A 72-year-old-man, recently treated for resistant Escherichia coli urosepsis, is sent to the emergency department from his nursing home because of new left-sided hemiparesis. He has a past history of chronic kidney disease (CKD), hypertension, and osteoarthritis. Medications include lisinopril, 20 mg/d and naproxen, 400 mg twice a day. On physical examination, he has a low-grade fever (100.4°F), his initial blood pressure is 130/66 mm Hg, and his heart rate is 88 beats per minute (bpm). His respiratory rate is 28 breaths per minute, and his hemoglobin oxygen saturation by pulse oximetry is 89% on supplemental oxygen by nasal cannula. He has a flaccid left hemiparesis and is stuporous.
He undergoes computed tomography (CT) of the head, which shows no hemorrhage. He has a CT angiogram of the chest, which shows no evidence of pulmonary embolism. His temperature rises quickly to 102°F, the blood pressure falls to 78/50 mm Hg, and the heart rate rises to 120 bpm. His initial white blood cell count is 29.9 with 44% bands, and a urine analysis shows pyuria and bacteriuria. Treatment is initiated with vancomycin, gentamicin, and cefepime. Intravenous normal saline is given by rapid infusion, according to the sepsis protocol. The patient is intubated and placed on mechanical ventilation. The plasma creatinine, 1.6 mg/dL on arrival, increases to 2.0 mg/dL by the following day, and the blood urea nitrogen (BUN) rises from 22 mg/dL to 36 mg/dL. Urine output has been about 20 mL/h for the past 8 hours.
The patient’s daughter, a registered nurse, is in the room when you make rounds. She is aware of her father’s history of CKD and wants to know if he is in “kidney failure.” What do you tell her?
Although acute renal failure (ARF) is conceptually simple to characterize as “an abrupt decrease in renal function,” a commonly accepted definition of ARF emerged only very recently. Absence of a uniform definition of ARF substantially hampered research and limited comparisons between different populations. Therefore, in 2002, an international group of experts developed a consensus definition of ARF—using changes in plasma creatinine concentration and hourly urine output—and gave it the acronym RIFLE (Risk, Injury, Failure, Loss, and End-stage).1 Many investigators have since validated that classification scheme in various clinical settings, and a recent meta-analysis showed a graded impact on mortality by RIFLE stage.2
The RIFLE criteria represented real progress in the field of ARF research. Nonetheless, shortcomings of RIFLE were soon recognized: there was frequent discordance between the stage assignment by the plasma creatinine and the urine output criteria.3 In addition, smaller changes in plasma creatinine (≥ 0.3 mg/dL)4 over a short time (48 hours) were shown to be associated with important clinical outcomes.5
With the goal of refining the ARF definition, a second international group met in 2004. Their consensus produced the Acute Kidney Injury Network (AKIN) criteria.6 They recommended that the term acute kidney injury (AKI) replace ARF, to reflect the fact that failure is at the extreme end of a broad spectrum of injury to the kidney.6 They defined stages of AKI based on smaller changes in plasma creatinine concentration over a shorter period of time. They stipulated that the AKIN staging was only to be applied once urinary tract obstruction was excluded or relieved and the patient’s hemodynamics and volume status were optimized. The most recent and comprehensive definition of AKI comes from KDIGO (Kidney Disease: Improving Global Outcomes).7 Table 47-1 compares the RIFLE, AKIN, and KDIGO criteria.
| Definitions | ||||
|---|---|---|---|---|
| RIFLEa | AKINb | KDIGO | ||
| Risk | GFR ↓ 25% from baseline PCr ↑ 1.5-2 times baseline UOP < 0.5 mL/kg/h for > 6 h | Stage 1 | PCr ≥ 0.3 mg/dL, or PCr ↑ 1.5-2 times baseline UOP < 0.5 mL/kg/h for > 6 h | PCr ≥ 0.3 mg/dLa PCr ↑ 1.5-2 times baselineb UOP < 0.5 mL/kg/h for > 6 h |
| Injury | GFR ↓ 50% from baseline PCr ↑ 2 times baseline UOP < 0.5 mL/kg/h for > 12 h | Stage 2 | PCr ↑ 2-3 times baseline UOP < 0.5 mL/kg/h for > 12 h | PCr ↑ 2-3 times baselineb UOP < 0.5 mL/kg/h for > 12 h |
| Failure | GFR ↓ 75% PCr ↑ 3 times PCr > 4 mg/dL or acute ↑ 0.5 mg/dL UOP < 0.3 mL/kg/h for ≥ 24 h | Stage 3 | PCr ↑ 3 times PCr > 4 mg/dL or acute ↑ 0.5 mg/dL UOP < 0.3 mL/kg/h for ≥ 24 h Acute RRT | PCr ↑ 3 times PCr > 4 mg/dL with either ↑ 0.3 mg/dL/48 hours OR PCr ↑ 1.5 times baseline/7 days UOP < 0.3 mL/kg/h for ≥ 24 h Acute RRT |
| Lossc | Dialysis dependence > 4 weeks | |||
| ESRDc | Dialysis dependence > 3 months | |||
In studies of critically ill patients, all criteria agreed substantially in the classification of AKI and were similarly correlated with mortality.8,9 (Whether mortality is the proper outcome by which to validate a definition of AKI is open to question.10)
It is important to recognize that these definitions of ARF or AKI were devised to facilitate research. From a practical standpoint, clinicians will diagnose AKI by a rise in the plasma creatinine concentration and BUN over hours to days.11 Using this practical criterion, or any of the consensus definitions, our patient has AKI.
