Advanced Therapy for Acute Renal Failure
ACVIM 2008
Merilee F. Costello, DVM, DACVECC
Monroeville, PA, USA

Acute renal failure is defined as a potentially reversible condition characterized by an abrupt deterioration in renal function resulting in impaired excretion and subsequent accumulation of uremic waste products. Oliguria can be difficult to identify in some patients--"Lack of urine output in the acutely hypovolemic patient is renal success, not renal failure."Ronald V. Maier, MD. Oliguria is defined variably, as <0.27 ml/kg/hr, <0.48 ml/kg/hr, <1-2 ml/kg/hr. In uremic patients on IV fluids, absolute oliguria = <1 ml/kg/hr, relative oliguria = 1-2 ml/kg/hr.

Oliguria--Systemic Effects

There are numerous deleterious effects of oliguria including metabolic acidosis, hyperphosphatemia, hypocalcemia, hyperkalemia, and hypermagnesemia (generally not a clinically significant problem). The systemic effects include accumulation of "uremic toxins", fluid overload / edema, hypertension, and platelet dysfunction.

Hypertension is defined as persistently elevated blood pressure. This is difficult in our patients, but a SBP >160 or DBP >100 that is repeatable, in a calm animal. Hypertension has a wide range of deleterious effects, and treatment can be challenging. β-blockers (atenolol, propanolol) and considered tx of choice in hypertensive, hyperthyroid cats. ACE inhibitors are not recommended in the acute setting due to the effects on renal function. Calcium channel blockers are considered by many to be the anti-hypertensive drug of choice in ARF. Oral amlodipine (can be given rectally)--dose 0.25 to 0.75 mg/kg per day. Nifedipine--injectable calcium channel blocker and has been shown to be as effective as nitroprusside in people. This is given as CRI and is very expensive. Nitroprusside causes direct relaxation of arteriolar and venous smooth muscle by directly activating guanylate cyclase. Common indications in people include congestive heart failure and hypertensive emergencies. It is administered intravenously and has only been evaluated in dogs. Complications include cyanate or thiocyanate toxicity when this drug is given for a long period (days), especially in patients with hepatic or renal dysfunction. This is a very effective medication with a fast onset of action, given as CRI. Other options include hydralazine, acepromazine, fenoldopam, and pain management.

In ARF--platelets don't work effectively for multiple reasons, including decreased availability of platelet factor 3, decreased intracellular content of ADP, ATP, ATPase, β-thromboglobulin, plt factor 4 and serotonin, increased activity of adenylate cyclase, increased cAMP content, impaired function of gp IIb-IIIa, impaired plt-endoth adhesion, reduced aggregation, and inadequate release reaction. This occurs due to uremic toxins--likely players include urea, creatinine, phenols and guanidinosuccinic acid. Another big factor in bleeding diathesis in ARF is anemia and correction of anemia (with erythropoietin) improves platelet function in people. Treatment for uncontrolled bleeding in azotemic patients includes treating the anemia with transfusions, GI protectants, +/- DDAVP. Advanced therapies include hemodialysis and recombinant factor VIIa.

Advanced Therapies for ARF

Lasix

Lasix has long been a therapy for the oliguric or anuric patient in acute renal failure (ARF). In addition, it has been recommended as a potential therapy to delay or even prevent ARF. There are numerous theoretical benefits for this therapy. Lasix may produce "resting state" in cells of thick ascending loop of Henle via Na/K/2Cl pump inhibition. It increases tubular flow rate (possibly "washing out" casts and cellular debris) and may inhibit tubuloglomerular feedback by blocking chloride flux at macula densa. Finally, Lasix therapy is thought to reduce renal vascular resistance and increase renal blood flow. Unfortunately, numerous studies have been done and have documented no firm evidence of lowered mortality with lasix therapy in ARF. There has been documentation of improved outcome in patients that respond to lasix versus those that do not respond, but these may be patients with less severe renal damage and therefore more able to respond to diuretic therapy. In addition, some studies have actually associated the use of loop diuretics with increased mortality and delayed renal recovery. It is important to note that all of the clinical trials in this area have been done in human patients or animal models--no clinical trials investigating the use of Lasix in naturally occurring ARF in veterinary patients have been done.

