Approach to the Patient with Acute Kidney Injury

Fadi Tohme

General Principles

Acute kidney injury (AKI) is among the most commonly encountered clinical syndromes in the hospital setting, with an incidence rate approaching 20%.
Sepsis, major surgery, hypovolemia, and heart failure are the four major causes of AKI in hospitalized patients.
In the acute setting, small changes in serum creatinine (SCr; 0.3 mg/dL) or in urine output are independently associated with increased mortality and substantial financial cost to the health care system.
Awareness of AKI is limited by the sensitivity of SCr, the standard biomarker of kidney damage, and therefore requires clinical context to either anticipate or mitigate the disease course.
Early recognition of AKI by the physician is essential to the care of the hospitalized patient.

Definition

An abrupt reduction in kidney function as measured by one of the following criteria, based on the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines¹:

Rise in SCr by ≥0.3 mg/dL within 48 hours
1.5-fold increase in SCr compared to baseline within the prior 7 days
Documented oliguria of <0.5 mL/kg/hr for more than 6 hours.

Classification

Criteria for AKI are standardized to facilitate communication between practitioners and to clarify the results of outcome-based analyses.
A staging system compiled by the KDIGO group that categorizes the severity of AKI is shown in Table 7-1.
AKI is commonly subclassified into prerenal, postrenal, and intrinsic renal injuries.
Inclusion of novel biomarkers in the definition of AKI allows use of an alternate terminology: functional, subclinical, and structural AKI.
Intrinsic renal injury can be from glomerular, vascular, interstitial, or tubular causes.
The different intrinsic etiologies of AKI, as well as cardiorenal and hepatorenal syndromes, and specific management strategies, will be discussed in the following chapter. Glomerulonephritis and vasculitis are discussed elsewhere.

Epidemiology

Generally, AKI is a disease of the hospitalized patient, with 13% to 21% of all hospitalized patients meeting the diagnostic criteria for AKI depending on the definition used. As can be expected, the number is much higher (approaches 50%) in patients with multiorgan failure and in the intensive care unit (ICU). In contrast, only ∼1% of all patients presenting to the emergency room have the diagnosis of AKI.

TABLE 7-1 CLASSIFICATION/STAGING SYSTEM FOR AKI

Stage	Serum Creatinine Criteria	Urine Output Criteria
1	Rise in SCr ≥0.3 mg/dL (within 48 hrs) or ≥150–200% from baseline (within the prior 7 days)	<0.5 mL/kg/hr for >6 hrs
2	Rise in SCr >200–300% from baseline	<0.5 mL/kg/hr for >12 hrs
3	Rise in SCr >300% from baseline, or SCr >4 mg/dL with an acute increase of at least 0.5 mg/dL, or initiation of renal replacement therapy	<0.3 mL/kg/hr for >24 hrs or anuria >12 hrs
AKI, acute kidney injury; SCr, serum creatinine.

AKI is associated with high mortality, which has not changed significantly in the last 60 years. The average mortality in an ICU patient with AKI is quoted anywhere from 45% to 60%. Studies have demonstrated that AKI is an independent factor contributing to the mortality and not just an innocent bystander, as previously believed.²
Some of the possible reasons for the persistent poor survival in AKI include:
- Delay in diagnosis of AKI: By the time a patient’s SCr increases 0.3 mg/dL, renal function would have declined by at least 25%. Creatinine remains a late marker of AKI and is being challenged by more sensitive and biologically significant biomarkers.
- Absence of effective therapies to reverse AKI: Management of AKI remains largely supportive and focuses on prevention of further injury. There are no pharmacologic therapies yet known to hasten recovery of renal function after AKI.
- Inability of dialysis to provide actual renal replacement: The endocrine, cytokine, and immunologic functions of the kidney are not being replaced with dialysis.

Diagnosis

The initial diagnostic evaluation of a patient suspected to have AKI is triggered by either an increase in SCr or decrease in urine output over several hours.
A stepwise approach should always focus on delineating whether AKI is the result of prerenal or postrenal processes, with the understanding that intrinsic renal injury will likely take a more thorough battery of testing and may not be forthcoming by evaluation of the patient’s volume status and urinary outlet alone.
By definition, prerenal and postrenal lesions impose functional restraints on renal performance and anticipate dramatic improvement in solute clearance after removal of such lesions, if achieved in a timely fashion.
In contrast, intrinsic AKI is not expected to reverse swiftly and the clinical course and prognosis depend on the underlying cause.
In the ICU, the most common cause is acute tubular necrosis (ATN), usually due to both ischemic and toxic insults (multifactorial ATN).

Clinical Presentation

The following questions should be answered by the end of the history and physical examination in a patient with AKI.

