INTRODUCTION — Acute kidney injury (AKI) due to ischemic acute tubular necrosis (ATN) typically lasts 7 to 21 days [1], with most patients returning to or near their previous baseline level of kidney function as the necrotic tubular cells regenerate.
Possible preventive and therapeutic measures for ischemic ATN will be reviewed here.
The pathogenesis and prognosis of ATN are discussed separately. (See "Kidney and patient outcomes after acute kidney injury in adults" and "Pathogenesis and etiology of ischemic acute tubular necrosis".)
ACUTE KIDNEY INJURY (AKI) VERSUS ACUTE TUBULAR NECROSIS (ATN) — AKI is characterized by an acute reduction of glomerular filtration rate (GFR) and defined by a rise in the serum creatinine concentration or a decline in urine output that has developed within hours to days (table 1). (See "Definition and staging criteria of acute kidney injury in adults".)
AKI is commonly, though not always, caused by ATN, particularly among critically ill hospitalized patients.
Other causes of AKI are discussed elsewhere. (See "Evaluation of acute kidney injury among hospitalized adult patients", section on 'Major causes and classification of AKI'.)
ATN is caused by ischemia, nephrotoxins, and sepsis and is often multifactorial. In patients with septic shock, it is often not clear whether ATN is caused by ischemia or sepsis.
PATHOPHYSIOLOGY — The pathophysiology of ischemic ATN is discussed elsewhere. (See "Pathogenesis and etiology of ischemic acute tubular necrosis".)
PREVENTION — The first step in preventing ischemic ATN is to identify the patient at increased risk. In patients at risk for or who may have early ischemic ATN, we optimize volume status with intravenous (IV) fluids (if necessary), with the goal of optimizing cardiac preload, cardiac output, and ultimately renal blood flow.
Additional measures include the avoidance of nephrotoxins and hypotension, which is a surrogate for reduced renal blood flow. Inotropes may be used in clinically significant hypotension refractory to volume optimization. (See "Use of vasopressors and inotropes".)
Identification of high-risk patients — In settings associated with ischemic ATN (including high-risk surgical procedures), patients at increased risk should be identified and carefully assessed.
Procedures and conditions that are associated with ATN include:
●Major surgery (particularly cardiac surgery, abdominal aortic aneurysm surgery, surgery to correct obstructive jaundice, emergent surgery, or surgical re-exploration)
●Sepsis
●Marked hypovolemia
●Severe pancreatitis
●Cardiogenic shock
●Hemorrhagic shock
All patients who are undergoing major surgery or who have sepsis, marked hypovolemia, or severe pancreatitis should be evaluated for underlying ATN risk.
The following comorbidities increase the risk for ischemic ATN [2-9]:
●Chronic kidney disease (CKD; either reduced estimated glomerular filtration rate [eGFR] or proteinuria with normal eGFR)
●Severe atherosclerosis
●Diabetes mellitus, even in the absence of microalbuminuria or reduced eGFR
●Advanced malignancy, obesity, and/or poor nutrition
●Heart failure
All patients with the comorbidities listed above who are undergoing major surgery or have sepsis, hypovolemia, or pancreatitis should have interventions designed to reduce ATN risk. (See 'Interventions to decrease risk' below.)
Interventions to decrease risk — Patients who are at high risk for ischemic ATN should have interventions to change modifiable risk factors, such as nephrotoxins, hyperglycemia, and hypovolemia/hypervolemia. These interventions include optimizing volume status, avoiding or stopping nephrotoxins, if possible, and dose adjustment for drugs excreted by the kidney. Using these preventive measures can improve outcomes in cardiac surgery-associated acute kidney injury (AKI) [10,11]. In one study for example, implementing the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines strategy, which included avoidance of nephrotoxic agents, discontinuation of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), avoidance of hyperglycemia after surgery, and careful monitoring of serum creatinine, urine output, and volume status reduced the rate of AKI in high-risk patients after cardiopulmonary bypass surgery (55 versus 72 percent) [10].
Obvious nephrotoxins include aminoglycosides, amphotericin, nonsteroidal antiinflammatory agents (NSAIDs), and radiocontrast agents. Vancomycin alone [12] or in combination with piperacillin/tazobactam [13] may also increase the risk of ATN.
●(See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)
●(See "Amphotericin B nephrotoxicity".)
●(See "NSAIDs: Acute kidney injury".)
●(See "Prevention of contrast-associated acute kidney injury related to angiography".)
