria, glucosuria, cellular or granular casts. Other findings suggestive of renal azotemia include mineral and electrolyte derangements, namely changes in phosphorus, calcium, magnesium and potassium (1). Of these, phosphorus is most consistently elevated in both acute and chronic renal disease, as it is primarily excreted by the kidneys via glomerular filtration. 

 

Table 2. Causes of renal azotemia.

 

 

Post-renal azotemia overview

Post-renal azotemia refers to the buildup of nitrogenous waste products as a result of ureteral or urethral obstruction (either mechanical: urolithiasis, stricture, mass/infiltrative disease; or functional: detrusor atony, functional outflow obstruction (FOO)) or rupture of the urinary tract (1) (Table 3). In this scenario, normal collection and/or expulsion of waste products is prevented. These patients often have a history and physical exam findings consistent with urinary tract obstruction (dysuria/stranguria, pain, renomegaly, distended urinary bladder) or urinary tract rupture (painful abdomen, peritoneal or retroperitoneal effusion) (4). Further evidence to support a post-renal azotemia can be obtained through urinary system imaging (radiography/ultrasound) and ancillary diagnostics (including placement of a urinary catheter, sampling and assessment of any effusion).

 

Table 3. Causes of post-renal azotemia.

 

 

Diagnostic protocol

As prerenal and post-renal causes of azotemia are often less ambiguous than causes of renal azotemia, it is recommended to rule these out first. Once azotemia is identified on biochemical testing and extrarenal causes have been ruled out, a USG is paramount to interpret those renal values (Table 4). A USG >1.030 in a dog with elevated renal values is consistent with a prerenal azotemia, and any dehydration or hypovolemia should be corrected. It is possible that the renal values will return to normal if dehydration/hypovolemia are corrected without prolonged ischemic damage to the kidneys. A USG <1.030 rules out prerenal as the sole cause of the azotemia; however, a patient with underlying renal azotemia can also be dehydrated with a prerenal component contributing to their azotemia. A USG in the isosthenuric range (1.008-1.012) means that the kidneys are neither diluting nor concentrating the glomerular filtrate, and when accompanied by elevated urea and/or creatinine is suggestive of renal azotemia. Response to fluid therapy can also aid in the differentiation of prerenal from renal azotemia. Patients with a prerenal azotemia from dehydration, for example, will have resolution of their azotemia from fluid therapy, while patients with renal azotemia will not. 

 

Table 4. Urine specific gravity (USG) ranges and their interpretation in the dog.

 

 

Urine specific gravity is less consistently helpful in differentiating cases of post-renal azotemia. Here, urinary system imaging is required to rule out a post-renal component. Abdominal radiographs may show evidence of renomegaly (Figure 2) or an enlarged urinary bladder consistent with a urinary tract obstruction. Radiodense opacities within the kidneys, ureters, urinary bladder or urethra suggestive of urolithiasis may also be seen. Importantly, the dogma that certain uroliths are not radiopaque is no longer supported. Certain stone types such as cysteine and urate are less radiodense, and therefore more difficult to see radiographically. In addition to the urolith composition, the size of the urolith also plays a role in the degree of radiodensity. Radiographic appearance continues to be one of the most reliable tools for predicting urolith composition. Abdominal ultrasound may show evidence of hydronephrosis (Figure 3) or hydroureter consistent with ureteral obstruction secondary to a ureterolith, ureteral stricture or a mass. Additionally, imaging may show evidence of peritoneal or retroperitoneal effusion, which can raise suspicion of urinary tract rupture. Sampling of free fluid and measurement of fluid creatinine and/or fluid potassium compared to serum creatinine and/or potassium, respectively, would be recommended to rule in or out a uroabdomen. Treatment of post-renal azotemia largely depends on the underlying etiology, but it is important to remember that if left untreated, nephron damage and renal azotemia can develop. 

Once post-renal causes of azotemia have been ruled out and the urine specific gravity is inconsistent with prerenal azotemia as a sole cause (USG <1.030), a diagnostic work-up for intrinsic renal disease is performed. This condition occurs when there is damage to and loss of a significant number of nephrons. Additional biochemical changes that accompany renal azotemia include other markers of decreased glomerular filtration rate such as hyperphosphatemia, hyperkalemia, and disturbances in acid/base status. Renal azotemia can be further categorized as an acute kidney injury (AKI), acute kidney disease (AKD), or chronic kidney disease (CKD). By definition, the decrease in renal function accompanying an AKI occurs within a 7-day period, while AKD manifests between 7-90 days, and CKD develops >90 days (6). It is also possible for dogs with pre-existing CKD to suffer from an AKI (“acute-on-chronic disease”). While these disease processes were once thought to be separate from one another, they are now seen to be interrelated, with the main difference being the rate of disease progression (7). 

