Approach Considerations
Measures to correct underlying causes of acute kidney injury (AKI) should begin at the earliest indication of kidney dysfunction. Serum creatinine does not rise to abnormal levels until a large proportion of the renal mass is damaged, because the relationship between the glomerular filtration rate (GFR) and the serum creatinine level is not linear, especially early in disease. Indeed, the rise of serum creatinine may not be evident before 50% of the GFR is lost.
It cannot be overstated that the current treatment for AKI is mainly supportive in nature; no therapeutic modalities to date have shown efficacy in treating the condition. Therapeutic agents (eg, dopamine, nesiritide, fenoldopam, mannitol) are not indicated in the management of AKI and may be harmful for the patient.
Maintenance of volume homeostasis and correction of biochemical abnormalities remain the primary goals of treatment and may include the following measures:
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Correction of fluid overload with furosemide
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Correction of severe acidosis with bicarbonate administration, which can be important as a bridge to dialysis
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Correction of hyperkalemia
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Correction of hematologic abnormalities (eg, anemia, uremic platelet dysfunction) with measures such as transfusions and administration of desmopressin or estrogens
Volume overload
Furosemide can be used to correct volume overload when the kidneys are still responsive; this often requires high intravenous (IV) doses. Furosemide plays no role in converting an oliguric AKI to a nonoliguric AKI or in increasing urine output when a patient is not hypervolemic. However, response to furosemide can be taken as a good prognostic sign.
Hyperkalemia
Hyperkalemia in patients with AKI can be life-threatening. Approaches to lowering serum potassium include the following:
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Decreasing the intake of potassium in diet or tube feeds
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Exchanging potassium across the gut lumen using potassium-binding resins
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Promoting intracellular shifts in potassium with insulin, dextrose solutions, and beta agonists
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Instituting dialysis
Nephrotoxic agents
In AKI, the kidneys are especially vulnerable to the toxic effects of various chemicals. All nephrotoxic agents (eg, radiocontrast agents, antibiotics with nephrotoxic potential, heavy metal preparations, cancer chemotherapeutic agents, nonsteroidal anti-inflammatory drugs [NSAIDs]) should be avoided or used with extreme caution. Similarly, all medications cleared by renal excretion should be avoided, or their doses should be adjusted appropriately.
A 2013 study indicated that triple therapy using NSAIDs with 2 antihypertensive medications—a diuretic along with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB)—significantly increases the risk of hospitalization for AKI, particularly in the first 30 days of treatment with these drugs. The retrospective, case-controlled study involved a cohort of 487,372 users of antihypertensive drugs between 1997 and 2008. During a mean follow-up of almost 6 years, 2215 cases of AKI were identified (incidence rate of 7 per 10 000 person-years), and each was compared with up to 10 matched controls. [86, 87]
A retrospective, observational cohort study of 500 adult patients who received vancomycin for ≥72 h found that the incidence of AKI correlated with vancomycin trough levels, ranging from 8.02% with first trough levels below 10 µg/mL to 31.82% with first trough levels of 20 µg/mL or higher On multivariate logistic regression, factors significantly associated with increased incidence of AKI included first or average trough levels above 15 µg/mL as well as methicillin-resistant Staphylococcus aureus infection and morbid obesity. [88]
Consultation
Nephrology consultation should be sought early in the course of AKI. A nephrologist can help to optimize management and avoid the preventable complications of AKI. [89]
Vasodilators
The rationale for vasodilator therapy in AKI is that improved renal perfusion may reduce kidney damage. Strong evidence in support of this approach is lacking, however.
A meta-analysis of 16 randomized studies concluded that the vasodilator fenoldopam reduces the need for renal replacement therapy and lowers the mortality rate in patients with AKI. [90] However, larger trials need to be conducted before the use of fenoldopam can be recommended.
Dopamine in small doses (eg, 1-5 mcg/kg/min) causes selective dilatation of the renal vasculature, enhancing renal perfusion. Dopamine also reduces sodium absorption; this enhances urine flow, which helps to prekvent tubular cast obstruction. However, most clinical studies have failed to establish this beneficial role of low-dose dopamine infusion, and one study demonstrated that low-dose dopamine may worsen renal perfusion in patients with AKI. [90]
Dietary Modification
Dietary changes are an important facet of AKI treatment. Restriction of salt and fluid becomes crucial in the management of oliguric kidney failure, wherein the kidneys do not adequately excrete either toxins or fluids.
Because potassium and phosphorus are not excreted optimally in patients with AKI, blood levels of these electrolytes tend to be high. Restriction of these elements in the diet may be necessary, with guidance from frequent measurements. In the polyuric phase of AKI, potassium and phosphorus may be depleted, so that patients may require dietary supplementation and IV replacement.
