Acute uremia (Proceedings)


Intrinsic renal failure occurs when damage to the renal parenchyma occurs.

Intrinsic renal failure occurs when damage to the renal parenchyma occurs. The damage may be reversible or irreversible, and includes damage to the glomerulus, tubules, interstitium, or renal vasculature. Pre-renal azotemia occurs when blood flow to the kidney is diminished, as may occur with hypovolemia, hypotension, or increased renal vascular resistance. Pre-renal azotemia is rapidly reversible once the underlying disorder has been controlled. Post-renal azotemia occurs when there is an obstruction to urine flow, from the level of the renal pelvis to the urethra, or when urine leaks into surrounding tissue and is reabsorbed (i.e, ruptured bladder, ureter, or urethra). Post-renal azotemia can also be rapidly reversed by diverting the urine either by a urinary catheter or peritoneal catheter (in cases of an intraabdominal rupture). With both pre-renal and post-renal causes of azotemia, long standing problems may progress to intrinsic renal failure. On initial presentation, pre-renal and intrinsic azotemia frequently occurs together.


Vomiting, nausea, and anorexia may be caused by uremia induced gastric ulceration or by circulating uremic toxins that affect the chemoreceptor trigger zone of the brain, causing a central nausea. Oliguria and anuria are classic signs of severe acute renal failure, but dehydration from non-renal causes will cause a decrease in urine volume with an increase in urine specific gravity as the kidneys try to retain fluid to replace deficits. Acute kidney injury (AKI) can be polyuric; this usually signifies a less severe renal injury.

Dehydration is common, although the patient may appear normally hydrated. Overhydration is rarely seen on first presentation but is common after fluid therapy. Uremic halitosis and oral ulceration may be present. The tip of the tongue may be discolored and necrotic, due to thrombosis of the blood supply. Other signs include injected mucus membranes, melena, diarrhea, and subnormal body temperature. Swollen, painful kidneys are a hallmark of AKI and some animals with AKI have such severe radiating flank pain and abdominal splinting that they will not allow abdominal palpation. Seizures are an uncommon manifestation of uremia.

Differentiating acute from chronic kidney disease (CKD) can have profound prognostic implications. Pertinent findings with AKI include a previously healthy state without weight loss and no polyuria or polydipsia prior to the recent illness, and good body condition with a good hair coat; however, AKI is a catabolic disease that can cause rapid deterioration. Small irregular kidneys are a sign of pre-existing chronic disease. Anorexia, vomiting, diarrhea, or melena does not help differentiate, nor does the presence of oral ulceration.

With AKI, the PCV may be high (due to hemoconcentration, dehydration), normal, or low (due to blood loss via gastric ulceration) although the expectation is that the PCV will be normal with AKI and low with CKD. Changes in total solids reflect changes in PCV in AKI, as opposed to CKD, in which a low PCV may be accompanied by high total solids when there is dehydration in the face of anemia. Venous blood gas analysis will usually reveal a metabolic acidosis (low pH, low HCO3 -) in both acute and chronic disease. Sodium level can be low, normal, or high with AKI, depending on disease process and prior fluid therapy. Potassium can be a useful differentiating factor between acute and chronic disease. A high serum potassium is usually an indication of oliguria or anuria, although other differential diagnosis (ruptured bladder, Addison's disease, muscle necrosis, Akita breed) may need to be considered.

Urinalysis is a particularly useful test. With both acute and chronic disease, the urine specific gravity will be isothenuric (1.007-1.015). In AKI caused by acute tubular necrosis (the majority of AKI), a urine dipstick may reveal glucosuria without hyperglycemia. Proteinuria is caused by tubular leakage and necrosis of the tubular epithelial cells, and microscopic hematuria can be present from glomerular or tubular damage. The urine pH is usually acidic, unless there is a concurrent bacterial urinary tract infection. Examination of the urine sediment may show granular casts. These casts are fragile and disintegrate with handling and storage; examination of fresh sediment is always preferable. Calcium oxalate crystals in large numbers are indicative of ethylene glycol intoxication, although a few oxalate crystals can be present normally. White and red blood cells may also be seen. Urine culture is an important test to document pyelonephritis and guide antimicrobial therapy, although it is not uncommon to have pyelonephritis in the absence of a positive urine culture.

The complete blood count is usually essentially normal. Even though the platelet count is usually normal, uremia causes a functional platelet defect. The coagulation profile will be normal, but buccal mucosal bleeding time will be prolonged, which is important if planning invasive procedures.