The patient’s daughter wants to know how common it is to develop AKI in this setting and whether her father was at particular risk.
Most of the research in the field of AKI has focused on critically ill and hospitalized patients. Recently it has been recognized that a substantial proportion of patients have community-acquired AKI.12 Therefore, the true incidence of AKI has been difficult to estimate. In critically ill patients, AKI is common, and its frequency increases with severity of illness.8 Overall, its occurrence varies from 5% in all hospitalized patients,13 10% to 20% in patients after cardiac surgery,14 20% in patients with sepsis, and up to 50% in those with positive blood cultures.15 AKI was diagnosed in 23% of patients with acute subarachnoid hemorrhage16 and in 14% to 27% after acute stroke.17-19
AKI occurs in approximately 15% to 30% of patients with acute stroke.19 Risk factors for AKI in patients with strokes include age, underlying CKD, heart disease, and stroke type (hemorrhagic more than ischemic19) and severity.17,18 In patients with subarachnoid hemorrhage, poor Hunt and Hess score on admission and higher admission plasma creatinine concentration were associated with AKI (Table 47-2).16 One recent study identified hypernatremia as an additional risk factor for AKI in patients with subarachnoid hemorrhage, with each increase of 1 mEq/L in plasma sodium concentration associated with a 5% increased risk of AKI.20
| Clinical Setting | Incidence | Risk Factor | Impact |
|---|---|---|---|
| Stroke | 14-27% | CKD Age Stroke type/severity | ↑ 30-day and long-term mortality Short- and long-term disability |
| Subarachnoid hemorrhage | 23% | Poor H&H scale (IV-V) Higher admission PCr Hypernatremia | ↑ Mortality and cardiovascular outcomes |
| Rhabdomyolysis induced by seizures | Rare | Prolonged seizure Status epilepticus CK > 15,000 Volume depletion | No long-term impact Might require short-term RRT |
| CT angiography | 3-3.5% | CKD | No RRT |
| Mannitol | 0-11% | CKD Higher mannitol dose | Unclear |
The patient’s daughter wants to know whether the AKI itself will affect her father’s prognosis.
AKI is associated with worse outcomes in critically ill patients as it aggravates morbidity, neurologic disability, and both short- and long-term mortality.19,21 AKI has both direct effects (eg, volume overload, electrolyte and acid-base derangements, uremia) and effects on other organs at distances both in space and time.
Animal data show that AKI induces or worsens acute lung injury by increasing pulmonary vascular permeability and neutrophil infiltration,22 via cytokine production.23-25 Moreover, it leads to cardiac dysfunction by stimulating inflammation,26 fibrosis,27 and apoptosis.22 The neurologic system may be affected by AKI, with reported increases in cerebral vascular permeability, inflammation, and functional impairment.28 In addition, uremic toxins also have deleterious effects on the bone marrow and on liver function.29 Thus, it is not surprising that AKI is reported to have an independent association with mortality.15,30-32 This association, however, does not equate with causation; current evidence is inconclusive as to whether patients die from, or die with, AKI.
Until recently, it was generally thought that if patients survived their episode of AKI, their renal function was likely to recover to its baseline. It is now increasingly apparent that AKI predisposes to the development of CKD30,33 and end-stage (dialysis-dependent) renal disease (ESRD),33-35 the latter being more common in patients with underlying CKD and in older patients. Longer duration of AKI may be an additional risk factor for worse outcomes.36
The etiology of AKI can be divided into prerenal, postrenal, and renal causes. Prerenal failure is due to altered renal hemodynamics, such that if normal renal perfusion were restored, the AKI would resolve immediately. Prerenal states often are evident by history (eg, history of negative fluid balance or hemorrhage) or physical examination. It is important to recognize, however, that physical assessment of volume status may be quite unreliable,37 and perhaps all the more so in critically ill patients, where the usual indices (vital signs, edema) may be misleading. In oliguric patients (urine output < 0.5 mL/kg/h), the fractional excretion of sodium (FENa) may improve diagnostic accuracy: a FENa < 1% is evidence of avid sodium reabsorption by functional renal tubules and is consistent with a prerenal state.38,39 FENa, expressed as percent, is calculated from a “spot” urine and simultaneous plasma sample as follows:
where UNa is the urine sodium concentration, and PNa is the plasma sodium concentration (both in mEq/L), UCr is the urine creatinine concentration, and PCr is the plasma creatinine concentration (both in mg/dL).