Calculation of the nitrogen balance can be challenging, especially in the presence of volume contraction, hypercatabolic states, GI bleeding, and diarrheal disease. Critically ill patients should receive at least 1 g/kg/day protein but should avoid hyperalimentation, which can lead to an elevated blood urea nitrogen (BUN) level and water loss resulting in hypernatremia.
Dialysis
Dialysis, especially hemodialysis, may delay the recovery of patients with AKI. Most authorities prefer using biocompatible membrane dialyzers for hemodialysis. Indications for dialysis (ie, renal replacement therapy [RRT]) in patients with AKI are as follows:
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Volume expansion that cannot be managed with diuretics
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Hyperkalemia refractory to medical therapy
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Correction of severe acid-base disturbances that are refractory to medical therapy
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Severe azotemia (BUN > 80-100)
-
Uremia
Timing and intensity
Great controversy exists regarding the timing of dialysis. Older studies suggested decreased mortality with early, versus late, initiation of dialysis, but timing of dialysis initiation has not been assessed in large, randomized, controlled trials. [91] Approaches vary widely at present.
The Acute Renal Failure Trial Network (ATN) Study found that increasing the intensity of dialysis (either intermittent or continuous) did not improve clinical outcomes (morbidity/mortality). [92] The current recommendation by Kidney Disease: Improving Global Outcomes (KDIGO) in dialysis-dependent AKI patients is to deliver a kt/v of 3.9 per week when using intermittent or extended RRT and an effluent volume of 20-25 mg/kg/hr when using continuous renal replacement therapy (CRRT). [1]
Continuous renal replacement therapy
There seems to be no difference in outcome between the use of intermittent hemodialysis and CRRT, but this question is currently under investigation. CRRT may have a role in patients who are hemodynamically unstable and who have had prolonged renal failure after a stroke or liver failure. Such patients may not tolerate the rapid shift of fluid and electrolytes caused during conventional hemodialysis.
Peritoneal dialysis
Peritoneal dialysis is not frequently used in patients with AKI. Nevertheless, it can technically be used in acute cases and probably is tolerated better hemodynamically than is conventional hemodialysis.
Prevention of Contrast-Induced Nephropathy
Saline
In patients undergoing imaging studies with contrast, prophylactic administration of IV fluid has been shown to decrease the incidence of contrast nephropathy. Although controversy exists regarding the ideal fluid, normal saline and isotonic sodium bicarbonate have proved to be effective. A normal saline solution of 1 mL/kg/h administered 6-12 hours before the procedure and then 6-12 hours after the procedure is recommended for most hospitalized patients. A recent large, randomized clinical trial did not find an additional benefit when using sodium bicarbonate over normal saline in decreasing contrast nephropathy. [93]
N-acetylcysteine
Another prophylactic agent, used with varying success, is oral N-acetylcysteine at a dosage of 1200 mg every 12 hours. This used to be administered to high-risk patients the day before performing a contrast study, but it provided borderline benefit. [94] More recent data from a large randomized trial did not demonstrate a reduction in AKI incidence using N-acetylcysteine. [93]
Statins
A meta-analysis found that statin treatment before coronary angiography can reduce contrast-induced AKI. Risk was 3.91% in the statin group versus 6.98% in the control group. On subanalysis, benefit was highly significant benefit in patients whose GFR was ≥60 mL/min (relative risk [RR] 0.40, P < 0.0001). [53]
A meta-analysis of intensive statin therapy before coronary angiography and percutaneous coronary intervention reported that in patients with acute coronary syndrome (ACS), statin treatment significantly reduced the incidence of contrast-induced AKI (RR 0.37, P < 0.0001). In patients without ACS, however, only a nonsignificant positive trend was seen (RR 0.65, P=0.07), so there is no recommendation in these patients to initiate a statin prior to receiving contrast for solely preventing contrast-related AK. [54]
Forced diuresis
A study in 92 patients undergoing coronary angiography documented a significantly increased risk of contrast-induced nephropathy in patients who received forced euvolemic diuresis with saline, mannitol, and furosemide, compared with those who received saline hydration. [95] A systematic review and meta-analysis of mannitol administration for AKI prevention concluded that mannitol is in fact detrimental for contrast-induced nephropathy. [96]
However, studies of forced diuresis with matched controlled hydration have reported a decrease in the incidence of AKI. [97, 98, 99] These studies have used a device, the RenalGuard System (RenalGuard Solutions, Inc; Milford, MA), that matches saline infusion rates to the patient’s urine output by volume and time. The device is commercially available in Europe but is still under study in the United States. [100]
ACE Inhibitors and ARBs
There are conflicting results based on randomized and non-randomized studies about the association of ACE inhibitors and ARBs with the risk for contrast-induced nephropathy (CIN); some of these studies suggested possible increased risk while others showed either no difference or even decreased risk of AKI when comparing patients who were on an ACE inhibitor or an ARB versus controls prior to angiography. [101, 102, 103, 104] Similar findings were reported in the subgroup of patients with chronic kidney disease (eGFR < 60 mL/min). [105, 106]
Long-Term Monitoring
Renal recovery in most cases is not complete, with the kidneys remaining vulnerable to the nephrotoxic effects of all therapeutic agents. Therefore, agents with nephrotoxic potential are best avoided.