The management of high-risk patients who are on ACE inhibitors and ARBs is not always clear. These agents are held in patients with low blood pressure, which is a common characteristic of many conditions that predispose to ATN. Among high-risk patients who are not hypotensive, we generally stop ACE inhibitors and ARBs if patients are receiving other nephrotoxins, particularly in the setting of pancreatitis or sepsis. (See 'Identification of high-risk patients' above.)
The management of high-risk patients who are taking ACE inhibitors and ARBs preoperatively is discussed elsewhere. (See "Perioperative medication management", section on 'ACE inhibitors and angiotensin II receptor blockers'.)
Implementation of strategies to prevent AKI is often hampered by a delay in diagnosis, and frequently the diagnosis of AKI is missed by the clinicians who fail to notice a small change in serum creatinine. Automated alerts have emerged as a modality to alter clinician behavior, although these have not been shown to improve survival or reduce the need for kidney replacement therapy (KRT) [14-16].
We do not administer any pharmacologic agent (such as diuretics or dopamine/fenoldopam) for the prevention of ischemic ATN. Although some pharmacologic agents have shown promise in the prevention of ischemic ATN, conflicting results have been reported in different studies or their efficiency is yet to be confirmed. (See 'Experimental and unproven measures for the prevention of ischemic ATN' below.)
Optimizing volume status and maintaining hemodynamic stability — Among all patients at increased risk for ATN, we optimize volume status with IV fluids (if necessary) and maintain adequate hemodynamic status to ensure renal perfusion. (See "Treatment of severe hypovolemia or hypovolemic shock in adults".)
The exact approach varies based upon patient characteristics and the particular clinical setting.
The rationale for optimizing volume status relies on numerous well-designed studies that showed that volume expansion prior to exposure to iodinated radiocontrast agents or nephrotoxins lowers the risk of ATN. Details concerning the studies that have examined this issue are available in separate topic reviews:
●(See "Prevention of contrast-associated acute kidney injury related to angiography".)
●(See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)
●(See "Cisplatin nephrotoxicity", section on 'Intravenous saline'.)
●(See "Amphotericin B nephrotoxicity", section on 'Salt loading'.)
By comparison, a paucity of data exists concerning the efficacy of volume expansion to lower the risk of ischemic ATN, and many of the studies may reflect interventions that target early secondary prevention (ie, injury has occurred already) rather than true primary prevention. The best data are provided by a meta-analysis of 20 randomized, controlled trials that investigated the renoprotective effects of perioperative hemodynamic optimization among 4220 surgical patients who were undergoing elective or emergent procedures [17].
Postoperative AKI was reduced by perioperative hemodynamic optimization compared with the control group (odds ratios [OR] 0.64, 95% CI 0.50-0.83). This benefit was seen when optimization was initiated preoperatively, as well as intraoperatively and postoperatively, suggesting that ischemic injury can be prevented or effectively treated with prompt reperfusion.
Fluid administration should be assessed at regular intervals intraoperatively and postoperatively. (See "Maintenance and replacement fluid therapy in adults".)
Inotropes should be reserved for consideration in patients with remarkable hemodynamic instability despite adequate volume repletion. (See "Use of vasopressors and inotropes".)
The preferred choice of IV fluids for volume expansion, such as crystalloid (eg, isotonic saline, Lactated Ringer's, or bicarbonate solution) or synthetic colloid (eg, hydroxyl ethyl starch), is unclear and depends on the clinical scenario [18-20].
●(See "Management of acute pancreatitis", section on 'Initial management'.)
Avoiding nephrotoxins — Obvious nephrotoxins, such as aminoglycosides, amphotericin, radiocontrast agents, and NSAIDs, should be avoided, if possible, among patients who are at high risk for ATN either because of comorbidities or because of characteristics of the planned procedure. The use of ACE inhibitors and ARBs is discussed elsewhere. (See 'Interventions to decrease risk' above and "Perioperative medication management", section on 'ACE inhibitors and angiotensin II receptor blockers'.)
Procedure-related measures — As noted, the major surgeries most commonly associated with ATN are cardiac surgery, particularly valve surgery, abdominal aortic aneurysm surgery, and surgery to correct obstructive jaundice. (See 'Identification of high-risk patients' above.)
Among patients undergoing cardiopulmonary bypass surgery, multiple measures to decrease the risk of ATN have been evaluated including cardioplegia, temperature manipulation, use of specific materials to decrease inflammation, pulsatile perfusion via an intra-abdominal balloon pump, and off-pump surgery [2].
