Although acute renal failure (ARF) remains a relatively uncommon problem in horses, it is a serious disorder that if not properly recognized and treated often has a poor outcome. Acute renal failure in the horse can develop as a complication of another disease process that causes hypovolemia (colic, colitis, hemorrhage, or exhaustion).
Acute renal failure
Although acute renal failure (ARF) remains a relatively uncommon problem in horses, it is a serious disorder that if not properly recognized and treated often has a poor outcome. Acute renal failure in the horse can develop as a complication of another disease process that causes hypovolemia (colic, colitis, hemorrhage, or exhaustion). Recently, there have also been a few reports of ARF developing with leptospirosis in equids. ARF may also develop after exposure to nephrotoxins including oxytetracycline (when administered for correction of flexural deformities in neonatal foals), endogenous pigments (myoglobin or hemoglobin), vitamin D or vitamin K3, heavy metals (mercury, cadmium, zinc, arsenic and lead), or acorns. Due to widespread use of gentamicin and nonsteroidal anti-inflammatory drugs (NSAIDs) in equine practice, potential nephrotoxicity with these medications will be discussed in further detail.
Administration of aminoglycoside antibiotics is one of the most common causes of acute tubular nephrosis in the horse. The aminoglycoside antibiotics exert their toxic effect by accumulating within proximal tubular epithelial cells. Once toxic amounts are sequestered within the cell, cellular metabolism is disrupted, and tubular cell swelling, death, and sloughing into the tubular lumen occur. Most cases of aminoglycoside nephrotoxicity are not the result of a single overdose or initial administration of the drug to an azotemic patient. The healthy kidney can usually tolerate a single major overdose (10 times the normal amount) without detrimental effects. Toxicity is almost always the cumulative effect of repeated administration of aminoglycosides. Nephrotoxicity typically develops after several days of aminoglycoside administration to horses with diarrhea or septicemia that are not adequately hydrated or because of other factors that may exacerbate a decrease in renal perfusion (e.g., endotoxemia and concurrent treatment with NSAIDs).
When aminoglycosides are administered to high-risk patients (those with concurrent dehydration or neonates), volume deficits must be replaced and serum creatinine concentration (Cr) should be monitored closely. Because nephrotoxicity is a cumulative effect of repeated dosing, delay of administration of the initial dose of an aminoglycoside pending rehydration of a critical patient (e.g, a septic neonate or a markedly dehydrated horse) is unwarranted. It is rare for aminoglycoside nephrotoxicity to develop in horses receiving appropriate fluid therapy. The shift to once daily aminoglycoside dosing, compared to previous dosing of aminoglycosides two to three times daily, has become a standard practice that likely reduces the potential for nephrotoxicity (by ensuring a longer period of the day with low serum drug concentrations).
Aminoglycoside nephrotoxicity should be considered in horses that become inexplicably depressed and have a decreased appetite while being treated with aminoglycosides or within a few days after aminoglycoside therapy is discontinued. A tentative diagnosis of nephrotoxicity is based on history of aminoglycoside use and supportive laboratory data. Renal failure can develop even after the drug is withdrawn; thus, monitoring renal function 2 to 4 days after discontinuing aminoglycoside therapy may be advised in high-risk patients. When ARF from aminoglycoside use develops, it is usually manifested as nonoliguric to polyuric renal failure and outcome is generally favorable as long as the duration of ARF is not prolonged and other underlying disease processes can be corrected.
