Diagnosing and managing acute kidney injury (Proceedings)

Acute renal failure may be defined as an abrupt reduction in renal function resulting in accumulation of nitrogenous waste products and dysregulation of water, electrolyte, and acid base balance. Differentiating acute from chronic kidney disease is important for both therapeutic and prognostic reasons. Inherent in the diagnosis of acute kidney injury is the potential for complete functional recovery. In contrast, patients with end-stage CKD lack substantial recovery potential. Careful examination of medical history, physical exam, past and current laboratory data and imaging studies will usually enable differentiation.

Acute uremia may be classified as pre-renal, intrinsic renal, and/or post-renal in origin. A thorough clinical exam of patients presenting with signs of an acute uremic crisis usually provides adequate information to identify pre-renal, renal and post-renal components of uremia. Although these categories help establish cause and predict prognosis, they share many features and may overlap. Pre-renal azotemia develops as an adaptive response to any cause of reduced renal perfusion (e.g., hypovolemia, inadequate cardiac output, marked vasodilatation). Initially, nephrons remain intact allowing a rapid return to function once perfusion has been restored. If correcting renal perfusion does not ameliorate the azotemia, the patient should be carefully evaluated for intrinsic renal and/or post-renal causes of azotemia. Acute intrinsic renal failure occurs when damage occurs to the nephron itself. Acute intrinsic renal failure is commonly caused by nephrotoxins or an ischemic event; other etiologies include infection, prolonged urine outflow obstruction, and severe non-renal systemic disease (e.g., pancreatitis, neoplasia).

There are generally 4 stages of acute intrinsic renal failure; 1) initiation, 2) extension, 3) maintenance, and 4) recovery. Clinically, transition from one stage to the next may not be clearly evident and not all stages need be present in an individual patient. Initiation is the period during which the kidneys are exposed to the damaging agent or event. Initiation may last hours to days and is often clinically silent; however, therapeutic intervention at this phase may reduce severity of renal damage and enhance the likelihood of recovery. During the extension phase, damage occurs to the tubular epithelium leading to a decline in glomerular filtration rate (GFR), the loss of urine concentrating ability and potentially oliguria.

During the maintenance phase, polysystemic signs of kidney damage may become apparent and the animal may be presented for veterinary care. Unfortunately, significant renal damage may have already occurred thus limiting management to supportive and symptomatic therapies. The forth stage, recovery, represents tubular epithelial regeneration, and, if it occurs, may last for days to months. Recovery is characterized by increasing GFR, improved urine quality, and amelioration of the polysystemic consequences of renal dysfunction.

Post-renal azotemia results from obstruction of urine flow after it has left the nephron, or leakage of urine from the urinary tract within the body. Fairly classic clinical signs and physical exam findings of urethral obstruction facilitate rapid diagnosis and relief of the obstruction. Likewise, urinary tract leakage from the urinary tract is usually readily identified from physical exam and imaging.

Overview of the Clinical Management of Acute Uremia

The first step in the management of acute uremia is to identify and correct any life-threatening fluid electrolyte and acid-base abnormalities. Once the patient has bee stabilized initially, pre or post-renal problems should be identified and reversed. If an underlying cause of the azotemia is identified, specific therapy should be initiated immediately. Aggressive supportive and symptomatic care will optimize the chance for recovery of renal function. Table 1 provides a summary of the general clinical approach to patients with acute uremia.

Fluid Balance: It is critical to correct dehydration and maintain euvolemia. Rapid restoration of extracellular volume and renal perfusion corrects prerenal azotemia and helps prevent further ischemic renal damage. The calculated fluid deficit should be replaced over 4-6 hours. Normal (0.9%) saline is the fluid of choice for volume deficit replacement. Body weight must be reliably measured at least twice per day. Rapid gain or loss of 1 kg represents a corresponding gain or loss of one liter of fluid. One the patient is euvolemic, the quantity of fluid given is adjusted so body weight remains stable. Overhydration is one of the most common, life-threatening, complications encountered in patients with acute kidney injury. If a patient becomes fluid overloaded, ALL parenteral fluid administration must cease and diuretics may be needed.

Urine Production: Normal urine production for a euvolemic, normotensive dog or cat is 1-2 ml/kg/hr. Euvolemia and a mean arterial blood pressure >60 mmHg are essential prerequisites to correctly interpreting urine production. Urine production of < 0.5 ml/kg/hr represents oliguria, and should prompt vigilant patient monitoring. Maintaining urine production greatly facilitates the management of fluid and electrolyte imbalances.