●Off-pump cardiopulmonary bypass surgery – Some [21-23], though not all [24-26], studies have suggested that there is a benefit to off-pump cardiopulmonary bypass surgery in decreasing the risk of mild AKI but not severe, dialysis-requiring AKI, especially among patients with underlying CKD.
A 2010 meta-analysis including 22 randomized trials (4819 patients) found that off-pump coronary artery bypass grafting (CABG) was associated with a 40 percent lower odds of postoperative AKI and a nonstatistically significant 33 percent lower odds of dialysis requirement, with no discernible mortality benefit [27].
No difference in effect was seen based on preoperative serum creatinine [28].
The best data subsequent to this meta-analysis are from the CABG Off or On Pump Revascularization Study (CORONARY) trial, which randomly assigned 4752 patients scheduled to undergo isolated CABG surgery to either an off- or on-pump procedure [29]. The use of off-pump CABG did not reduce the risk of the primary composite outcome, which included dialysis-requiring new-onset kidney injury at 30 days, although it did reduce the risk of mild AKI at 30 days. The CORONARY trial is discussed at length elsewhere. (See "Off-pump and minimally invasive direct coronary artery bypass graft surgery: Clinical use", section on 'Outcomes'.)
Subgroup analysis of the CORONARY trial showed that the relative risk (RR) reduction conferred by off-pump surgery was greater among patients with baseline eGFR <60 mL/min/1.73 m2 CKD (RR 0.63) compared with those with eGFR ≥60 mL/min/1.73 m2 (RR 0.98) [30]. However, there was no difference between groups in kidney function at one year, even in subgroup analysis of patients with CKD.
●Pulsatile perfusion ─ Pulsatile perfusion via an intra-abdominal balloon pump using an automatic mode (in which the pump continues to function throughout cardioplegic arrest) may protect kidney function, although studies that have examined this are limited due in part to inaccurate estimates of kidney function.
In one study that compared pulsatile perfusion using the automatic mode versus nonpulsatile perfusion among patients with mild to moderate CKD (eGFR >45 mL/min/1.73 m2), a higher eGFR was observed with pulsatile perfusion (74 versus 58 mL/min/1.73 m2), with a greater difference observed in those with eGFR 45 to 60 mL/min/1.73 m2 [4].
Experimental and unproven measures for the prevention of ischemic ATN — Multiple pharmacologic agents have been studied for the prevention of ischemic ATN. Selected measures are discussed here.
Diuretics — As noted, we do not administer diuretics as prophylaxis for ischemic ATN [31-33]. This is consistent with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [34].
Although animal models of AKI have suggested that loop diuretics and mannitol minimize kidney injury [35-37], this has not been shown in clinical studies. No benefit and a possible detrimental effect of furosemide were shown in a study in which 126 patients with normal kidney function were randomly assigned to a continuous infusion of furosemide, low-dose dopamine, or isotonic saline, all initiated at the beginning of elective cardiac surgery and continued for 48 hours [31]. The renal outcomes between patients given dopamine and isotonic saline were equivalent. However, furosemide resulted in an increase in both the plasma creatinine concentration (an average maximal change of 0.3 mg/dL versus 0.1 mg/dL [27 versus 9 micromol/L] for both dopamine and saline) and in the incidence of AKI (15 versus 2 and 0 percent); AKI was defined as an increase in the plasma creatinine of >0.5 mg/dL (44 micromol/L).
Uncontrolled studies of patients with recent onset of oliguria and kidney function impairment (who may not yet have established AKI) have shown that patients who respond to furosemide and dopamine or mannitol with an increase in urine output have a better outcome than nonresponders [38-40]. However, the responders may simply have had less severe disease, as evidenced by a shorter duration of oliguria (<24 hours), a higher urine output, and a higher urine osmolality (suggesting better preservation of tubular function). Additionally, a multicenter, prospective, observational study including 17 Finnish intensive care units (ICUs) suggested that pre-ICU use of diuretics was an independent risk factor for development of AKI (OR 1.68, 95% CI 1.41-2.00) [41].
Furosemide-induced diuresis and preservation of intravascular volume through an automated matched hydration system has been tested in randomized, controlled trials with mixed results in the prevention of radiocontrast-induced nephropathy [42-44]. More adequately powered studies are needed to better understand the role of furosemide-induced diuresis in the prevention of radiocontrast-induced nephropathy. (See "Prevention of contrast-associated acute kidney injury related to angiography".)
