Review of Azotemia in Foals

1. Introduction

Azotemia in neonatal foals (≤7 days of age) may be an indicator of pre-renal failure, acute kidney injury (AKI), obstructive disease, congenital renal disorders, or disruption of the collecting system leading to uroperitoneum. Because clinical signs of renal failure may be similar to those with septicemia or asphyxia (weakness, recumbency, or poor nursing vigor), performing a serum biochemical analysis in compromised neonates is an essential part of the minimum database to detect azotemia. Spurious hypercreatininemia may also be a transient finding in asphyxiated foals or foals delivered from mares with placentitis.¹  Neonates with spurious hypercreatininemia have normal serum electrolyte concentrations, supporting normal renal function, and creatinine concentration, which may exceed 20 mg/ dL, typically drops by 50% or more over the first 1 to 2 days of life, as long as foals are well hydrated and nursing well (Fig. 1). In older foals, azotemia and renal failure are almost always a consequence of another primary disease process, although limited renal function with congenital anomalies may delay onset of renal failure until foals are several years old.

2. Neonatal Renal Development and Physiology

Nephrogenesis, in terms of nephron numbers, is essentially complete at birth, and, as foals grow, the kidneys increase in size through the first 1 to 2 years of life. Foals are born with about 10 million glomeruli in each kidney, and these enlarge in size as the kidneys grow.² Of interest, low birth weight and premature infants may be born with fewer nephrons, and there is mounting evidence that this reduced renal endowment may increase the risk of developing hypertension and chronic kidney disease (CKD) in later life.³

Normal term colts typically first urinate between 5 and 6 hours of age, whereas fillies initially urinate later, at 10 or 11 hours of age.⁴ Initial urine may be dilute or concentrated (specific gravity up to 1.040), but hyposthenuria develops by 24 hours of age in all foals that are nursing well. Urine pH is nearly neutral, and significant proteinuria (2 to 3+ on re-agent strips) is commonly observed from 24 to 48 hours of age in foals that received good passive transfer of colostral antibodies.⁵ Serum urea nitrogen (BUN) and creatinine (Cr) concentrations are variable during the initial 24 hours of life, with values in the range of 15 to 30 mg/dL (~5–10 mmol/L) and 2 to 4 mg/dL (~175–350 μmol/L), respectively. BUN generally drops below the lower limit of the adult reference range by 24 hours of age, whereas Cr may not drop below 2 mg/dL until 48 hours of age. By 1 to 2 weeks of age, BUN is typically below 10 mg/dL (~3.5 mmol/L) and Cr may fall below 1.0 mg/dL (~90 μmol/L). These low values can be attributed to the large volume of fluid intake as milk (5-fold greater fluid intake as compared with adult horses on a mL/kg basis) and associated diuresis that may persist for the first 3 to 4 months of life, as long as foals continue nursing their dams.⁶

Renal function of neonatal foals, as assessed by glomerular filtration rate (GFR), is similar to that of adult horses.^7,8 Further, the kidneys of foals are capable of excreting a sodium load provided by fluid administration,⁹ and fractional electrolyte clearance values are similar to those of adult horses, supporting that renal tubular function in foals is similar to that of adult horses.⁵
 

3. Pre–Renal Failure

Renal hypoperfusion leading to pre-renal azotemia is common in compromised neonates. Several compensatory mechanisms accompany decreased renal perfusion to maintain renal blood flow and GFR over a range of perfusion pressures (autoregulation). These include a decrease in afferent arteriole tone and intrarenal production of vasodilatory prostanoids (PGE2 and PGI2) to maintain blood flow, particularly in the medulla.¹⁰ Renal hypoperfusion increases the risk of nonsteroidal anti-inflammatory drugs (NSAID) associated AKI; for example, nearly 40% of premature infants that receive indomethacin to speed closure of the ductus arteriosus develop alterations in renal function.¹¹ When the more selective COX-2 NSAIDs were initially introduced, there was hope that they would be more sparing of renal function than nonselective COX inhibitors. However, it is now recognized that these newer NSAIDs provide little benefit of limiting renal damage; thus, all NSAIDs should be used sparingly in compromised foals.¹²

Renal tubular function remains essentially normal with pre-renal failure. Thus, serum electrolyte concentrations are typically normal, and urine sodium concentration is <20 mEq/L. Depending on hydration status, urine specific gravity may be variable, but the classic finding that supports pre-renal azotemia is a specific gravity ≥ 1.025 and a urine osmolality (U_osm) exceeding 500 mOsm/kg.

4. Intrinsic Renal Failure

Intrinsic renal disease and acute renal failure (ARF) can develop as a consequence of hypoxic-ischemic injury associated with birth asphyxia, septicemia, or leptospirosis or treatment with nephrotoxic medications (aminoglycoside antibiotics and NSAIDs).^11,13-17 It is often difficult to separate the effects of these factors because many compromised foals are routinely treated with nephrotoxic medications. Over the past decade, there has been a shift away from routine use of penicillin and an aminoglycoside for broad-spectrum antimicrobial therapy of neonatal foals (largely replaced by ceftiofur), and this change has probably decreased the incidence of aminoglycoside nephrotoxicity in foals. Further, the shift away from multiple daily doses to once-daily dosing regimens for aminoglycoside antibiotics has been well documented to decrease the risk of nephrotoxicity in infants.¹⁸ Unfortunately, during the same time period there has been increased use of oxytetracycline in foals with contracted tendons, and tetracycline-associated ARF may go undetected in compromised neonates unless a serum chemistry profile is submitted as part of case management. The incidence of ARF in foals in neonatal intensive care units is not well documented, but human neonatal intensive care units have reported incidences ranging from 6% to 24%, with cardiac surgery and severe asphyxia being recognized risk factors. Of interest, ARF was nonoliguric, oliguric, and anuric in 60%, 25%, and 15% of patients, respectively.¹¹ Consequently, adequate urine production cannot be used to exclude AKI and ARF in compromised equine neonates.

Although there are no specific values for BUN and Cr that separate pre-renal failure from intrinsic renal failure, azotemia is generally greater with intrinsic renal failure. Further, there is not a sudden transition from pre-renal failure to intrinsic renal failure; rather, these are overlapping conditions. To emphasize the point that some intrinsic renal damage probably occurs with simple renal hypoperfusion, the term acute kidney injury, characterized by a 50% increase in Cr, has been introduced to describe early damage with intrinsic renal disease.¹⁹ This predominantly tubular damage may be characterized by proteinuria, microscopic hematuria, glucosuria, increased urine sodium and chloride concentrations and excretion, increased urinary enzyme activities, and detection of novel biomarkers of tubular epithelial damage in urine (kidney injury molecule 1 and others). [...]