The serum chemistry panel provides much information helpful in diagnosing renal failure. Azotemia is defined as increased BUN and creatinine. Uremia is the constellation of signs that accompany renal failure. The severity of azotemia depends on disease and duration. In humans, a 0.5 mg/dl increase in creatinine over 24 hours is considered AKI. BUN:creatinine ratio can be high from GI bleeding or dehydration, or it can be low in early stages of AKI. Phosphorus increases with the diminished GFR. The level of hyperphosphatemia is not a clear indicator of chronicity. Calcium tends to be normal, but acute severe hyperphosphatemia can decrease total calcium due to the law of mass-action. Ethylene glycol, however, will cause a particularly profound hypocalcemia. In addition to hyperphosphatemia from decreased GFR and from the phosphate contained in the antifreeze solution, the oxalate that forms as ethylene glycol is metabolized chelates calcium (to form calcium oxalate crystals). Anion gap is high due to retained organic and inorganic acids that the damaged kidney is unable to excrete.

Survey abdominal radiographs may show renomegaly with normal shape or normal sized kidneys. Nephroliths or ureteroliths may be noted. Survey radiographs do not usually help in differentiating between causes of AKI. Abdominal ultrasound usually shows enlarged kidneys with normal architecture. Bilateral pyelonephritis, characterized by renal pelvic dilatation, or lymphosarcoma, characterized by a diffusely thickened cortex, could cause AKI. With ethylene glycol intoxication, as oxalate crystals deposit in the kidneys, they increase the echogenicity, making the kidneys hyperechoic, or "bright." There may be a hyperechoic region between the cortex and medulla (the "rim sign"), although this is not pathognomonic. Excretory urography may be used to define obstructing ureteroliths, but the anuric kidney may not excrete sufficient radiographic contrast medium to provide an adequate study. Antegrade pyelography may be useful in that setting, if the renal pelvis is dilated. Computed tomography (CT Scan) or MRI can add information about architecture and obstruction but requires anesthesia.

A variety of other tests may be employed in the diagnosis of AKI. Because the renal function tends to be rapidly changing for better or worse, GFR studies (iohexol clearance, endogenous creatinine clearance, Technetium labeled DHTP, etc.) have limited applicability in the initial management of KI.

Ethylene glycol intoxication is an emergency situation that requires immediate specific therapy, making accurate and timely diagnosis crucial. Owners occasionally observe ingestion or know of exposure potential (open container in garage, recent radiator leak, etc.). Initial signs occur 30 minutes to 12 hours after exposure, and include polydipsia, polyuria, vomiting, depression, and ataxia. These signs usually resolve, and evidence of renal failure is not apparent until 48 to 72 hours later in the dog, 12 to 24 hours later in the cat. A high anion gap metabolic acidosis is usually present. Calcium, both total and ionized, may be low from chelation with oxalate, and patients may exhibit signs of hypocalcemia (spasms, tetany). Calcium oxalate crystals appear in the urine within 3 to 6 hours of exposure. An in-house ethylene glycol test kit can detect ethylene glycol and propylene glycol, which is a vehicle for a variety of medications, to levels as low as 50 mg/dl.

The leptospirosis serovars that are clinically important in dogs include L. canicola, L. icterohemorrhagica, L. pomona, L. grippotyphosa, L. hardjo, L. bratislava, and L. autumnalis. There is considerable cross reactivity between serovars. Titers may be negative within the first 7-10 days; a four-fold rise after 2-4 weeks confirms infection. A single titer of 800 or greater with appropriate clinical signs is also suggestive. Vaccinal titers are usually less than 300 unless the vaccine was administered in the previous 3 months. Rocky Mountain Spotted Fever (Rickettsia rickettsii), Ehrlichia canis, and Lyme disease (Borrelia burgdorferi) can cause AKI.

Renal biopsy can be helpful in establishing a diagnosis with some causes of AKI, especially LSA. Renal damage that has destroyed the tubular basement membrane is thought to be irreversible damage, whereas an intact basement membrane holds the theoretical potential for repair. The risk of bleeding when uremia is severe is high due to the thrombocytopathy.


Treatment of acute renal failure involves therapy for azotemia, extra renal manifestations, supportive care, and in some cases, therapy specific for the underlying disease process. Fluid therapy is the mainstay of treatment for both acute and chronic kidney disease. Dehydration should be replaced with a balanced polyionic solution like LRS or Plasmalyte, but a solution with less sodium such as half-strength LRS is prudent for maintenance fluid needs. Sodium derangements should be reversed at the same rate at which they developed. Colloidal support (Hetastarch, Dextran, or plasma) may also be indicated depending on the clinical status of the patient.