If oliguria persists after rehydration, administration of mannitol may promote osmotic diuresis. An initial mannitol bolus of 0.5-1.0 gm/kg IV is given over 10 to 20 minutes. If significant diuresis occurs within 60 minutes, the bolus may be repeated every 8 hours. Mannitol increases renal blood flow, decreases tubular cell swelling, increases tubular flow, and helps prevent tubular obstruction and collapse. Mannitol is also a weak vasodilator and a free radical scavenger. Osmotic agents are contraindicated with overhydration, as increasing intravascular volume may precipitate pulmonary edema.

A meta-analysis of studies performed in human medicine revealed that dopamine does not enhance renal recovery or reduce mortality, and that its use may be associated with tachyarrhythmias, pulmonary shunting, and possibly necrosis of the gut and extremities. Dopamine is NOT currently a recommended therapy for humans, or cats with ARF and its use in dogs is controversial.

Preliminary studies of the selective DA1 agonist, fenoldopam, have shown promising results in humans. There has only been one published study in feline medicine that demonstrated a delayed increase in urine output when administered as a CRI to a group of healthy cats.

Electrolyte and Acid-Base Abnormalities

Acidemia: Metabolic acidosis is a common sequela of acute uremia and occurs secondary to reduced renal acid excretion and decreased bicarbonate generation. Mild metabolic acidosis may resolve with volume replacement and the onset of diuresis. However, more aggressive correction of metabolic acidosis may be indicated if the acidosis is very severe or if hyperkalemia is also present. Appropriate treatment of severe acidosis ([serum bicarbonate] < 16mmol/L) is based on the bicarbonate concentration in serum or on venous blood gas evaluation. Sodium bicarbonate is given IV to attain target bicarbonate concentrations (> 20mmol/l) or until sodium overload or hypocalcemia precludes further administration. The estimated bicarb deficite may be calculated with the following formulae: mEq HCO3- required. = Body wt in kg X 0.3 X base deficit or (20-TCO2). To minimize iatrogenic complications, ½ the calculated dose is given over 30 minutes, then the remainder may be given with IV fluids over the next 2-4 hours. Serum or blood gas TCO2, and electrolytes should be reassessed after initial replacement, to assess treatment efficacy and determine need for additional replacement therapy.

Potassium Imbalance: Serum potassium concentration varies substantially in acutely uremic patients, and life-threatening cardiac arrhythmias may develop with serum [K+ ] > 7mEq/L. Hypocalcemia, acidosis and certain medications potentiate the electromechanical cardiac effects of hyperkalemia. Initial changes in the pattern of the ECK include peaking of the T waves, followed by QT interval shortening and P wave flattening. As serum [K+ ] increases, the P wave disappears, the QRS complex widens, and the QT interval becomes prolonged. Eventually a sine wave patter develops which is rapidly followed by cardiac arrest.

Moderate hyperkalemia (serum [K+ ] <7.0 mEq/L) will often resolve with fluid deficit correction using normal saline. This will lower the potassium by hemodilution and increased excretion from improved renal blood flow. If volume replacement and diuresis does not adequately reduce the potassium, medical management is indicated. The interventions outlined in below may prevent or reverse hyperkalemic cardiotoxicity by decreasing serum [K+ ] or, in the case of calcium gluconate, by stabilizing cardiac cell membranes.

Sodium bicarbonate increases extracellular pH and induces exchange of extracellular potassium with intracellular hydrogen ions. Improvement may be seen in minutes and may persist for 1 to 2 hours. Sodium bicarbonate is contraindicated in patients with compromised respiratory function and in patients with significant hypernatremia. It must also be used with care if hypocalcemia is present (especially common in ethylene glycol intoxication), as it may exacerbate hypocalcemia and precipitate a hypocalcemic crisis.

Another way to reduce serum potassium levels is to administer dextrose either alone or in combination with regular insulin. Glucose stimulates insulin release and promotes cellular potassium uptake. If insulin is given, blood glucose must be closely monitored to avoid iatrogenic hypoglycemia.

Calcium gluconate does not alter serum [K+ ], but mitigates cardiotoxicity by permitting cardiac cell membrane depolarization in the face of severe hyperkalemia at the recommended initial dosage is 0.5 to 1.0 ml/kg IV of a 10% solution over 10 to 15 minutes, to reverse life-threatening ECG abnormalities. Effects on the ECG are rapid in onset but short-lived, lasting approximately 25 minutes. Calcium infusion is a bridging measure only, enabling prompt application of other more durable therapies.