Nonsteroidal anti-inflammatory drugs
Most horses do not experience appreciable adverse effects from NSAIDs as long as they are administered at the proper dose and animals are not dehydrated. However, NSAID use may produce ARF in an occasional horse when excessive doses are administered or when dehydration is not corrected promptly. When renal blood flow decreases as a consequence of dehydration, vasodilatory mediators are produced and released within the kidney to attenuate the decrease in renal blood flow. The best studied of these vasodilatory mediators include renal prostaglandins (PGI2 and PGE2) and dopamine. Renal prostaglandins are important mediators of vasodilation during periods of renal hypoperfusion. Further, production of renal prostaglandins is several-fold greater in medullary tissue such that action of these mediators leads to a greater increase in medullary blood flow, regions of the kidney that normally function in a relatively hypoxic environment. Thus, it should not be surprising that the lesion associated with NSAID toxicity is medullary necrosis that can be manifested by gross hematuria. Unless severe, however, this lesion rarely causes overt clinical signs and Cr may actually decrease with fluid therapy in the face of medullary necrosis.
Recently, use of COX-2 selective NSAIDS has received considerable attention in both the scientific literature as well as the lay press. With the introduction of firocoxib paste (Equioxx™) to equine practice, it is logical to assume that use of this NSAID may be less nephrotoxic than the other non-specific NSAIDs. However, a word of caution is warranted as the new generation of more COX-2 selective NSAIDs has not really been demonstrated to be renoprotective or less damaging to the kidneys in experimental studies in other species.
Diagnosis of acute renal failure
ARF should be suspected in patients showing more marked depression and anorexia than would be expected with the primary disease process and in patients that fail to produce urine (often manifested as dry bedding) within 12-18 hours of initiating fluid therapy. Careful monitoring of patients receiving intravenous fluids may detect an inappropriate weight gain (fluid retention) 1-2 days before edema can be observed. Occasionally, horses with severe ARF may develop marked conjuctival edema and they may also be ataxic or manifest neurological signs similar to hepatoencepalopathy. Although the pathophysiologic relationship to ARF is not well defined, diarrhea and severe laminitis may develop in more serious cases. Rectal palpation in horses with ARF may reveal enlarged, painful kidneys in some cases and enlargement can be supported by renal ultrasonography. Renal ultrasonography may also reveal perirenal edema, increased echogenicity of the renal cortex, and/or dilation of renal pelvis.
A diagnosis of ARF is confirmed on the basis of history, potential exposure to nephrotoxins, clinical signs, and laboratory findings. With regard to the latter, the increase in Cr is often several-fold greater (to 5-15 mg/dl) than that for blood urea nitrogen concentration (BUN, to 50-100 mg/dl) resulting in a BUN to Cr ratio that is often less than 10:1. Hyponatremia, hypochloremia, and hypocalcemia are usually present and, in more severe cases, hyperkalemia, hyperphosphatemia, and metabolic acidosis may also be detected. Urinalysis should be performed on all horses in which ARF is suspected. Low urine specific gravity (1.020 or less) in the face of dehydration and gross or microscopic hematuria are common findings with ARF. Glucosuria may also be detected in an occasional horse with ARF as a consequence of proximal tubular damage. Examination of urine sediment may reveal casts and increased numbers of erythrocytes and leukocytes while the amount of urine crystals may be decreased.
Treatment of acute renal failur
Initial treatment of ARF should focus on judicious fluid therapy to replace volume deficits and correct electrolyte and acid-base abnormalities. Sodium and chloride replacement are often required in horses with polyuric ARF and can be accomplished by IV administration of a polyionic replacement fluid or through electrolyte supplementation in grain feedings or as oral pastes. Serum potassium concentration in horses with nonoliguric ARF is often normal, and, except for post-renal problems (obstruction or rupture), therapy intended to lower serum potassium concentration is usually not necessary. Next, it is important to determine if the horse is oliguric or nonoliguric (polyuric) because prognosis for recovery is more favorable with nonoliguric ARF. In horses with prerenal azotemia, rather than intrinsic ARF, Cr should decrease by at least 30-50% within the initial 24 hours of fluid therapy. In contrast, Cr remains little changed, or may increase, with ARF.
