Acute Kidney Injury: Common Considerations and Complications

Does this patient have acute kidney injury?

Acute kidney injury (AKI) is a sudden loss in kidney function leading to an increase in the serum creatinine (SCr) concentration and blood urea nitrogen (BUN) concentration, and often a reduction in urine output. A recently introduced definition of AKI specifies a rise in SCr above baseline of at least 0.3 mg/dL within 48 hours or 50% above baseline within 7 days, or the presence of oliguria (< 0.5 ml/kg/h) for 6 hours.

AKI may be subdivided into three broad categories corresponding loosely to the anatomical site of the abnormality or injury.

Pre-renal azotemia, the most common cause of AKI, is caused by a decrease in perfusion to the kidney. Normal kidney function is restored if the cause of impaired perfusion can be corrected. The major causes of pre-renal azotemia are:

  • Hypovolemia from poor fluid intake or fluid loss (hemorrhage, diarrhea, vomiting, shifts into extravascular space

  • Decreased cardiac output

  • Decreased effective circulating volume (congestive heart failure, liver failure)

  • Impaired renal autoregulation (non-steroidal anti-inflammatory drugs [NSAIDS], angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), cyclosporine)

  • Abdominal compartment syndrome

Intrinsic AKI refers to parenchymal injury to one or more anatomical sites within the kidney. The most common causes of intrinsic AKI are sepsis, ischemia, and nephrotoxins (exogenous or endogenous ). Other causes of intrinsic AKI are less common and can be grouped according to the anatomical site of injury: glomerulus, tubulointerstitium, or other blood vessels.

  • Sepsis is commonly associated with AKI, particularly in cases of severe sepsis in which the incidence of AKI may exceed 50%.

  • Ischemia from systemic hypotension, often in the peri-operative setting or septic shock, leads to AKI especially in those with limited kidney reserve due to older age and/or pre-existing chronic kidney disease.

  • Drugs are an important iatrogenic cause of AKI. Nephrotoxins may cause tubular injury (e.g., aminoglycoside antibiotics, cisplatin, tenofovir, and zoledronate), interstitial inflammation (e.g., penicillin, rifampin, NSAIDs, others), glomerular dysfunction (e.g., vascular endothelial growth factor inhibitors), or thrombotic microangiopathy (cyclosporine, quinine). Iodinated contrast agents may cause AKI through a number of mechanisms including direct tubular toxicity, impaired regional perfusion in the kidney microcirculation, and tubular luminal obstruction. Bowel purgatives containing oral phosphosoda have been reported to cause AKI and subsequent chronic kidney disease (CKD) from acute phosphate nephropathy.

  • Endogenous nephrotoxins may cause AKI in the setting of rhabdomyolysis, hemolysis, tumor lysis syndrome, and multiple myeloma.

  • Other causes of AKI include acute glomerulonephritis, vasculitis, tubulointerstitial nephritis, thrombotic microangiopathy, atheroembolic disease, and malignant hypertension.

Post-renal AKI occurs when the flow of urine is acutely blocked either partially or totally. Obstruction may be caused by functional or structural problems anywhere from the renal pelvis to the urethra. Unilateral obstruction may lead to AKI in the setting of a solitary kidney or in those with advanced underlying CKD. Common settings for post-renal AKI include:

  • Bladder neck obstruction from benign prostatic hypertrophy, prostate cancer, neurogenic bladder, or therapy with anticholinergic drugs

  • Obstructed Foley catheters

  • Ureteral obstruction from calculi, blood clots, sloughed renal papillae, tumor, retroperitoneal fibrosis, or abscess

Key elements in the history include a careful review of medications, including prescribed, over the counter, and herbal or traditional remedies. A history of vomiting, diarrhea, or poor oral intake may suggest pre-renal azotemia. A history of prostatic disease, nephrolithiasis, or pelvic or para-aortic malignancy would suggest obstruction. Difficulty urinating may also be reported with obstruction, but it should be noted that partial obstruction may cause significant AKI with preserved urine output, and that changes in urination may be reported from any cause of oliguric AKI.

The medical history should be reviewed carefully for pre-existing chronic kidney disease, cardiovascular disease, liver disease, malignancy, rheumatologic conditions, and recent infections. A history of arthralgias, rash, and/or fever may point towards an inflammatory condition such as interstitial nephritis, glomerulonephritis, or vasculitis.

Physical examination should be carefully performed to assess volume status. Orthostatic hypotension, tachycardia, reduced jugular venous pressure, decreased skin turgor, and dry mucous membranes are often present in pre-renal azotemia. Volume overload inferred by elevated jugular venous pressure, pulmonary edema, and peripheral edema can complicate AKI from any cause.

