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Home , Metabolic acidosis, Uremia

Updates in management of Acute injury (AKI): IV fluids can cause harm! Larry G. Adams, DVM, PhD, Diplomate ACVIM (SAIM) Purdue University College of Veterinary , West Lafayette, Indiana, USA

Key points: (AKI) is a common condition that may result from infectious, toxic or ischemic causes. Leptospirosis is a treatable cause of AKI in dogs that responds well to treatment in the majority of cases. Administration of too large of volume of IV fluids is a common error in management of AKI, which can further damage the kidneys resulting in potentially fatal complications. is common in patients with AKI and requires adequate control to facilitate renal recovery and prevent additional kidney damage. Introduction Acute kidney injury (AKI) spans a spectrum of injury from subclinical, non-azotemic injury to fatal oliguric AKI. AKI manifests as either rapid rise in serum or indicating rapid deterioration of renal function. Causes of AKI include infection (leptospirosis, Lyme nephropathy), ischemia or nephrotoxicity. Acute inflammatory diseases causing AKI include acute , immune mediated , and acute interstitial . Although leptospirosis can cause AKI along with acute liver disease (or ), AKI without severe liver disease has become the most common clinical presentation of leptospirosis in dogs.1-3 Postrenal causes include obstructive uropathy (ureteroliths) and urinary tract rupture. Ureteroliths (and concurrent ureteral stricture) have become a very common post renal cause of in cats with a markedly increased incidence.4,5 Urine output is highly variable with AKI with differences in the same patient at different stages of the disease. AKI can be classified as oliguric (<0.5 ml/kg/hour) or nonoliguric (>0.5 ml/kg/hour). Nonoliguric patients may be (or may become) profoundly polyuric as the kidney begins to recover from the AKI. Oliguria is associated with common complications as a result of low distal tubular flow rates including , severe metabolic , and overhydration from fluid therapy. Conversion from oliguria to nonoliguric state precedes improvement of the patient’s GFR by several days during recovery phase of AKI. may be useful to increase urine output for oliguric AKI to assist with patient management.

1 Conservative Medical Management The key principles involved in conservative medical management are to control clinical signs of , treat underlying causes of the AKI (e.g., antibiotics for leptospirosis), maintain adequate hydration status, manage acid base and imbalances, control hypertension, and provide nutritional support. These measures are aimed at maintaining the animal until the kidneys have time to recover from the acute insult. Strict aseptic placement and care of all IV and urinary catheters is essential to avoid ascending UTI and . Fluid therapy for patients with AKI must be adjusted based on urine output and hydration status. The most common error in fluid therapy is to give more fluids that necessary resulting in overhydration and associated complications of SQ , pleural and peritoneal effusion, and . Overhydration also contributes to tissue edema within the renal parenchyma further impairing renal function. This occurs because edema in the renal parenchyma combined with the renal capsule causes marked increased interstitial pressure within the kidney and decreased GFR. Placement of urinary catheter and monitoring of urine output using a closed collection system facilitates balancing “ins and outs”. The older concept of diuresis of the kidneys to flush out the kidneys by forcing them to make urine is not physiologically accurate and often leads to overhydration. The goal of fluid therapy is to maintain adequate perfusion of the kidneys to avoid any ischemic injury from inadequate renal blood flow (). Overhydration of the patient does not increase renal blood flow or GFR any more than maintaining normal hydration. Furthermore, many dogs and cats with AKI develop hypertension during the course of the disease, yet GFR is persistently decreased which is observed through worsening or stable azotemia despite hypertension. This further illustrates that giving more fluids to increase blood pressure does not improve GFR. Patients with AKI may become profoundly polyuric either initially or during the recovery phase. During these periods of intense diuresis, it is important to give enough fluids to maintain hydration without causing overhydration. The role of diuretics in conservative management of AKI is another important concept. Diuretics may be useful in conversion from oliguria to non-oliguric state, but this increase in urine output does not change GFR. Increasing urine output makes the patient easier to manage to allow some IV fluid support to adjust electrolyte and acid- base balance while the patient is managed until GFR improves later in the clinical course. Increasing urine output using furosemide (1-2 mg/kg bolus followed by CRI if successful) or (0.5 g/kg slow IV) may increase renal excretion of to help manage hyperkalemia. Unfortunately, most animals with severe oliguric AKI resulting in hyperkalemia have minimal response to diuretics and often require to effectively manage the resulting hyperkalemia, , clinical uremia and overhydration.

