What to do When “Urine” Trouble: Review of Diuretic Use in AKI

Julie Pfeifer, DVM Emergency and Critical Care Resident Department of Small Animal Clinical Sciences College of Veterinary Medicine Veterinary Medical Center Michigan State University East Lansing, MI 48824-1314

Introduction: Acute kidney injury (AKI) is a commonly encountered condition in both human and veterinary medicine. Homer W. Smith introduced the term “acute renal failure” in a textbook in 1951. Since that time there have been many definitions of acute renal failure, but currently the preferred nomenclature for this clinical syndrome is referred to an Acute Kidney Injury. In an attempt to create a universal and accurate definition of AKI classifications systems were created. Current human classifications/definitions of AKI include the RIFLE (Risk, Injury, Failure, Loss, and End Stage Renal Disease), and AKIN (Acute Kidney Injury Network). Veterinary medicine has also established classification systems including VAKI (Veterinary Acute Kidney Injury) and the IRIS (International Renal Interest Society) staging system of AKI.

Pathophysiology: The pathophysiology of acute kidney injury is multifactorial, and greatly depends on the type of insult that has occurred. Acute ischemic kidney injury can be separated into four stages, initiation, extension, maintenance, and recovery. The Initiation stage is characterized by decreased renal blood flow resulting in cellular ATP depletion. Injury in this stage also leads to activation of the inflammatory cascade. Injury occurring at this stage is generally subclinical. The extension phase is characterized by two major events: continued hypoxia and inflammatory response. Cellular injury progresses to cell death, and clinical signs may manifest. During the maintenance phase GFR (glomerular filtration rate) remains low, and cell death and regeneration are occurring simultaneously. Blood flow returns toward normal and cells undergo migration, apoptosis, and proliferation. After several days the recovery phase begins and the epithelium is reestablished. Cellular function and GFR return toward normal.

Treatment: The first goal of therapy is to treat the underlying cause. This often entails fluid therapy. The main goal of fluid therapy is to provide adequate replacement, maintain renal perfusion, all while avoiding fluid overload, and oliguria or anuria. This is most often accomplished with the use of isotonic crystalloids, and to much lesser extent colloids. Oliguria/anuria are associated with a higher morbidity and mortality as they can lead to fluid overload, electrolyte disturbances, and the need for renal replacement therapy. Unfortunately, renal replacement therapy is not commonly available in veterinary medicine, and is often financially burdensome. Diuretics are frequently used in the management of anuric/oliguric renal failure and their use has been reported in up to 60% of human cases. However, there is little clinical evidence to support their use. Many diuretics have been evaluated in both human and veterinary medicine including: furosemide, bumetanide, mannitol, diltiazem, dopamine, and fenoldopam. At this time there is limited clinical evidence in human or veterinary medicine to support their use in AKI.

Current research:

Methods: Medical records from Michigan State University’s Veterinary Medical Center were searched from January 2012 to December 2018 to identify dogs with AKI. Cases were included if they had a clinical diagnosis of AKI, and a urinary catheter placed during hospitalization with documentation of UOP. Exclusion criteria included lack of urinary catheter, incomplete medical records, or diagnosis of a urinary obstruction. Oliguria was defined as UOP between 0.51- 1.0ml/kg/hr, and anuria was defined as UOP of 0-0.5ml/kg/hr.

Results: Four hundred and twenty-five dogs were diagnosed with AKI, and 110 met inclusion criteria (25.8%). Sixty-seven cases had documented oliguria (16/67) or anuria (52/67).

Twenty-four dogs (21.8%) received furosemide alone, 3 (2.7%) received mannitol alone, 27 (24.5%) received both furosemide and mannitol, and 56 (50.9%) received no diuretics. UOP increased from anuria/oliguria to >1ml/kg/hr within 24 hours in 54.1% (13/24) of dogs receiving furosemide alone, 0 dogs receiving mannitol alone, 18.5% (5/27) of dogs receiving both diuretics, and 50% (8/16) of dogs receiving no diuretics. Median total dosage for furosemide was 1.0mg/kg (range 0.25mg/kg-5.0mg/kg), and 0.5g/kg (range 0.25g/kg-6.6g/kg) for mannitol administered as either a bolus dose or continuous rate infusion. The change in UOP (delta UOP) at 12h was significantly increased (0.52ml/kg/hr, [range 0.0 – 5.62]) in anuric/oliguric dogs receiving furosemide alone, compared with 0.0ml/kg/hr (range 0- 4.69) in dogs receiving no diuretics (p = 0.0062). No difference in delta UOP was identified between dogs that received both diuretics compared to dogs that received no diuretics. No difference could be determined for dogs receiving mannitol alone due to low number of patients.

The overall mortality rate in the evaluated population was 57.2%, which increased to 71.6% in cases with documented oliguria (16/67) or anuria (52/67). Mortality rates in anuric/oliguric dogs that received furosemide alone, mannitol alone, both furosemide and mannitol, or no diuretics were 65.2%, 66.7%, 77.8%, and 81.3%, respectively. No correlation between delta UOP and survival to discharge could be determined.

Conclusion: Oliguric and anuric renal failure carry significant mortality rates. Furosemide may increase UOP when administered to oliguric or anuric dogs, however the efficacy of diuretics and association with survival requires further evaluation and prospective studies.

Drug Dose Mechanism of action Adverse effects Furosemide 0.25 – 1mg/kg IV Inhibits Na+/K+/2Cl pump Hypovolemia, aciduria, bolus on thick ascending loop of electrolyte losses henle 0.25-1mg/kg/hr CRI Bumetanide 0.01mg/kg IV dogs Inhibits Na+/K+/2Cl pump Hypovolemia, aciduria, (experimental) on thick ascending loop of electrolyte losses henle (transported differently into tubules) Mannitol 0.25 -0.5 g/kg IV over Osmotic diuretic Induces AKI at doses of > 20-30 min or 2-4g/kg/day, and contraindicated in fluid 1mg/kg/min CRI overloaded animals as a large volume is needed Diltiazem 0.1-0.5mg/kg IV bolus Calcium channel blocker Sinus bradycardia, followed by CRI of 1- (benzothiazepines) hyperkalemia, hypotension Reversal of renal 5 mcg/kg/min vasoconstriction Dopamine 0.5-3 mcg/kg/min Dopamine-1 (DA-1) renal Arrhythmias, GI upset afferent arteriole receptor agonist- vasodilation Fenoldopam 0.8mcg/kg/min dogs, Dopamine-1 (DA-1) renal Hypotension, reflex 0.5mcg/kg/min cats afferent arteriole receptor tachycardia, increased agonist- vasodilation intraocular pressure

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