Is the patient volume depleted?
Does the patient have a urinary tract obstruction?
Has this patient been exposed to a major nephrotoxin (medications, IV contrast, over-the-counter agents, herbal products, and so forth)?
Could this patient have intrinsic renal disease?
Does the patient have a pre-existing condition (e.g., decompensated congestive heart failure, liver cirrhosis, diabetes, peripheral vascular disease) increasing vulnerability to renal injury?
Is there a need for further serologic testing and/or renal biopsy?

History

Urine patterns and frequency
- Estimate daily urine volumes and recent trends (1 “Dixie” cup = 75 mL, 1 coffee cup = 225 mL, 1 soda can = 350 mL, 24-hour urine container = 2.5 L).
- Elicit any history of hematuria, dysuria, or pyuria.
- Urgency, frequency, dribbling, and incontinence, especially in elderly men, may point toward prostatic disease.
- Onset of urinary symptoms may also provide a temporal clue to the duration of illness.
- For hospitalized patients, a careful review of the intake, output, and daily weights is essential.
Volume status
- History of dizziness, orthostatic instability, dependent lifestyle, prolonged nursing home residence, and unmonitored chronic diuretic use, may point toward intravascular depletion, whereas weight gain, edema, or periorbital swelling (especially in the mornings) may signify fluid retention.
- Consider the possible mechanisms of fluid loss—hemorrhage, diarrhea, polyuria, and situations leading to excessive insensitive losses (e.g., fever or diminished intake due to dysphagia, surgical wounds closing by secondary intention)—as they all predispose to volume depletion.
- Review the patient’s records or hospital chart in detail for episodes of blood pressure swings.
- For postoperative patients with AKI, it is essential to review the intra- and postoperative records. These provide important information such as perioperative hemodynamic changes, cardiopulmonary bypass time (cardiac surgery), and aortic cross-clamp time (vascular surgery).
Medications
- A thorough review of the patient’s medications is essential in pinpointing the correct diagnosis.
- This includes over-the-counter medicines (nonsteroidal anti-inflammatory drugs [NSAIDs], high-dose acetaminophen), herbal products, and other health and food supplements.
- Scout for nephrotoxins in the hospital chart (e.g., NSAIDs, renin–angiotensin–aldosterone system inhibitors, aminoglycosides, cisplatin, methotrexate, proton-pump inhibitors).
- In hospitalized patients, exclude covert nephrotoxic exposure, such as iodine-based IV contrast media with radiologic studies and angiograms.
- Some drugs may precipitate or exacerbate urinary retention and should be considered as possible causes of postrenal AKI (e.g., tricyclic antidepressants, carbidopa, disopyramide, and certain antihypertensive agents).
- Several herbal products, such as herbal appetite suppressants (Hoodia gordonii) and herbal diuretics (Radix Tripterygium), have been implicated in AKI because of volume depletion.
- Herbal products containing aristolochic acid may cause interstitial nephritis and tubular necrosis.
Infections
- The source and severity of infection, as well as the treatment strategies for the infection, in a patient with AKI must be carefully reviewed.
- Sepsis initiates an innate immune response and can lead to renal vasoconstriction and ATN. Sepsis can also cause tubular damage independently of renal blood flow and perfusion. It is associated with endothelial and microvascular dysfunction, leading to an excessive inflammatory response and subsequent stress and damage to the tubular epithelial cells.³
- Some infectious organisms directly lead to renal involvement: For example, Legionella infection can cause an interstitial nephritis.
- Indirect causes include bacterial endocarditis or hepatitis C with cryoglobulinemia, both of which can cause an immune complex deposition glomerulonephritis.
- Finally, the many different antibiotics in use today can cause nephrotoxicity, either directly or by causing acute allergic interstitial nephritis.
Other potential etiologies
- Patients should be carefully questioned for other symptoms of systemic diseases.
- Severe myalgias, dark urine (with or without decreased urine output), and appropriate clinical scenarios (exercise, crush injury, recent surgery, drug or alcohol use, medications, immobilization, and so forth) may point toward rhabdomyolysis.
- Arthralgias, arthritis, skin rash, oral ulcers, hair loss, and significant cytopenias in the past may suggest the possibility of a connective tissue disorder (e.g., systemic lupus erythematosus).
- Sinusitis, cough, and hemoptysis may suggest diseases such as Wegener granulomatosis or Goodpasture syndrome.
- A history of recent sore throats or significant skin infections may suggest acute poststreptococcal glomerulonephritis.
- Bone pain and anemia may suggest underlying multiple myeloma.
- Also important is a history of chronic liver disease. Common causes of AKI in cirrhosis include prerenal AKI (sepsis from spontaneous bacterial peritonitis, diarrhea associated with lactulose use, decreased oral intake, diuretics, hepatorenal syndrome) and intrinsic renal disease (ATN, membranoproliferative glomerulonephritis with or without cryoglobulinemia in patients with hepatitis C).
Risk factors
- Appraisal of a patient’s comorbidities may identify a handicapped autoregulatory system.
- For example, in decompensated heart failure, a patient’s increased sympathetic tone may cause an increased susceptibility to nephrotoxic radiocontrast.
- Similarly, the presence of hypertension, diabetes, or significant peripheral vascular disease should also raise the possibility of dysfunctional microvasculature due to increased atherosclerotic burden, intimal hyperplasia, and decreased arterial capacitance.