2 Anti-emetics are required to control uremic induced and . Ondansetron and maropitant should be administered concurrently for animals with uremia. During the initial uremic crisis and associated vomiting, avoid feeding the animal until vomiting has been effectively controlled with anti-emetics (and hemodialysis if necessary). Once nausea has been controlled, if the animal doesn’t eat adequate calories, placement of an esophagostomy tube should be strongly encouraged to allow adequate nutritional support. Animals treated by hemodialysis have an esophagostomy tube placed during the anesthesia for catheter placement. AKI is a highly catabolic state and inadequate nutritional support may impair renal functional recovery and increases the risk of GI translocation of bacteria resulting in sepsis. The optimal nutritional support for animals during recovery from AKI is not known. Dietary phosphorus intake should be moderately reduced, but excessive dietary protein restriction is not advisable. Some studies involving surgical reduction of renal mass show less recovery of renal function in dogs fed reduced dietary protein compared to normal maintenance levels of dietary protein. Amlodipine is recommended for treatment of hypertension from AKI. Depending on the severity of the hypertension, amlodipine is administered at 0.2-0.4 mg/kg PO q 12- 24 h as needed to maintain systolic blood pressures below 160-180 mmHg. In patients with malignant hypertension resulting in neurologic or ocular injury, a loading protocol is to administer 0.2 mg PO every 2-4 hours for 2-3 doses until systolic blood pressure is within target range. Overtreatment resulting in hypotension should be avoided to prevent additional ischemic injury to the kidneys. Dogs and cats with AKI are prone to developing metabolic acidosis from lack of renal H+ excretion. Therefore, alkalinizing IV fluids such as Plasmalyte A or Normosol-R are most commonly utilized. Administration of dextrose and insulin are useful short-term to drive K into cells to minimize cardiac effects of severe hyperkalemia. For patients with bradycardia from severe hyperkalemia, IV administration of gluconate increase ionized Ca2+ to stabilize the heart rhythm. However, the effects are short lived and repeated administration of calcium in patients with severe is not recommended. Therefore, these therapies are most useful for stabilizing the heart prior to anesthesia such as brief anesthesia for hemodialysis catheter placement. Administration of (slow in IV fluids) may also be used to help drive K into cells, but this should not be done with patients with ionized . Alkalinization of the blood shifts some of the blood calcium from the ionized state to non-ionized state, thus this may worsen cardiac from the hyperkalemia before K has enough time to move into cells. Hemodialysis Hemodialysis is available at some referral hospitals for management of patients with AKI. Indications for hemodialysis are primarily for management of moderate to severe

3 AKI. Persistent oliguria often necessitates referral for hemodialysis to address hyperkalemia, metabolic acidosis and overhydration. Likewise, animals with severe clinical uremia from AKI despite appropriate medical management benefit from hemodialysis. Animals with AKI that are candidates for hemodialysis should ideally be referred as soon as possible to optimize patient management and allow placement of the hemodialysis catheter while the patient is relatively more stable to decrease anesthetic risk. Please avoid using the jugular veins for venipuncture or catheter placement prior to referral for hemodialysis. Prognosis of patient with AKI For patients managed conservatively, patients with nonoliguric AKI have a better prognosis than those with oliguric AKI, because this reflects less severe damage and less severe complications. Prognosis for nonoliguric AKI is guarded to fair for functional recovery of renal function. Prognosis for oliguric AKI is guarded to poor depending on severity and cause (without hemodialysis). The prognosis for oliguric AKI caused by is poor, therefore, it is important to treat with ethanol or perform hemodialysis to remove the toxin before renal damage occurs. Severe hyperkalemia, acidosis, and overhydration that accompany severe oliguria contribute to poor prognosis in patients treated conservatively. These complications often necessitate referral for hemodialysis. Functional recovery of renal function after AKI is variable resulting in normal renal function (in some patients) or residual chronic (CKD).6 The severity of residual CKD is staged using the IRIS classification scheme 1-3 months after recovery from AKI. Dogs and cats that recover to stage 1-2 CKD have much better long- term prognosis than those with residual stage 3-4 CKD. Early referral and optimal patient management may increase the chance of renal functional recovery to stage 1-2 CKD or better. The underlying disease process resulting in AKI also affects prognosis. In general, dogs with AKI from leptospirosis have a better prognosis relative to some forms of toxic or ischemic AKI.7-9 Cats with severe AKI may also be managed by hemodialysis.10 We have performed hemodialysis to stabilize cats with ureteral obstruction prior to surgical placement of subcutaneous ureteral bypass (SUB) for cats that are severely overhydrated or severely uremic.

References 1. Goldstein R, Lin R, Langston C, et al. Influence of infecting serogroup on clinical features of leptospirosis in dogs. J Vet Intern Med 2006;20:491-494. 2. Sessions JK, Greene CE. Canine leptospirosis: treatment, prevention, and zoonosis. Compendium on Continuing Education for the Practicing Veterinarian 2004;26:700-706. 3. Sessions JK, Greene CE. Canine leptospirosis: epidemiology, pathogenesis, and diagnosis. Compendium on Continuing Education for the Practicing Veterinarian 2004;26:606-622.

4 4. Kyles AE, Stone EA, Gookin J, et al. Diagnosis and surgical management of obstructive ureteral calculi in cats: 11 cases (1993-1996). J Am Vet Med Assoc 1998;213:1150-1156. 5. Kyles AE, Hardie EM, Wooden BG, et al. Management and outcome of cats with ureteral calculi: 153 cases (1984-2002). J Am Vet Med Assoc 2005;226:937-944. 6. Segev G, Langston C, Takada K, et al. Validation of a Clinical Scoring System for Outcome Prediction in Dogs with Acute Kidney Injury Managed by Hemodialysis. J Vet Intern Med 2016;30:803-807. 7. Adin CA, Cowgill LD. Treatment and outcome of dogs with leptospirosis: 36 cases (1990- 1998). J Am Vet Med Assoc 2000;216:371-375. 8. Eatroff AE, Langston CE, Chalhoub S, et al. Long-term outcome of cats and dogs with acute kidney injury treated with intermittent hemodialysis: 135 cases (1997-2010). J Am Vet Med Assoc 2012;241:1471-1478. 9. Segev G, Kass PH, Francey T, et al. A novel clinical scoring system for outcome prediction in dogs with acute kidney injury managed by hemodialysis. J Vet Intern Med 2008;22:301- 308. 10. Langston CE, Cowgill LD, Spano JA. Applications and outcome of hemodialysis in cats: a review of 29 cases. J Vet Intern Med 1997;11:348-355.

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