FENa is not a reliable descriminator between prerenal and intrinsic renal disease. It may be high in a volume-depleted patient who is undergoing diuresis38 and may be low with some causes of intrinsic renal failure, most notably radiocontrast-induced40 and pigmenturia-associated kidney injury.41 FENa in the setting of sepsis is often < 1%, even in patients who ultimately require dialsyis.42
The plasma BUN:creatinine ratio, long touted as a discriminator of prerenal from intrinsic kidney injury, appears to be of little clinical utility.43,44 Newer biomarkers of kidney injury are under active investigation, but their use in clinical medicine has yet to be defined.45
Prerenal failure due to “renal autoregulatory failure” is a common phenomenon. The kidney depends on a variety of humoral mediators of vascular tone—among which are components of the renin-angiotensin system and vasodilatory prostaglandins—to autoregulate its blood flow over a wide range of mean arterial pressure and to autoregulate its glomerular filtration rate (GFR) over a wide range of renal blood flow. This elaborate autoregulation serves to maintain GFR in states of hemodynamic compromise.46 Medications that interrupt renal autoregulation (eg, angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers, and prostaglandin-synthesis inhibitors) lead to prerenal AKI in the setting of modest volume depletion or hypotension that would otherwise be well tolerated.47 Our patient was taking both an ACE inhibitor and a cyclo-oxygenase (COX) inhibitor and so is at risk for prerenal failure.
Postrenal failure is due to obstruction of the urinary tract distal to the renal collecting ducts. Common causes are listed in Table 47-3. In elderly men, the most common cause is bladder outlet obstruction from prostate enlargement. Stroke may amplify the tendency to have bladder-outlet obstruction. After stroke, bladder dysfunction is common, and bladder-emptying disorders may be more common after ischemic than hemorrhagic stroke.48 Other factors that may predispose to bladder-outlet obstruction include underlying autonomic neuropathy (eg, from diabetes mellitus) and medications with anticholinergic activity. Renal ultrasound has > 95% sensitivity for detecting urinary tract obstruction, manifested by dilation of the urinary collecting system (hydronephrosis with or without hydroureter).49
|
The classification of intrinsic or renal parenchymal causes of AKI follows a histologic nosology (Table 47-3). Diagnosis is guided by urinalysis with microscopic examination of the sediment (Table 47-4).50
| Lesion | Urine Dipstick | Urine Sediment |
|---|---|---|
| ATN | Sp. gr. 1.010-1.020 1+ protein reaction | Many granular casts “Dirty” or “dusty” background |
| AGN | Sp. gr. 1.020-1.030 1-3+ protein reaction > 2+ heme reaction | RBCs > WBCs Dysmorphic RBCs RBC casts |
| AIN | Sp. gr. 1.010-1.020 1+ protein reaction | WBCs > RBCs WBC casts Eosinophiluria |
| Vasculitis | Sp. gr. variable 1-2+ protein reaction Variable heme reaction | Bland sediment or RBCs |
| Intratubular obstruction | Sp. gr. variable Variable heme reaction | Crystalluria |
Among the types of intrinsic renal failure, acute tubular necrosis (ATN) is by far the most common in the intensive care unit.51,52 ATN may be caused by a nephrotoxic or ischemic insult, or a combination of the two.52,53 Common nephrotoxins include radiocontrast dye, aminoglycoside antibiotics, amphotericin and endogenous pigments such as myoglobin and free hemoglobin. Ischemic insults include shock, sepsis, and major vascular surgery, which may compromise renal perfusion. In a patient suspected of having ATN, the likelihood of having ATN is proportional to the number of granular casts on urine microscopy; the positive predictive value of finding any casts approaches 100%.50
Of particular relevance to the neurologic intensive care unit (NeuroICU)—but not a factor in the current case—is the role of mannitol in the development of AKI. Mannitol infusion for treatment of increased intracranial pressure (ICP) is recognized to be associated with AKI,54,55 especially with the use of very high doses.55,56 High-dose mannitol may have a vasocontrictive effect and also induces “osmotic nephrosis” in renal proximal tubule cells.57 AKI also has been reported with hypertonic saline infusion for treatment of increased ICP.58
Acute glomerulonephritis (AGN) and acute renal vasculitis are rare causes of AKI in critically ill patients.15,59 AGN or renal vasculitis in a patient with a critical brain disorder should trigger a search for a systemic disease that might explain both phenomena, such as systemic lupus erythematosus or cryoglobulinemia. The suggested serologic evaluation of a patient suspected of having AGN or vasculitis is presented in Table 47-5.
C3, C4 complement components ANA, anti-ds-DNA Anti-GBM antibody ANCA antibodies (MPO, PR3) Hepatitis serologies Cryoglobulins |
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