Hypokalemia is commonly associated with polyuric renal failure. And is more common in the recovery phase of acute kidney damage. Administration of potassium-free fluids (saline) or diuretics (furosemide, mannitol), inadequate dietary potassium intake, vomiting, and diarrhea may all contribute to development of hypokalemia. Correction of hypokalemia usually involves supplementation of the intravenous fluids with potassium. The rate of IV potassium administration should not exceed 0.5 mEq/kg/hour. Once hypokalemia is corrected, appropriate oral or IV potassium therapy maintains normokalemia.

Sodium Imbalance: Damage to the kidneys alters the ability to handle water and sodium. Extremely careful monitoring is warranted in patients with acute kidney injury as both hypo- and hypernatremia are common in these patients, and are usually iatrogenic. Oliguric patients are often hyponatremic due to limited renal free water clearance. Hypernatremia may result from hypotonic fluid losses (GI loss, osmotic diuresis, insensible loses), administration of sodium-rich fluids (0.9% saline, sodium bicarbonate, lactated Ringer's), and inadequate free water intake. Frequent monitoring of fluid balance and serum sodium concentration, and appropriate adjustment of fluid composition will minimize the occurrence of this complication.

Hyperphosphatemia: Marked hyperphosphatemia is a hallmark of acute uremia, and may exacerbate hypocalcemia, promote soft tissue calcium and phosphorous deposition, and further impair renal function. The mainstay of managing hyperphosphatemia is dietary phosphorous reduction in conjunction with administration of enteral phosphate binders (e.g., aluminum hydroxide).

Hypertension: Patients in uremic crisis are frequently hypertensive, which may exacerbate renal injury. Careful monitoring of blood pressure and physical exam during fluid resuscitation is essential to prevent hypertension secondary to volume overload. The choice of antihypertensive medications varies, although the calcium channel blocker amlodipine is effective in both dogs and cats with few side effects. If blood pressure cannot be controlled with amlodipine, the addition of an angiotensin converting enzyme inhibitor (ACEi) and/or alpha-1 antagonist should be considered.

Gastrointestinal complications: Nausea and vomiting are common clinical manifestations of acute uremia that must be controlled to facilitate caloric intake and improve patient comfort. Uremic vomiting is mediated centrally via the effects of uremic toxins on the chemoreceptor trigger zone (CRTZ) in the brain, and peripherally via gastrointestinal (GI) irritation. Derangements in GI motility and the presence of gut edema (with overhydration) may also contribute.

Dopaminergic antagonists (e.g. metoclopramide) are commonly used as a first line therapy in the management of uremic vomiting. Metoclopramide also has a pro-motility affect in addition to its centrally acting anti-emetic effects. The a2 adrenergic antagonists (e.g. prochlorperazine) are effective anti-emetic agents in dogs, but have been associated with significant hypotension and/or tranquilization in cats. This class of anti-emetics should only be used in volume replete, normotensive patients with careful blood pressure monitoring. The 5-HT3 antagonists (ondansetron and dolasetron) appear to be very effective in controlling uremic vomiting and have not been associated with significant adverse effects.

Acute gastritis and enteritis may be managed with H2-receptor antagonists such as famotidine. Since these drugs undergo renal elimination, the dose is reduced in the face of severe renal failure. As an alternative to H2 receptor antagonists, proton pump inhibitors such as omeprazole may be used to decrease gastric acid secretion, minimizing gastric mucosal irritation.

Nutritional Management of Acute Renal Failure

Patients with acute uremia are often profoundly catabolic. Metabolic causes of anorexia and vomiting must be managed aggressively and oral intake of calories should be encouraged. While hospitalized, patients should be offered diets unrelated to the preferred long term diet (i.e., don't force-feed a renal diet in-hospital). This helps prevent development of food aversion to the preferred therapeutic diet.

Proactive intervention with enteral feeding tubes combats catabolism and helps prevent loss of lean body mass. An esophagostomy tube (E-tube) or percutaneous gastrostomy tube (PEG tube) should be considered if nutritional support is anticipated for more than a few days. At our hospital, E-tubes are routinely placed for long-term provision of nutrition, hydration, and/or medications. Esophagostomy tubes are well tolerated and permit feeding of a blenderized, prescription renal diet.