In horses that remain oliguric after 12-24 hours of appropriate fluid and electrolyte replacement, furosemide (1-3 mg/kg, IV, q 2 h) should be administered. Unfortunately, furosemide treatment is often ineffective in producing urine flow in horses with oliguric ARF. If urine is not voided after the second dose, administration of mannitol (1 mg/kg as a 10-20% solution) can be instituted although use of this osmotic diuretic is controversial. If these treatments are successful in converting oliguria to polyuria (may require 24-72 hours), they can be discontinued but maintenance of urine production must be monitored closely over the next few days. Fortunately, the majority of horses with ARF are nonoliguric rather than oliguric and administration of furosemide or mannitol is not needed with nonoliguric ARF. When oliguria persists for more than 72 h, the prognosis becomes grave and dialysis may be pursued in select cases.
After volume deficits have been restored and polyuria has been achieved, patients usually only require continued fluid therapy to promote a continued decrease in Cr. During the week after fluid therapy is discontinued, Cr should be measured again to ensure that it has not increased. Occasionally, Cr may not decrease to below 2-4 mg/dl despite continued fluid therapy. As long as the horse is eating and drinking well, IV fluids can be discontinued. In some horses Cr may return to the normal range over the next couple of months while in other patients a persisting elevation in Cr is indicative of a permanent loss of renal function.
Chronic renal failure
Chronic renal failure (CRF) in the horse may be divided by clinical and pathologic findings into two broad categories: primary glomerular disease (glomerulonephritis [GN]) and primary tubulointerstitial disease (chronic interstitial nephritis). However, pathology in one portion of the nephron usually leads to altered function and eventual pathology in the entire nephron such that CRF is an irreversible disease process characterized by a progressive decline in glomerular filtration rate (GFR). However, the rate of decline in GFR is variable between affected horses making the short-term (months to a couple of years) prognosis guarded to favorable while the long-term prognosis remains poor. Unfortunately, because renal disease is often advanced when horses are first presented for clinical evaluation, the inciting cause leading to CRF may be difficult to ascertain, and end stage kidney disease (ESKD) may be the pathologic diagnosis.
Clinical signs and laboratory findings
The most common clinical sign observed in horses with CRF is weight loss. A small plaque of ventral edema, usually between the forelimbs, is another frequent finding. Moderate polyuria and polydipsia (PU/PD) are also usually present at some stage of the disease process. Often, urine produced by horses with CRF is light yellow in color and transparent as it is relatively devoid of normal crystals and mucus. Accumulation of dental tartar, especially on the incisors and canine teeth and oral ulcers are other findings that may be detected in horses with CRF. Decreased performance may be an early complaint in competitive horses while growth may be stunted in horses with renal hypoplasia or dysplasia.
Laboratory findings in horses with CRF vary depending on diet and the cause and severity of renal damage. Most horses with clinical signs of CRF have moderate to severe azotemia (Cr usually 5 mg/dl or greater). The BUN to Cr ratio may vary, depending on protein intake, muscle mass, hydration and degree of azotemia but is usually 10:1 or greater. Mild hyponatremia and hypochloremia may accompany CRF but serum concentrations of these electrolytes can often remain within reference ranges. Hypercalcemia, with serum concentrations sometimes approaching 20 mg/dl, appears to be a laboratory finding that is unique to affected horses, as compared to CRF in other species. The magnitude of hypercalcemia is dependent on diet and high values can return to the reference range within a few days of changing from alfalfa to grass hay. Acid-base balance usually remains normal until CRF becomes advanced but metabolic acidosis may be found in horses with end stage disease. Many horses with CRF are moderately anemic (packed cell volume 25-30%) as a consequence of decreased erythropoietin production. Horses with GN may have hypoalbuminemia and hypoproteinemia while horses with advanced CRF of any cause may also have mild hypoproteinemia associated with intestinal ulceration.