Determining the amount of fluid to use in AKI is a challenge that requires frequent reassessment of the patient's status. Calculate an amount to rehydrate the patient (usually over 8 to 24 hours). If the patient appears hydrated, give 5% of body weight to account for undetectable dehydration. However, if the patient is anuric or oliguric, continued IV diuresis is not helpful and can be dangerous. For the oliguric or anuric patient, fluid administration may need to be guided by volume of urine output, or "Ins and Outs." The volume put out by a patient equals the insensible loss (respiration, stool) plus urine output plus ongoing losses (vomiting, fluid exudation into wounds, nasogastric suctioning, etc.). Insensible loss is 10 ml/lb/day (22 ml/kg/day). To measure urine output, use a urinary catheter and record volume produced at least every 4 to 6 hours, and replace this volume over the next 4 to 6 hours. Ongoing losses, like vomiting, diarrhea, gastric suction, etc. can be measured but are usually estimated.

If the patient is anuric, he will get only insensible loss. If he is overhydrated, withhold the insensible loss. Overhydration in an anuric patient or inability to start diuresis an oliguric or anuric patient is a clear indication for dialysis, which is the only other effective therapeutic option.

Monitoring fluid status is an ongoing process. Skin turgor may be affected by vasculitis or hypoproteinemia. Trends in body weight, PCV and total solids, blood pressure, and central venous pressure can give some indication of volume status.

Determining urine volume can be performed by a variety of methods, including 1) urinary catheter and closed collection system, 2) collect urine when naturally voided, 3) metabolic cage, 4) weigh cage bedding/litter pans (1ml of urine = 1 gm), and 5) using body weight to verify accuracy. Urine volume can be categorized by the following guidelines: anuria = none to negligible amount, oliguria <0.5 ml/kg/hr, polyuria >2.0 ml/kg/hr. Polyuric AKI has a better prognosis than anuric because the degree of renal damage is likely less severe.

There are a variety of methods to attempt to increase urine output. Osmotic diuretics like mannitol are freely filtered at glomerulus but not reabsorbed by tubules. Increased osmolality of filtrate draws in water, increasing flow through the tubules without increasing GFR. The mannitol dose is 0.5 gm/kg over 5-10 minutes IV, up to a maximum of 2 gm/kg per 24 hours. Do not use mannitol in dehydrated or overhydrated animals; it can exacerbate pulmonary edema if the patient is overhydrated. Mannitol can also be used as constant rate infusion (CRI) of 1 mg/kg/min to decrease BUN in animals that are producing urine.

Chemical diuretics work by inhibiting Na+ carrier systems in tubules. Since different segments of tubules have different transport molecules, different drugs affect corresponding segment. Loop diuretics are most potent, since 25% of filtered sodium is resorbed in the loop of Henle. Thiazide diuretics work on the distal convoluted tubule, where 3-5 % of filtered sodium is resorbed. Spironolactone and other collecting duct diuretics are least potent, since only 1% of filtered sodium is available. Loop diuretics are the only ones helpful in converting oliguria or anuria. A starting dose for Furosemide (Lasix), a loop diuretic, is 2 mg/kg IV. If there is no urine production in 20-30 minutes, double the dose to 4 mg/kg. If there is still no urine in 20-30 minutes, increase the dose again (6-8 mg/kg). If still no response, add a second diuretic. High doses of furosemide (10 mg/kg) can cause ototoxicity. Dehydration and electrolyte imbalances can be severe with higher doses of furosemide, if the patient is making urine. This increased urine flow does not increase GFR. In people, regardless of an effect on urine output, furosemide did not improve the outcome. IV diltiazem has been used to increase urine output.

There are a variety of acid/base and electrolyte disturbances that occur commonly in AKI. Hyperkalemia can be an immediately life-threatening electrolyte problem. Typical EKG changes include tall spiked T waves, a shortened QT interval, wide QRS complex, and a small or wide or absent P wave. Severe hyperkalemia can lead to a sine wave, ventricular fibrillation, or standstill. Treatment consists of insulin to drive potassium intracellularly. It takes up to 30 minutes to have an effect. The dose is 0.5 units/kg IV of regular insulin, and dextrose must be given concurrently to avoid hypoglycemia. Dextrose induces endogenous insulin release in nondiabetic patients and avoids hypoglycemia when insulin is administered. It is dosed at 0.5 gm/kg IV or 1-2 gm per unit of insulin given IV and 1-2 gm per unit in next dose of IV fluids. Metabolic acidosis causes extracellular shift of K+ as H+ increases intracellularly. Correction of metabolic acidosis with bicarbonate allows an intracellular shift of K+ as the H+ is combined with HCO3 and removed. The dose is based on base deficit or 2 mEq/kg IV. Calcium gluconate 10% can be used when death seems imminent. It restores membrane excitability without decreasing potassium concentration. It has an effect in 10 minutes, which can "buy" time for potassium lowering maneuvers to work. Calcium chloride is very irritating if perivascular and therefore is not used. The calcium gluconate dose is 0.5-1.0 ml/kg IV to effect, given slowly. During infusion the ECG must be monitored, and the infusion slowed or stopped if the arrhythmia worsens. Cation-exchange resins bind to potassium in the GI tract in exchange for sodium but are not useful in the acute setting. Dialysis is the only method that actually removes potassium.