The exam should also focus on eliciting findings of heart failure, cirrhosis, dermatologic, and rheumatologic conditions. Signs of limb ischemia may be a clue to the diagnosis of rhabdomyolysis. A tense abdomen may signal the presence of abdominal compartment syndrome.

The distinction between AKI and pre-existing CKD may not be straightforward when previous laboratory data on SCr are unavailable. The clinical setting, nadir SCr, and certain laboratory or radiologic findings may be helpful.

What tests to perform?

Serum creatinine concentration is the main test used to diagnose AKI. In non-steady state conditions such as AKI, the SCr concentration may not provide an accurate estimate of glomerular filtration rate because changes in SCr may lag by many hours. In the setting of AKI, daily measurements of SCr should be performed. More frequent measurements may be indicated in critically ill individuals.

The pattern of rise in SCr may be helpful diagnostically. Pre-renal azotemia usually leads to modest rises in SCr that return to baseline with treatment of the underlying condition. Contrast nephropathy typically leads to a rise in SCr within 24 to 48 hours, a peak within 3 to 5 days, and subsequent resolution within 5 to 7 days. Atheroembolic disease usually shows more subacute rises in SCr, though rapid increases may be observed in severe cases. Increases in SCr of 0.5 mg/dL or greater within 24 hours may reflect substantially reduced kidney function, and such patients should be monitored carefully.

Blood urea nitrogen (BUN) increases in AKI but can also increase due to hypercatabolic states, upper gastrointestinal bleeding, hyperalimentation, and corticosteroid therapy. A disproportionate rise in BUN compared to SCr, in the absence of other causes of BUN elevation, may be observed in pre-renal azotemia.

Complete blood count may reveal anemia, which is common in AKI and usually multifactorial. Severe anemia in the absence of bleeding can suggest hemolysis, multiple myeloma, or thrombotic microangiopathy. Thrombocytopenia can also be seen in thrombotic microangiopathy. Peripheral eosinophilia can be seen in interstitial nephritis, atheroembolic disease, polyarteritis nodosa, and Churg-Strauss vasculitis.

Electrolyte complications can be severe in AKI. The serum or plasma potassium concentration should be measured in any patient suspected of having AKI. Frequent (every 6 to 8 hours) measurements may be necessary if elevated in order to assess the response to therapy and need for potential dialytic therapy. Hyperphosphatemia, hypocalcemia, and low serum bicarbonate concentration (due to metabolic acidosis, usually associated with an anion gap) may also be seen in AKI. Marked hyperphosphatemia with hypocalcemia suggests rhabdomyolysis or the tumor lysis syndrome.

The anion gap may be elevated due to retained anions such as urate, hippurate, and sulfate. The co-occurrence of an increased anion gap and an osmolal gap may suggest ethylene glycol poisoning, which can also present with oxalate crystalluria. A low anion gap may point towards the presence of a circulating unmeasured cationic paraprotein from multiple myeloma.

Fractional excretion of sodium (FeNa) may be measured in those with oliguria and AKI in order to help identify the reason for oliguria. In patients with pre-renal azotemia, the FeNa may be below 1%, although this finding can also be seen in rhabdomyolysis, sepsis-associated AKI, contrast nephropathy, and acute glomerulonephritis. FeNa above 1% may be seen in the setting of acute tubular necrosis, although this finding can also be seen with diuretic therapy and pre-renal azotemia in the setting of CKD.

The FeNa should not substitute careful physical examination to assess volume status in order to guide the decision to give intravenous fluids in patients with oliguric AKI. Urine osmolarity may be above 500 mOsm/kg in pre-renal azotemia. Loss of concentrating ability is common in septic or ischemic AKI, resulting in urine osmolality below 350 mOsm/kg, but the finding is not specific.

Urinalysis and urine sediment examination should be performed to identify potential causes of AKI. Heme positive dipstick examination without identifiable red blood cells on urine microscopy suggests the presence of filtered heme pigments from rhabdomyolysis or hemolysis. Pyuria and leukocyte esterase on the urine dipstick may suggest interstitial nephritis, but can also be seen in urinary tract infection. Urine eosinophils are likely of little benefit to help aid in the diagnosis of interstitial nephritis.

Proteinuria is usually mild (< 1gm/d, < 3+ on dipstick) in AKI without pre-existing proteinuria from CKD. Extremely heavy proteinuria (“nephrotic range”, > 3.5 gm/d) can occasionally be seen in glomerulonephritis, vasculitis, collapsing glomerulopathy, interstitial nephritis, or in cases of minimal change disease associated with acute tubular necrosis.

Laboratory studies performed when glomerulonephritis or vasculitis are suspected include complement levels, antinuclear antibodies, anti-double stranded DNA antibodies, antineutrophilic cytoplasmic antibodies, anti-glomerular basement membrane antibodies, and cryoglobulins.