It is not always readily apparent whether a newly identified renal azotemia is acute or chronic in nature, but there are generally clues found on history, physical examination and diagnostics to differentiate. As the name implies, AKI patients tend to have more severe clinical signs associated with their illness, such as lethargy and vomiting (8). Physical exam findings tend to reveal normal to large, possibly painful kidneys. The most common causes of acute renal azotemia include ischemia, inflammation, exposure to nephrotoxins, and infectious disease (8). Other etiologies include hypercalcemia and glomerular disease such as glomerulonephritis. Inflammation/ischemia can occur from a number of underlying disease processes, including but not limited to pancreatitis, peritonitis, pyometra, pneumonia, severe gastroenteritis, diabetic ketoacidosis, and heatstroke. Common nephrotoxins include ethylene glycol, grapes/raisins, and overdose of non-steroidal anti-inflammatory drugs. Of the infectious diseases that can occur in the kidneys, pyelonephritis and leptospirosis occur most frequently. With these differentials in mind, a common diagnostic work up for renal azotemia of acute nature may include a thorough history, complete blood count, chemistry panel, urinalysis with sediment examination, aerobic urine culture, urine protein to creatinine ratio if appropriate, abdominal ultrasound, thoracic radiographs, and leptospirosis microscopic agglutination test. However, the etiology remains unknown in around 25% of cases of acute kidney injury (8). 

Chronic kidney disease is an irreversible and progressive decline in renal function resulting from damage to functional nephrons (9). As the name implies, it often has a more chronic or insidious history, with associated clinical signs including polyuria/polydipsia, weight loss, and hyporexia (7). Physical exam findings often point to the chronic nature of their illness and include muscle wasting, small and irregular kidney(s), and dehydration. The most common causes of CKD include infection, inflammation, prior or partial obstructive renal disease, ischemia, and familial renal disease. Primary or metastatic renal neoplasia can also be a cause, but most often the etiology that initiates nephron damage and leads to chronic kidney disease remains unknown. A common diagnostic work up for renal azotemia of chronic nature includes those as listed above, as well as renal biopsies in cases where familial disease is suspected or significant proteinuria is present. Treatment for both acute and chronic renal azotemia patients is aimed at the underlying etiology, if known. Infectious disease tends to carry the best prognosis, as these are generally treatable to some extent. 

Possible sequelae to azotemia

Important sequelae that are often seen in patients with azotemia include hypertension, hyperphosphatemia and proteinuria, all of which can affect morbidity and mortality. Azotemia is a common cause of secondary hypertension in dogs, with a reported prevalence of up to 93% (10). Unmanaged hypertension can lead to target organ damage including the kidneys, and thus cause progressive renal injury and azotemia. Routine measurement of systolic blood pressure and fundic examination is recommended. Proteinuria can be a consequence of underlying renal disease, and is also thought to be a mediator of progressive renal injury. Furthermore, uncontrolled proteinuria is associated with increased risk of adverse outcomes in dogs (11). Quantification of proteinuria via a urine protein to creatinine ratio is recommended in all patients with dipstick-positive protein that have an inactive sediment. Phosphorus is primarily eliminated via renal excretion, and as such blood levels will increase in patients with inappropriate glomerular filtration. Managing hyperphosphatemia decreases the development of renal secondary hyperparathyroidism (9). Nutritional therapy, with a veterinary prescription renal diet, is considered first line therapy for managing hyperphosphatemia and proteinuria. These diets are restricted in both protein and phosphorus, and in CKD patients have been shown to decrease the risk of uremic crisis, slow the disease progression, and improve the patient’s quality of life (12). Dogs with CKD should have additional monitoring of their red blood cell indices, including a reticulocyte count, as the development of non-regenerative anemia is a common occurrence. Additional monitoring in chronic disease includes parathyroid hormone and ionized calcium levels to screen for renal secondary hyperparathyroidism.

Conclusion

Azotemia is a common laboratory finding in dogs that requires a thorough history, thorough physical examination, and careful evaluation of ancillary diagnostics in order to differentiate prerenal, renal and post-renal causes. Measurement of urine specific gravity in any patient with an elevation in renal values is the first diagnostic step that should be performed when investigating azotemia. Differentiating between prerenal, renal and post-renal causes of azotemia allows us to form differential diagnoses, make diagnostic recommendations, and correctly treat/manage the underlying disease process. 

References

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