Dopamine, fenoldopam, atrial natriuretic factor — We do not use dopamine, fenoldopam, or atrial natriuretic factor to prevent ischemic ATN. This is consistent with the 2012 KDIGO guidelines [34].
●Dopamine – Numerous placebo-controlled studies and meta analyses have found that low-dose dopamine is ineffective in preventing ATN [31,45-49].
In addition, there is some evidence that low-dose dopamine may cause harm by reducing renal blood flow in patients with early ischemic ATN, in contrast to the typical dopamine-induced increase in renal blood flow observed in normal subjects [48].
There are potential risks associated with low-dose dopamine, including tachycardia, arrhythmias (particularly among cardiac surgery patients), myocardial ischemia, and intestinal ischemia (due to precapillary vasoconstriction), which might promote bacterial translocation from the intestinal lumen into the systemic circulation [39,50,51]. In one study in cardiac surgery patients, for example, low-dose dopamine was independently associated with an increased risk of postoperative atrial fibrillation [50].
●Fenoldopam – Clinical equipoise exists for the use of the dopamine receptor-1 agonist, fenoldopam, to prevent ischemic AKI, and we believe further adequately powered randomized trials are warranted before it is used.
Some studies have shown benefit, while others have not confirmed a clinically relevant benefit [52-60]. These trials have been limited in part due to small sample size and design. The most informative studies are discussed here:
•In a 2007 meta-analysis that included 16 randomized studies with a total of 622 patients administered fenoldopam and 668 given placebo or other therapy (principally low-dose dopamine), fenoldopam reduced the risk for AKI (OR 0.43, 95% CI 0.32-0.59), need for KRT (OR 0.54, 95% CI 0.34-0.84), and in-hospital death (OR 0.65, 95% CI 0.45-0.91) [58].
Limitations with this analysis included the lack of consistent criteria for initiating KRT, heterogeneity of enrolled patients (both surgical and nonsurgical critically ill patients), lack of placebo control in six studies, and inability to independently verify the change in glomerular filtration with infusion of fenoldopam.
•This meta-analysis was followed by the largest randomized trial in critically ill patients with AKI, which showed no difference in KRT, length of ICU stay, or mortality but showed increased incidence of hypotension in patients receiving fenoldopam [61]. This study was stopped early due to futility. The limitations of the study were ill-defined criteria for initiating KRT, and AKI was defined by the RIFLE classification, rather than more recent criteria.
•In a subsequent systematic review and meta-analysis that included six randomized, controlled trials of 507 surgical patients (undergoing cardiovascular surgery, partial nephrectomy, and liver transplant), fenoldopam reduced the risk of AKI (OR 0.46, 95% CI 0.27-0.79) [62]. However, there was no difference in the risks of KRT and hospital mortality [62]. Although there was little statistical evidence of heterogeneity among the randomized trials, there was heterogeneity in the definition of AKI, and results may not be extrapolated to other surgeries. In addition, most of the randomized trials were underpowered, and mortality data were available for 130 patients only.
●Atrial natriuretic peptides (ANP) – We do not use natriuretic peptides for prophylaxis against ATN, although some studies suggest benefit [63-65]. Natriuretic peptides block tubular reabsorption of sodium, vasodilate afferent arterioles, and inhibit the renin-angiotensin system.
Among the best data is a meta-analysis that included 13 randomized trials and 934 adult patients with cardiovascular surgery-associated kidney dysfunction [63]. A subgroup analysis showed a reduction in dialysis-requiring AKI in patients receiving ANP compared with controls (OR 0.32, 95% CI 0.15-0.66). Interpretation of this meta-analysis is limited by the small size and variable quality of the included trials.
A randomized trial that was published after the meta-analysis showed that, among 285 patients with CKD who were undergoing on-pump CABG, patients who received ANP had a smaller postoperative rise in serum creatinine compared with control (1.27 versus 1.46 mg/dL) [66]. In the early postoperative period, fewer patients in the ANP group required dialysis compared with control (one versus eight). At one year, only one patient from the ANP group was on dialysis versus five in the placebo group. At the time of publication, the study drug, carperitide, was only available in Japan, although the authors suggest that nesiritide may be equivalent [66].
Vasopressin — One randomized trial evaluated the early use of vasopressin to reduce the risk of kidney failure compared with norepinephrine in patients with septic shock. The results demonstrate that the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days and should not be used in place of norepinephrine [67]. (See "Use of vasopressors and inotropes", section on 'Vasopressin and analogs'.)
N-acetylcysteine — We agree with the 2012 KDIGO guidelines that recommend not administering N-acetylcysteine to patients to prevent ischemic ATN [34].