Indications for Dialysis

Hemodialysis or peritoneal dialysis is often the only options for acutely uremic patients unresponsive to appropriate, aggressive medical management. Indications for initiating dialysis include severe hyperkalemia, volume overload refractory to fluid restriction and diuretics, intractable uremia and (especially for hemodialysis) acute toxicities and drug overdoses. Ideally, dialysis creates a window of stability long enough to enable renal recovery. In the earlier stages of progressive azotemia, hemodialysis may also be initiated proactively to forestall or preclude development of uremia. This approach improves quality of the life and owner satisfaction, and facilitates overall case management.

Prognosis and Outcome

The prognosis for patients with acute renal injury depends on the extent of renal injury, concomitant diseases, age, and response to therapy. A retrospective study from 1997 reported that 56% of dogs diagnosed with ARF and receiving non-dialytic management at a university hospital, were euthanatized or died before discharge. An overall mortality rate of 47% was recently reported for a group of 32 cats with acute, intrinsic renal failure. Overall, the long-term prognosis for patients surviving episodes of acute uremia is fair to good depending on the underlying etiology. Early diagnosis and appropriate intervention improve survival and minimize the potential of persistent renal injury.

Table 1: Clinical Approach to the Management of Acute Uremia

     • Obtain baseline blood and urine samples prior to initiating treatment

     • Identify and correct pre-renal and post-renal causes of azotemia if possible

     • Discontinue nephrotoxic drugs and adjust dosages of others as required

     • Place intravenous catheter aseptically and rapidly rehydrate with appropriate crystalloids

          o Fluid deficit (ml) = % dehydration x body weight (kg) x 1000

          o Replace deficit in 4-6 hours, monitor cardiovascular status

          o Avoid overhydration: monitor weight, blood pressure, central venous pressure, respiratory rate and effort, and clinical condition

     • Correct life threatening electrolyte and acid-base disturbances

          o Hyperkalemia (see text)

          o Metabolic acidosis

               ■ mEq bicarbonate required = body wt (kg) x 0.3 x base deficit or (20-TCO2)

               ■ administer ½ of the calculated dose over 15-30 minutes

               ■ reassess acid base status

               ■ ensure adequate respiratory function prior to administration

     • Following correction of dehydration and hypotension determine if patient is oliguric or nonoliguric

     • Attempt to convert oliguria, if present, to non-oliguria. Administer diuretics (benefit unproven)

          o Initially, Mannitol: 0.5-1.0 gm/kg IV over 10 to 20 minutes

          o If effective, repeat bolus of 0.5gm/Kg every 8 hours (monitor hydration and cardiovascular status very carefully).

          o Furosemide: 2-6mg/kg IV once. If effective, repeat dosage q8h OR administer 2mg/kg IV followed by CRI of 0.5mg/kg/h.

     • Ensure adequate fluid balance

          o Compensate for maintenance fluid requirements: 60ml/kg/day

          o Consider ongoing fluid losses: estimate fluid loss from vomit, feces, etc.

     • Identify and correct hypertension

          o Amlodipine: 0.625mg/cat q 24h, adjust to maintain systolic blood pressure 120-170mmHg

          o Monitor blood pressure frequently (bid-qid)

     • Optimize nutritional support

          o Supply adequate calories: ? 80kcal/kg/day, adjust to maintain lean body mass

          o Minimize nitrogenous wastes, feed "renal diet" if possible

          o Strongly consider early intervention with eneteral feeding tubes (e.g. E-tube)

     • Control hyperphosphatemia

          o Diertary phosphorous restriction

          o Enteric phosphorous binders

     • Manage gastrointestinal complications

          o Hypergastrinemia, consider either

               ■ Famotidine 0.5mg/kg PO, IV q24h

               ■ Omeprazole 0.7mg/kg PO q24h

          o Nausea,vomiting consider one of the following:

               ■ Metoclopramide 0.2-0.5mg/kg IV, SQ, PO q8h or CRI 1-2mg/kg/d

               ■ Prochlorperazine 0.1-0.5mg/kg SC, IM q6-8h

               ■ Dolasetron 0.4mg/kg IV q24h

               ■ Ondansatron 0.22mg/kg IV q8-12h

     • Manage anemia

          o If significant clinical signs, transfusion from compatible donor

          o Minimize sampling frequency and volume

          o Erythropoietin 100U/kg SQ 3xweek or Darbopoietin 6.25mcg/cat SQ q7d

     • Manage pain, initially consider either

          o Buprenorphine 0.005-0.03 mg/kg IM, IV, SC, sublingual q6-8h

          o Butorphanol 0.2-0.4 mg/kg SQ, IM q6-8h, 0.2mg/kg IV q6-8h

      If inadequate response to medical management consider peritoneal or hemodialysis