Radiologic imaging (renal ultrasound or non-contrast enhanced computed tomography) should be performed in virtually all patients to exclude post-renal AKI unless an alternate diagnosis is clearly apparent. Renal imaging may provide clues to the presence of pre-existing chronic kidney disease if the kidneys are small and echogenic or the cortex is thin.

Kidney biopsy should be performed if the cause of AKI is not clear based on the clinical setting, physical examination, and laboratory studies. Kidney biopsy is most commonly performed when pre-renal azotemia, post-renal AKI, and tubular injury from ischemia or nephrotoxins have been deemed unlikely.

How should patients with acute kidney injury be managed?

Prevention of AKI: Many causes of AKI, such as pre-renal azotemia and acute tubular necrosis from ischemia, may be prevented by careful attention to optimizing volume status, ensuring adequate renal perfusion, and discontinuing nephrotoxic medications.

General considerations: Systemic and renal hemodynamics should be optimized through volume resuscitation and the use of vasopressors if necessary. Drugs with nephrotoxic potential should be discontinued if possible. Renal replacement therapy should be instituted when indicated.

Indications for renal replacement therapy: Dialytic therapy should be instituted to prevent or treat complications of severe kidney injury including severe hyperkalemia, refractory metabolic acidosis or volume overload, pericarditis, uremic encephalopathy, and uremic platelet dysfunction. Dialytic therapy is also indicated in certain toxic ingestions.

Specific clinical scenarios

Contrast nephropathy: AKI following exposure to iodinated radiocontrast agents (“contrast nephropathy”) has been the subject of a number of randomized prevention trials. In patients with pre-existing chronic kidney disease and therefore at risk of contrast nephropathy, the following have been suggested to lower the risk of AKI: avoidance of high osmolar contrast agents; volume expansion with isotonic saline or sodium bicarbonate; and possibly the use of N-acetylcysteine. No specific therapy can treat or hasten recovery from established contrast nephropathy.

Rhabdomyolysis: Aggressive volume repletion is necessary to prevent AKI from rhabdomyolysis. The administration of alkaline fluids may prevent tubular injury but carries the risk of worsening hypocalcemia that frequently accompanies cases of rhabdomyolysis. Diuretics such as mannitol or loop diuretics can be used if urine flow rates are inadequate (below 200 mL per hour) despite adequate volume administration.

In the case of established AKI from rhabdomyolysis, treatment should be focused on supportive care including maintenance of fluid and electrolyte balance and tissue perfusion. Hypocalcemia is generally not treated unless signs and symptoms of hypocalcemia are present. Dialysis may be required in cases of severe AKI.

Ischemic or nephrotoxic acute tubular necrosis: No specific therapy has been shown to treat established AKI from tubular injury. In particular, dopamine and fenoldopam should be avoided. Loop diuretics may be used to treat volume overload, but should be discontinued if urine output remains low despite large doses (e.g., furosemide 100 – 200 mg intravenously). Meticulous attention must be paid to preventing or treating complications of AKI.

Tumor lysis syndrome: Aggressive fluid hydration may prevent AKI from tumor lysis syndrome; intravenous sodium bicarbonate administration may be used in the setting of metabolic acidosis. Rasburicase (recombinant uricase) should be administered in those at high risk. Allopurinol should be administered to those at intermediate risk.

Hepatorenal syndrome: The risk of hepatorenal syndrome may be reduced in the setting of spontaneous bacterial peritonitis by the administration of intravenous albumin along with antibiotics. Norepinephrine or combination therapy with octreotide and midodrine may improve outcomes in those with established hepatorenal syndrome. Although not approved for usage in the US, terlipressin, a vasopressin analogue, in addition to albumin infusion may lead to decreased kidney injury and mortality. The definitive therapy is liver transplantation if liver function does not improve.

Drug-induced interstitial nephritis: Discontinuation of the offending agent is imperative. Corticosteroids may be administered if renal function worsens despite withdrawal of the suspected drug.

Specific complications

Hyperkalemia: Restrict dietary potassium and discontinue potassium sparing diuretics, ACE inhibitors, ARBs, and NSAIDs. Calcium gluconate or calcium chloride (1gm) can be used to reduce the risk of myocardial arrhythmias. Loop diuretics can promote urinary potassium loss. Intravenous insulin (10 units regular) and glucose (50 mL of 50% dextrose), sodium bicarbonate (50 meq intravenously), and inhaled beta-agonists may promote potassium shift into the intracellular space. Potassium binding ion-exchange resin (polystyrene sulfonate) can be used to promote excretion into the stool. Dialysis may be necessary for severe hyperkalemia that does not respond to medical management.