Several systematic reviews and meta-analyses have examined the efficacy of N-acetylcysteine in the prevention of AKI following surgery [68-70]. A 2009 meta-analysis that included 10 studies and 1193 patients found that N-acetylcysteine, compared with placebo, did not prevent dialysis-requiring AKI (OR 1.04, 95% CI 0.45-2.37) or an increase in serum creatinine concentration greater than 25 percent (OR 0.84, 95% CI 0.64-1.11) [70].
Two randomized trials published after the meta-analysis showed no benefit of N-acetylcysteine compared with placebo in decreasing the risk of AKI in patients with new-onset hypotension [71] or undergoing off-pump coronary artery bypass surgery compared with placebo [72].
Intensive insulin therapy — We do not use intensive insulin therapy to prevent ATN among critically ill patients.
A number of studies have suggested that intensive insulin therapy may provide a renoprotective effect, although AKI was always a secondary outcome in these trials [73-77].
A 2007 meta-analysis that was performed on five studies (only three randomized trials; the other two were nonconcurrent prospective cohort studies) evaluated the effect of insulin therapy on outcomes including AKI among critically ill patients [78]. Although not statistically significant, intensive insulin therapy (target glucose of 80 to 100 mg/dL [4.4 to 5.6 mmol/L]) lowered the risk for dialysis compared with conventional insulin therapy (target glucose of 180 to 200 mg/dL [10 to 11 mmol/L]; RR 0.65, 95% CI 0.40-1.05).
However, the largest trial was published subsequent to the meta-analysis and showed no benefit of intensive insulin [77]. This was the multicenter Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, which randomly assigned 6104 medical and surgical patients to either intensive therapy (target blood glucose level of 81 to 108 mg/dL [4.5 to 6 mmol/L]) or conventional glucose control (target blood glucose of <180 mg/dL [<10 mmol/L]) [77]. There was no difference in the percentage of patients requiring KRT or in the duration of KRT. Other outcomes of this trial are discussed separately.
Intensive insulin therapy is also associated with adverse effects. In a multicenter randomized, controlled trial of patients with severe sepsis, intensive insulin therapy was associated with serious adverse events such as hypoglycemia, and the trial was stopped early due to safety reasons [79].
Other outcomes associated with intensive insulin therapy are discussed separately. (See "Glycemic control in critically ill adult and pediatric patients".)
Remote ischemic preconditioning — Remote ischemic preconditioning (RIPC) is a minimally invasive procedure by which the deliberate induction of transient, nonlethal ischemia of an organ protects against subsequent ischemic injury of another organ. (See "Prevention of contrast-associated acute kidney injury related to angiography", section on 'Remote ischemic preconditioning' and "Myocardial ischemic conditioning: Clinical implications", section on 'Remote ischemic preconditioning'.)
We do not use RIPC to prevent ischemic ATN.
Numerous clinical trials and meta-analyses have examined the effects of RIPC with conflicting results [80-89]. In addition, the safety of repeated episodes of transient ischemia has not been conclusively demonstrated [90].
The best data are from a meta-analysis of 28 randomized clinical trials and 6851 patients [91]. RIPC had no effect on the reduction of serum creatinine on postoperative day 1 (14 studies, 1022 participants), day 2 (9 studies, 770 participants), and day 3 (6 studies, 417 participants) [91]. RIPC also had no effect on need for dialysis (13 studies, 2417 participants), length of hospital stay (8 studies, 920 participants), or all-cause mortality (24 studies, 4931 participants).
Other — Other experimental measures include the administration of sodium bicarbonate, statins, corticosteroids and erythropoietin.
●Sodium bicarbonate – We do not give sodium bicarbonate to prevent ischemic ATN. Although numerous clinical trials and meta-analyses have studied the effect of sodium bicarbonate on contrast-induced AKI, there are fewer studies on the prevention of ischemic ATN. (See "Prevention of contrast-associated acute kidney injury related to angiography".)
An early study suggested that sodium bicarbonate may prevent ischemic ATN. In this pilot, double-blinded, randomized trial, the perioperative administration of sodium bicarbonate compared with sodium chloride reduced the risk of ATN among patients undergoing cardiopulmonary bypass-requiring cardiac surgery (OR 0.43, 95% CI 0.19-0.98) [92]. There was also an attenuated rise in urinary neutrophil gelatinase-associated lipocalin (NGAL, which is a putative biomarker for AKI) in the sodium bicarbonate group but no difference between groups in the requirement for KRT. (See "Investigational biomarkers and the evaluation of acute kidney injury", section on 'Neutrophil gelatinase-associated lipocalin (NGAL)'.)
