Introduction

Acute renal failure (ARF) has many etiologies which must be identified so as to treat the underlying cause. This applies to animals of ALL ages. Standard guidelines exist for management of acute renal failure; however, these are not always successful. Is there anything else we can do? This lecture will introduce diltiazem as a potential treatment for ARF, especially when due to leptospirosis. There is also the potential for renal failure to occur in hospitalized patients. What can we do to prevent this? Acetylcysteine has been used to prevent ARF secondary to illness and pharmaceutical agents in human medicine and will be presented here.

Prevention

In hospitalized patients, steps should be taken to avoid predisposing animals to ARF by ensuring normal hydration and normovolemia, especially prior to anesthesia. Nephrotoxic drugs (e.g., aminoglycoside antibiotics) should be avoided in situations where the possibility of hypotension, hypovolemia, or any other situation may exist, where splanchnic perfusion may be jeopardized (e.g., abdominal surgery, geriatrics) and pre-renal failure may occur. Furosemide is frequently used in oliguric states and will enhance aminoglycoside toxicity. Amphotericin and some non-steroidal anti-inflammatory analgesics may result in renal injury and should be used with caution. As renal failure can potentially occur in any hospitalized patient, vigilance is mandatory. Serum urea and creatinine, or at least a stick BUN, should be performed on all animals upon admission to hospital to screen for possible renal failure or insufficiency. Contrast studies requiring IV administration of the contrast media have the potential to worsen renal function. For IVU and angiogram, the contrast agent is usually ionic with high osmolality. Computed tomography also requires a contrast agent. Sepsis and systemic inflammation may also predispose patients to acute renal failure. What can we do, in addition to standard therapy of fluid/colloid support do to prevent potential renal injury?

Acetylcysteine, an anti-oxidant, has been reported to improve hepatosplanchnic blood flow and improve organ function during sepsis. We at the Ontario Veterinary College have used acetylcysteine at 150 mg/kg infusion diluted in 5% dextrose and water over one hour, followed by 10mg/kg over 30 minutes q12h until 'out of the woods' with no apparent ill-effects. Wide ranges of doses have been used in human patients.

With regards to contrast studies, fluid therapy pre-administration of contrast agent is, at the very least advised. The pathophysiology of potential renal failure with contrast agents is that initially, the renal artery responds to administration of an ionic contrast agent by a transient vasodilation, however this is followed by a prolonged period of vasoconstriction that has a tremendous negative effect on renal perfusion. Acetylcysteine, an antioxidant, has been shown to be renoprotective in human patients when administered orally at 8 to 9mg/kg twice daily starting the day prior to, and on the day of the contrast study, for a total of two days. A dosage of 15mg/kg IV over 30 minutes prior to contrast administration may also be of benefit and continued at 5mg/kg q12h IV. Calcium channel blocking agents have also been shown to be renoprotective. It has been postulated that calcium channel blocking agents can protect the kidney by antagonizing the vasoconstrictor effects induced by various pharmacological agents. ARF following invasive cardiac surgery and renal transplantation in people has been prevented by the perioperative administration of diltiazem. (See below Treatment for information.)

Treatment

The cause of ARF must be identified while attempting to establish urine flow. ARF is an emergency; it must be treated immediately, aggressively, but judiciously. The goals of treatment are to correct fluid, electrolyte and acid-base disorders, achieve and maintain normotension, and establish or maintain urine flow without overhydration. Discontinue any potential nephrotoxic drugs. The reader is directed elsewhere for specific treatment of the underlying cause of renal failure and standard therapy. However, as a potential problem that may be overlooked, adrenal insufficiency is noted here as a reminder. Adrenal insufficiency may be primary or secondary, or may develop post- trauma or surgery and during sepsis and other critical illness. Hypotension may also be noted and refractory to fluid management. It is recommended to administer corticosteroids (0.5-1 mg/kg, repeat at 0.25mg/kg q8h-12h) in this instance.