Hypocalcemia and hyperphosphatemia: Symptomatic hypocalcemia should be treated with intravenous calcium gluconate or calcium chloride. No specific phosphate lowering therapy is available other than minimizing dietary phosphate intake or absorption. Oral phosphate binders (calcium carbonate, calcium acetate, lanthanum carbonate, sevelamer, and aluminum hydroxide) may reduce gut absorption when given with meals.

Uremic bleeding: Platelet dysfunction may occur in severe azotemia (BUN typically above 100 mg/dL). Medical management may be beneficial acutely for active bleeding. Desmopressin acetate (0.3microg/kg intravenously) has a rapid onset but loses efficacy after repeat dosing due to tachyphylaxis from release of stored factor VIII:von Willebrand multimers from endothelial stores. Conjugated estrogens may provide longer duration of action but are not commonly used due to estrogen-related side effects. Cryoprecipitate (10 units intravenously every 12 to 24 hours) may be beneficial. Dialysis may be required when uremic bleeding cannot be controlled.

Volume overload: Pulmonary edema may be a life-threatening complication of severe AKI. High dose loop diuretics (furosemide up to 200 mg intravenously x 1, followed by a continuous infusion up to 20 mg per hour) may be used, but should not delay consideration of dialytic therapy or ultrafiltration.

Metabolic acidosis: For pH <7.20, sodium bicarbonate should be infused intravenously. Renal replacement therapy should be considered for refractory metabolic acidosis or toxic alcohol ingestions (methanol or ethylene glycol). Non-renal sources of metabolic acidosis must be investigated and treated appropriately.

Hyponatremia may occur when hypotonic fluids are ingested and renal free water excretion is limited due to low glomerular filtration rate. Intravenous drips should be concentrated and enteral free water restricted. Acute symptomatic hyponatremia is rare in the setting of AKI, and should be treated with hypertonic saline. In severely hyponatremic patients (< 120 meq/L) requiring hemodialysis, the dialysate sodium bath should be lowered to 130 mmol/L.

Drug dosing

Medications must be scrutinized to ensure appropriate dosing and intervals based on the approximate glomerular filtration rate. Certain medications may be contraindicated in severe renal failure and should be discontinued (e.g., low molecular weight heparin, unless Factor Xa levels are available for monitoring).

Gadolinium-based contrast agents have been associated with nephrogenic systemic fibrosis (NSF), a rare but potentially devastating fibrosing condition. NSF has been described primarily in patients with end stage renal disease but may also occur in cases of severe AKI.

In the setting of early AKI when SCr is increasing rapidly, the estimated glomerular filtration rate based on commonly used formulae such as the Modification of Diet in Renal Disease (MDRD) equation may over-estimate renal function.

What happens to patients with acute kidney injury?

The natural history of AKI is extremely variable and depends on the physiologic substrate of the patient, coexisting medical problems, and underlying cause. Mild pre-renal azotemia can be treated and resolve within hours to days without known long-term sequelae.

Severe oligoanuric acute tubular necrosis requiring dialysis may lead to permanent kidney failure in some individuals, particularly the elderly or those with pre-existing CKD. Other cases of severe acute tubular necrosis may recover towards baseline renal function after a period of several weeks. Obstructive uropathy can be transient and mild or, if not treated within days to weeks of onset, long-standing and lead to permanent tubulointerstitial fibrosis and consequent end-stage renal disease.

Epidemiologic evidence suggests that even mild degrees of AKI (increases in SCr of 0.3 mg/dL) are associated with an increased risk of short- and long-term mortality. A causal role for the association of mild AKI with mortality is uncertain, and may instead reflect clinical and pathophysiologic factors that increase the susceptibility to AKI.

Severe AKI can lead to permanent structural changes in the kidney such as tubulointerstitial fibrosis and capillary rarefaction that may account for the finding of an increased risk of subsequent chronic kidney disease and even end stage renal disease. Patients with an episode of moderate to severe AKI (i.e., doubling of SCr) should be referred for nephrology care even if renal function returns to a normal baseline.

How to utilize team care?

Nephrology consultation is advisable in cases of moderate to severe AKI, but also in any case in which the cause of AKI is not clear.

Nurses and phlebotomists and should be advised to avoid venipuncture and blood pressure measurements in the non-dominant arm of patients at risk of eventual chronic kidney disease and end stage renal disease, in order to preserve future vascular access for maintenance hemodialysis. Such patients include those with dialysis-dependent AKI or AKI in the setting of pre-existing CKD stage IV or V.

The involvement of pharmacists knowledgeable in drug dosing in kidney disease can be helpful in the setting of AKI. Dietitians may help in prescribing potassium, salt, and phosphate restricted enteral or parenteral feeding. Protein restriction should be avoided.

Are there clinical practice guidelines to inform decision making?

KDIGO Clinical Practice Guideline for Acute Kidney Injury (Kidney International Supplements, Volume 2, Issue 1, March 2012.)

Other considerations