Mannitol

Mannitol was one of the first agents utilized in the treatment of acute renal failure. Mannitol administration results in extracellular volume expansion and induces an osmotic diuresis. The potential benefits of mannitol in renal failure are numerous and include increased tubular flow, decreased renal vascular resistance with a potential increase in renal blood flow, reduced vascular congestion by preventing hypoxic cell swelling, prevention of erythrocyte aggregation, protection of mitochondrial function, and minimizing of free radical damage. As is the case with furosemide, no controlled studies have been done evaluating mannitol versus volume expansion alone. In addition, there are multiple reports of mannitol induced renal failure. These reports conclude that excessively high plasma mannitol concentrations (>1050 mg/dL) may induce ARF. Clinically, the plasma concentration of mannitol can be estimated using osmolal gap. Studies in humans have indicated that patients with osmolal gap >60-75 mOsm/kg are at highest risk. In one human case series (4 cases), mannitol infusion rate was approximately 0.25 mg/kg/hr for 58 +/- 22h. Again, no clinical studies of either the efficacy or safety of this therapy in our veterinary patients has been performed.

Dopamine

The use of dopamine in ARF is a bit controversial. In veterinary medicine, it has been shown that cat kidneys do not respond to dopamine at the "renal dose" as other species do. The use of dopamine in our canine patients (and in human medicine), is not so clear. Theoretically, at renal dose dopamine DA-1, DA-2 receptors are stimulated. This results in dilation of renal and splanchnic vasculature. Within the kidney, dopamine dilates interlobular arteries, afferent and efferent arteries and also acts as natriuretic hormone through decreased sodium reabsorption (primarily in the proximal tubule). However, higher doses lead to renal vasoconstriction and increased systemic vascular resistance. Overall, the results of studies are inconsistent. In a recent study looking at renoprotective effects of low dose dopamine in patients at risk for ARF, there was no benefit associated with dopamine administration. Recently, there has been increasing concern that low dose dopamine (defined as doses <5ug/kg/min) could be deleterious. Negative effects identified include: renal dose unpredictable in critically ill, worsened splachnic circulation, impaired GI function, impaired endocrine and immunological functions, and blunted ventilatory drive. Of course, further studies (both in human as well as veterinary medicine) are needed.

Calcium Channel Blockers

The use of calcium channel blockers is under a great deal of investigation in human medicine for both the prevention and treatment of acute renal failure. The renal effects of calcium channel blockers include dilation of the afferent arteriole with preservation of efferent tone, inhibition of mesangial cell contractility, renin release, redistribution of RBF to juxtamedullary nephrons, natriuresis, diuresis, and these drugs also act as a cytoprotectant. In human medicine there are numerous anecdotal and experimental studies. Most discuss the renoprotective effects in high risk patients (normotensive patients) and not their use in ARF. In addition, one report of acute interstitial nephritis in a person was thought to be "probably related" to diltiazem administration. Recently, diltiazem was investigated in dogs with leptospirosis. The authors of that study found that in patients with leptospirosis the renal recovery improved with the administration of diltiazem, with no deleterious effects on systemic blood pressure.

Fenoldopam

Fenoldopam is a selective DA-1 receptor agonist and widely used in people for hypertensive emergencies. There are, however, numerous renal effects including decrease renovascular resistance leading to increased renal blood flow and GFR and decrease sodium reabsorption and increase urine output. This drug does not stimulate DA-2 or alpha/beta receptors, therefore potentially minimizing many of the potential side effects and deleterious effects of dopamine therapy. In a study of critically ill patients with acute early renal dysfunction (prior to severe renal failure) fenoldopam was more effective than renal dose dopamine at reversing renal hypoperfusion. In a study evaluating the use of fenoldopam in critically ill patients at risk for acute renal failure, the use of fenoldopam reduced the need for renal replacement therapy and mortality in patients with acute renal injury. There are potential negative effects, in one study evaluated the effects of intravenous fenoldopam (0.1-1.0 microg kg(-1) min(-1)) or saline on renal blood flow and function in 10 dogs with experimentally induced rhabdomyolysis and myoglobinuric acute renal failure, fenoldopam increased the severity of the renal injury as compared to placebo. Studies evaluating the use of fenoldopam for acute renal failure in our veterinary patients are still needed, but a recent study evaluating fenoldopam administration to normal cats showed a diuretic effect due to a dopamine receptor induced natriuresis.

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Speaker Information
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Merilee Costello, DVM, DACVECC
Allegheny Veterinary Emergency Trauma & Specialty
Monroeville, PA


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