Currently, at the OVC we are using diltiazem as a treatment for acute renal failure when standard treatment fails in 24-48hours. Diltiazem, a calcium channel blocking agent, has been shown to be protective in the transplant kidney. The effects of diltiazem on the transplanted kidney are hypothesized to be due to the anti-endothelin effects, prevention of apoptosis and reduced workload of renal tubular cells. Following the allograft procedure and subsequent treatment with cyclosporine, renal vasoconstriction occurs. Endothelin is a potent vasoconstrictor and diltiazem is an endothelin antagonist; in addition diltiazem has a direct effect on reducing renal vascular tone. Following a hypoxic event, the 'health' of renal tubular epithelium is jeopardized; diltiazem prevents calcium cytosolic and mitochondrial calcium accumulation and inhibition of Ca-dependent and calmodulin-regulated enzyme activity thus reducing the generation of reactive oxygen metabolites and other radicals resulting in tubular epithelial cell death. While these events occur in the transplant kidney, similar events occur in ARF. Our current protocol uses diltiazem 0.3-0.5mg/kg slow push (10 mins), while monitoring systemic blood pressure, followed by 1-5 mcg/kg/min CRI for as long as it takes to lower the creatinine to normal values (48-96+ hours), assuming the dog was normal before the event. It may not be necessary to continue to normal values in all animals as the effects of diltiazem may persist beyond the time of discontinuation. Monitor blood pressure and heart rate several times/day. Reduce dose if heart rate or BP drop below normal, which has occurred in two very small (< 5kg dogs) of which were not hypertensive. Data to be presented indicate a potential benefit of diltiazem in the treatment of leptospirosis ARF.

Monitoring urine production is very important as this is very high with diltiazem therapy (up to ~11mL/kg/h) and fluid therapy must keep up with this. In addition monitoring urine production, following must be included in ongoing patient management to assess efficacy of therapy, and to prevent, identify and treat any abnormalities should they arise:

 Creatinine or urea or both (daily)

 Urine sediment (every 48 hours if acute tubular necrosis)

 Weight gain or loss (every 8 to 24 hours to assess fluid loss/gain)

 Serum electrolytes, specifically potassium (every 4 to 24 hours with hypo- or hyperkalemia)

 Venous blood gases, or total CO_2, (every 24 hours to assess metabolic status)

 Calculate anion gap (with electrolyte and blood gas or total CO₂ measurements)

 Urine protein:creatinine ratio (72 hours) to assess therapy and prognosis if acute glomerulonephritis

Urine output and assessment

Assume a weight loss of 0.1-0.3kg BW/1000 kcal energy requirement in an anorexic animal. Assess third space losses as weight loss will not be evident here. After urine flow has been established, regardless of the underlying problem, ongoing fluid requirements are calculated as follows:

 Divide the day into six 4-hour intervals, four 6-hour intervals or three 8-hour intervals.

 Determine urine produced during each time interval and add the estimated insensible and ongoing losses for that period (see below).

 Determine ongoing losses in vomitus, diarrhea and saliva over this same interval.

 Determine insensible loss, 20 ml/kg/day and for each degree Celsius above 38.5 add 10% of normal daily maintenance fluid requirement (if normal daily requirements are 1L and temperature is 40.5 then 200 mls should be added). Divide this amount by 6, 4 or 3 depending on intervals selected above. This total volume of fluid is to be delivered over the next time period in addition to the amount determined by urine produced and ongoing losses

Urine output will depend on the underlying problem. The goal is to maintain at least 1-2ml/kg/h. However, if there is loss of concentrating ability in addition to diltiazem therapy, urine output can be extremely high (25-40 ml/kg/h!). Hence the importance of measurement of urinary output and adequate fluid replacement. If urine output decreases below a desirable level, assess possible third space losses. Fluids should be gradually discontinued when hydration and urine production are restored and 'fluids in and urine out' are matched, the serum urea and creatinine are normal (or stabilized) and the patient is able to eat and drink. Taper fluids by 25-50%/ day, depending on the duration of therapy. If more rapid reduction is indicated, decrease by 5%/h. Should severe polyuria continue and the patient is unable to maintain adequate oral fluid intake, consider placement of an esophagostomy or gastrostomy tube where oral fluids can be administered by the owner at home. This has been very successful in both cats and dogs in our institution. Normal renal function has been maintained in a dog with renal failure secondary to trauma, for over tree years, by supplementation of fluids via a gastrostomy tube.

References

1.  Tepel M, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. New England J Med 2000;343:180-4

2.  Rank N et al. N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients; Results of a prospective, randomized, double-blind study. Crit Care Med 2000;28(12):3799-3807

3.  Rodicio JL et al. Calcium antagonists and renal protection. J of Hypertension 1993;11(supp1):S49-53

4.  Zanardo G et al Effects of a continuous diltiazem infusion on renal function during cardiac surgery. J of Cardiothoracic and vascular anesthesia; 1993;7(6):711-716