Metabolic acidosis is a common acid-base disturbance in renal failure. With renal failure, the kidneys are unable to excrete H+ and cannot resorb HCO3. There may be some contribution from lactic acidosis from dehydration and poor perfusion. Treatment with sodium bicarbonate is geared toward causing acid (H+ ) to combine with bicarbonate (HCO3) to form H2CO3, which dissociates to H2O and CO2 according to the following formula: H+ + HCO3 <=> H2CO3 <=> H2O + CO2. An elevated PCO2 is a contraindication to bicarbonate administration because it can lead to paradoxical CNS acidosis. The bicarbonate dose can be calculated from this formula: 0.3 X body weight (kg) X base deficit, where the base deficit = 24 - patient HCO3. Give ¼ to ⅓ dose IV and additional ¼ in IV fluids over the next 4 to 6 hours. Adjust the dose based on serial evaluation of blood gas determinations. Therapy is usually reserved for pH less than 7.2 or HCO3 < 12.

Ionized calcium tends to be normal despite moderate to severely decreased total calcium. Treatment should be based on ionized calcium and clinical signs of hypocalcemia (tetany). Excessive treatment in the face of hyperphosphatemia leads to soft tissue mineralization when the calcium X phosphorus product exceeds 70. Calcium gluconate 10% can be used at a dose of 0.5 - 1.5 ml/kg IV over 20-30 minutes. As when treating hyperkalemia, monitor EKG during infusion.

There are a variety of extra-renal manifestations of uremia, including anorexia, nausea and vomiting. Histamine blockers such as famotidine (Pepcid, 0.5-1.0 mg/kg IV q 24 hours), ranitidine (Zantac, 0.5 mg/kg IV q 24 hours), or cimetidine (Tagamet, 5-10 mg/kg IV slowly q 8 hours in dogs, q 12 hours in cats) are frequently prescribed. GI protectants help heal ulcers that have already formed. Sucralfate (Carafate, ¼ to 1 gm PO q 6 hours) works best in an acid environment and should be given 2 hours before antacids and separated from other drugs by 2 hours also. Centrally acting antiemetics are occasionally needed to control intractable vomiting. Metoclopramide (Reglan, 0.2-0.4 mg/kg SQ q 8 hours) should not be administered with concurrently with dopamine. Chlorpromazine (Compazine) (0.5 mg/kg IM q 8 hours) has hypotensive and sedative side effects. Experience with serotonin antagonists (i.e. odansetron, dolasetron) is limited, but these agents seem more potent than metoclopramide. Cerenia is a new antiemetic that appears to be quite effective.

Nutritional support in the early stages of AKI decreases morbidity in human studies. If enteral feeding is possible, nasoesophageal (NE), esophagostomy, or PEG tubes can be utilized. If vomiting cannot be controlled, partial or total parenteral nutrition (PPN or TPN) should be a consideration. In patients who are anuric or oliguric, the volume instilled, whether enterally or parenterally, must be taken into consideration.

Once a diuresis has been established, polyuria can be quite profound, and aggressive fluid support may be necessary to prevent additional prerenal insult from dehydration. Once the azotemia has resolved or reached a baseline, the fluid dose can be decreased by 10-20% per day. If the urine output diminishes by a corresponding degree and the azotemia does not return, continue tapering slowly. If the urine output does not diminish, the kidneys are unable to regulate fluid balance and further reduction in the fluid administered will lead to a dehydrated patient. It can take weeks for the kidneys to regain the ability to control fluid volume, but a rule of thumb used by some is to taper fluids over the same amount of time it took to diuresis them.

In many cases of AKI, the exact etiology is not known initially. However, there are some causes of acute renal failure that have specific treatments. When treating leptospirosis, penicillin G or ampicillin (22 mg/kg q 6 hours) is the antibiotic of choice for treating leptospiremia. The carrier state can be eliminated using tetracyclines (i.e. doxycycline 5 mg/kg q 12 hours for 2 weeks) or fluorquinolones (i.e. enrofloxacin). To minimize renal damage from antifreeze toxicity, emergency treatment with ethanol or 4 methylpyrazole (4-MP, Antizole-Vet) is indicated.

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