Physical Examination

Volume status
- Determination of the patient’s volume status by a thorough examination is an absolute prerequisite in the examination of the renal patient.
- Check the patient’s pulse and blood pressure. If blood pressure is normal or high, evaluate for orthostatic hypotension in the sitting and standing positions, paying careful attention to the pulse as well.
- Check for dry mucous membranes and decreased skin turgor
- Assess for jugular venous distention and edema in the dependent areas.
- Perform a passive leg raise test: >10% change in cardiac output or arterial pulse pressure is expected when both legs are passively raised to 45 degrees for about a minute in a hypovolemic patient.
Cardiac examination
- This should focus on the location and character of apical impulse, presence of S₃ (volume overload) or S₄ (pressure overload), and functional regurgitant murmurs suggesting valve ring dilatation because of volume overload.
- The presence of dyspnea and tachypnea suggests fluid overload. Acidosis may induce Kussmaul respiration, but this deep-sighing character is not to be confused with the dyspnea of pulmonary edema.
- Inspiratory crackles at the lung bases occur in pulmonary edema.
Abdominal examination
- Hepatomegaly, splenomegaly, and ascites can occur due to passive congestion in fluid overload states.
- The liver may be pulsatile if volume overload has resulted in severe functional tricuspid regurgitation.
- A distended and firm abdomen should raise the suspicion for abdominal compartment syndrome. Bladder pressures can help establish this diagnosis. These should be checked using a pressure transducing system that is connected to an indwelling urinary catheter, after injection of 25 cc of normal saline while the patient is in a supine position.
- Exclude obstruction by assessing bladder distention, performing a prostate examination, and placing a Foley catheter if indicated.
Other systemic signs
- Rash (e.g., vasculitis, atheroemboli, interstitial nephritis, lupus), arthritis (e.g., vasculitis, connective tissue disorders), and pulmonary hemorrhage (vasculitis, lupus) can also provide diagnostic clues.
- Large lower extremity muscle groups tender to palpation may alert the physician to a developing compartment syndrome and rhabdomyolysis.
- A complete and thorough examination is required in addition to the above to elicit possible causes of the AKI, to assess the degree of compensation, and to detect features suggestive of uremic syndrome.

Diagnostic Testing

Laboratories

Examination of urine

Urinalysis and microscopic examination of the urine sediment by a trained physician is probably the most important test in the evaluation of AKI.
The urinalysis should be bland, not reveal protein, blood, cells, or casts in prerenal azotemia and in uncomplicated postrenal failure, unless there is underlying chronic kidney disease.
The urinalysis and sediment may help to not only separate renal causes from pre- and postrenal etiologies but also to differentiate between a tubular, glomerular, or interstitial process (Table 7-2).
Presence of granular casts and tubular epithelial cells in the urine sediment correlates with prognosis for renal recovery.
If the urine dipstick tests strongly positive for blood but no red blood cells are seen, myoglobinuria or hemoglobinuria should be suspected, suggesting rhabdomyolysis or severe intravascular hemolysis leading to AKI.
It must be kept in mind that in certain diseases that affect the preglomerular blood vessels, such as thrombotic microangiopathies (e.g., thrombotic thrombocytopenic purpura or hemolytic uremic syndrome), the urine sediment may be bland despite a bona fide renal etiology.

The overall clinical presentation must therefore always be kept in mind. Indeed, the urine can be bland despite the diagnosis of ischemic ATN. This is typical in the
elderly patients with underlying dilated cardiomyopathy. Details of various types of casts and interpretations can be found in Chapters 1 and 2.

TABLE 7-2 URINALYSIS IN AKI

	UA Protein	UA Blood	FENa(%)	Sediment
Prerenal	No	No	<1	Bland; hyaline casts
Acute tubular necrosis	+	+	>1	Muddy brown granular casts; epithelial cells and epithelial cell casts
Glomerulonephritis	++	++	<1	Dysmorphic RBCs; RBC casts
Acute interstitial nephritis	+	+	>1	Eosinophils; WBCs and WBC casts; rarely, RBC casts
Postrenal	+/−	+/−	>1	Monomorphic RBCs and WBCs or crystals may be seen
AKI, acute kidney injury; FENa, fractional excretion of sodium; RBC, red blood cell; UA, urinalysis; WBC, white blood cell.