Urinalysis findings may also vary depending on the cause of CRF. As mentioned, urine is relatively devoid of normal mucus and crystals making samples transparent. Further, a hallmark of CRF is urine specific gravity in the isosthenuric range (1.008 to 1.014), although heavy proteinuria in an occasional horse with GN may produce values up to 1.020. Quantification of urine protein concentration is required to accurately assess proteinuria. Urine protein concentration in normal horses is usually less than 100 mg/dl and the urine protein to Cr ratio should be less than 0.5:1. With significant proteinuria, urine protein to Cr ratio is usually greater than 1:1 and may exceed 5:1. Horses with CIN usually do not have significant proteinuria.
Diagnosis of chronic renal failure
A diagnosis of CRF is most commonly made in horses with azotemia and isosthenuria that present with a complaint of weight loss and/or decreased performance. Concurrent detection of hypercalcemia also strongly supports chronic renal failure. Rectal examination may be helpful. Horses with ureteral calculi, often have enlarged ureters that can be palpated as they course through the retroperitoneal space. Although kidneys of horses with CRF are typically small with an irregular surface, these changes are not always apparent on palpation of the caudal pole of the left kidney. Ultrasonographic imaging is useful for evaluating kidney size and echogenicity and may reveal fluid distention (hydronephrosis, pyelonephritis, or polycystic disease) and/or presence of nephroliths. Horses with significant renal parenchymal damage and fibrosis often have increased echogenicity of renal tissue that may be similar or even greater than that of the spleen.
Treatment of chronic renal failure
Treatment of horses with CRF is most likely to produce improved renal function if there is an acute, reversible component exacerbating CRF (acute on chronic syndrome). If an acute component is detected, it should be corrected rapidly (as described for ARF) with the goal of minimizing further loss of functional nephrons. Further, surgical removal or fragmentation of stones via lithotripsy may be indicated in horses with calculi that are thought to be causing obstruction of urine flow. Treatment of horses with stable CRF consists of supportive care: providing sufficient water, electrolytes, and nutritional support. In addition to Cr, serum electrolyte concentrations and acid-base balance should be measured regularly (monthly or longer intervals). Although no adverse effects of hypercalcemia in horses with CRF have been documented, decreasing calcium intake (replacing alfalfa or other legume hays with grass hay) may result in a return of serum calcium concentration to the normal range. NSAIDs are best avoided in horses with chronic renal failure.
Nutritional management aimed at maintaining body condition is probably the most important aspect of supportive care of horses with CRF. Access to good quality pasture, increasing carbohydrate (grain) intake, and adding fat to the diet are recommendations to increase caloric intake. Fat supplements rich in omega-3 fatty acids (e.g., linseed oil, rice bran products, others) are preferred over other vegetable oils rich in omega-6 fatty acids because supplementation with omega-3 fatty acids has been demonstrated to slow progression of chronic renal disease in other species. Next, over the past couple of decades restricting dietary protein intake by human and veterinary patients with CRF was thought to have beneficial effects; however, the current recommendation is to provide adequate amounts of dietary protein and energy to meet or slightly exceed predicted requirements while maintaining a neutral nitrogen balance. In horses with CRF, adequacy of dietary protein intake can be assessed by the BUN to Cr ratio: values greater than 15:1 suggest excessive protein intake while values less than 10:1 may indicate protein-calorie malnutrition.
The progressive loss of nephron function that is characteristic of CRF precludes successful long-term treatment in horses. However, many horses with early CRF may be able to continue in performance or live as a pet for quite some time (months to a few years). In general, as long as Cr remains <5.0 mg/dl and the BUN to Cr ratio is <15:1, affected horses seem to maintain a reasonably good attitude, appetite, and body condition. However, once Cr exceeds 5.0 mg/dl, the rate of progression of CRF appears to accelerate and signs of uremia (anorexia, poor hair coat, and loss of body condition) become more apparent. Due to the variable nature of progression, each case should be managed on an individual basis with the emphasis on maintenance of body condition until humane euthanasia becomes necessary.