Renal recovery is usually observed within the first 2 weeks, and many nephrologists tend to diagnose patients with end-stage (ie, irreversible) kidney failure 6-8 weeks after the onset of AKI. It is always better to check these patients periodically, because some patients may regain kidney function much later.
Prevention of Perioperative Nephropathy
Remote ischemic preconditioning (RIPC) is a novel investigative method for preventing perioperative AKI. The rationale is that producing ischemia in a patient’s extremity immediately before surgery will stimulate the release of endogenous protective molecules, thereby reducing the likelihood that the surgery will precipitate AKI. [107]
In a randomized trial in 240 patients who were undergoing on-pump coronary bypass grafting and were at moderate to high risk for perioperative AKI, 37.5% of patients who received RIPC developed AKI within 72 hours after surgery, compared with 52.5% of controls (P = 0.02). In patients who developed AKI, 5.8% who had received RIPC required renal replacement therapy versus 15.8% of those in the control arm (10% absolute risk reduction). [107]
In this study, remote ischemia was induced by inflating a blood pressure cuff to 200 mm Hg on one upper extremity for 5 minutes; this was repeated twice, for a total of three cycles. Control patients received three cycles of blood pressure cuff inflation to 20 mm Hg for 5 minutes. [107] However, two multicenter randomized clinical trials reported no reduction of postoperative AKI among other outcomes using RIPC. [108, 109]
Pharmacologic agents
A review of randomized, controlled trials of pharmacologic measures used to protect kidney function perioperatively found no reliable evidence that any of the following interventions are effective [110] :
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Dopamine and its analogues
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Diuretics
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Calcium channel blockers
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Angiotensin-converting enzyme (ACE) inhibitors
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N-acetylcysteine [111]
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Atrial natriuretic peptide (ANP)
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Sodium bicarbonate
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Antioxidants
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Erythropoietin (EPO)
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Specific hydration fluids
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Pigmented, muddy brown, granular casts are visible in the urine sediment of a patient with acute tubular necrosis (400x magnification).
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Photomicrograph of a kidney biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules.
Tables
Stage |
GFR Criteria |
Urine Output Criteria |
Probability |
Risk |
SCreat increased × 1.5 or GFR decreased >25% |
UO < 0.5 mL/kg/h × 6 h |
High sensitivity (Risk >Injury >Failure) |
Injury |
SCreat increased × 2 or GFR decreased >50% |
UO < 0.5 mL/kg/h × 12 h |
|
Failure |
SCreat increased × 3 or GFR decreased 75% or SCreat ≥4 mg/dL; acute rise ≥0.5 mg/dL |
UO < 0.3 mL/kg/h × 24 h (oliguria) or anuria × 12 h |
|
Loss |
Persistent acute renal failure: complete loss of kidney function >4 wk |
High specificity |
|
ESKD |
Complete loss of kidney function >3 mo |
||
ESKD—end-stage kidney disease; GFR—glomerular filtration rate; SCreat—serum creatinine; UO—urine output Note: Patients can be classified by GFR criteria and/or UO criteria. The criteria that support the most severe classification should be used. The superimposition of acute on chronic failure is indicated with the designation RIFLE-FC; failure is present in such cases even if the increase in SCreat is less than 3-fold, provided that the new SCreat is greater than 4.0 mg/dL (350 µmol/L) and results from an acute increase of at least 0.5 mg/dL (44 µmol/L). |
|||
Stage |
Serum Creatinine Criteria |
Urine Output Criteria |
1 |
Increase of ≥0.3 mg/dL (≥26.4 µmol/L) or 1.5- to 2-fold increase from baseline |
< 0.5 mL/kg/h for >6 h |
2 |
> 2-fold to 3-fold increase from baseline |
< 0.5 mL/kg/h for >12 h |
3* |
> 3-fold increase from baseline, or increase of ≥ 4.0 mg/dL (≥35.4 µmol/L) with an acute increase of at least 0.5 mg/dL (44 µmol/L) |
< 0.3 mL/kg/h for 24 h or anuria for 12 h |
*Patients who receive renal replacement therapy (RRT) are considered to have met the criteria for stage 3 irrespective of the stage they are in at the time of RRT. |
||