However, subsequent studies suggested no benefit and, potentially, harm:
•A phase-IIb, multicenter, randomized trial showed no benefit of sodium bicarbonate compared with sodium chloride on the incidence of AKI following cardiac bypass [93]. Notably, hypertonic infusions were used in this study rather than hypotonic or isotonic solutions, which were used in the first trial [92].
•A larger randomized trial that used an identical protocol to that used in the first study cited above [92] demonstrated a higher rate of AKI in the sodium bicarbonate compared with sodium chloride group (47.7 versus 36.4 percent), although this difference was not statistically significant in the adjusted analysis [94].
●Statins – We do not give statins to prevent ischemic ATN. Although observational studies have suggested that statins are associated with reduced risk of ischemic AKI [95-97], placebo-controlled trials have not confirmed this observation [98,99].
In a randomized trial, statin-naïve patients were randomly assigned to atorvastatin or placebo before, the morning of, and daily following surgery [98]. A second group of patients already taking statins prior to surgery continued taking pre-enrollment statin until the day of surgery and were then randomly assigned atorvastatin the morning of surgery and the morning after surgery followed by resumption of pre-enrollment statin. There was no difference in AKI between atorvastatin and placebo groups among all participants (RR 1.06, 95% CI 0.78-1.46), among those naïve to statins (RR 1.61, 0.86-3.01), and among those already taking statins (RR 0.91, 0.63-1.32).
In a subgroup of patients naïve to statins who had CKD (eGFR <60 mL/min/1.73 m2), the AKI risk was greater in the atorvastatin group compared with placebo (RR 3.35, 95% CI 1.12-10.05). The trial was terminated early due to the lack of effect and increased risk of AKI.
●Corticosteroids – We do not use corticosteroids to prevent ischemic ATN. The effect of perioperative high-dose methylprednisolone on postoperative AKI was studied in a multinational, placebo-controlled, randomized trial including 7286 high-risk patients who were undergoing cardiac surgery [100]. Methylprednisolone did not reduce AKI irrespective of CKD status [100].
●Erythropoietin – We do not use erythropoietin to prevent ATN. A placebo-controlled trial that used biomarkers (gamma-glutamyl transpeptidase and alkaline phosphatase) to identify patients at risk for AKI showed no difference between erythropoietin and placebo in the change in the plasma creatinine over four to seven days [101]. Potential reasons for failure to show a benefit of erythropoietin included the selection of biomarkers and delayed randomization after entry to the ICU to the first dose of erythropoietin (6.3 hours).
●Angiotensin II – ATN due to sepsis is associated with low blood pressure and altered renal hemodynamics [102]. Angiotensin II can improve blood pressure in patients with vasodilatory shock when conventional vasopressors have failed [103]. In such patients with AKI who require dialysis, angiotensin II may also reduce the number of dialysis-dependent days, although these findings are preliminary [104].
●Adenosine analogues – We do not use theophylline for prevention of AKI. (See "Neonatal acute kidney injury: Evaluation, management, and prognosis", section on 'Theophylline and perinatal asphyxia'.)
TREATMENT
Our approach — The early management of patients with established ischemic ATN should include a determination of the likely etiology and assessment of volume status, systemic hemodynamics, electrolytes, and acid-base status.
Therapeutic measures include the maintenance of optimal hemodynamic status to ensure renal perfusion and the avoidance of potential nephrotoxins to prevent further kidney injury.
All other measures are to support the patient until the kidney recovers. (See "Overview of the management of acute kidney injury (AKI) in adults".)
Diuretics — We do not use diuretics to treat ATN, although diuretics may be used to manage volume status. This is consistent with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [34].
Among patients with ATN, numerous studies, including randomized trials, have shown that diuretics augment urine output but do not have an effect on kidney function or patient survival [105-111].
In the best designed and largest study, 388 patients with established dialysis-requiring acute kidney injury (AKI) were randomly assigned to furosemide (25 mg/kg per day intravenously [IV]; maximum of 2 g/day, given over four to six hours, or 35 mg/kg per day orally; maximum of 2.5 g/day) or placebo [106]. The use of furosemide was associated with a decreased time to a 2 L/day diuresis (5.7 versus 7.8 days in placebo), as well as an increased likelihood of obtaining such a diuresis (57 versus 33 percent in placebo). Despite the increase in urine output, there were no differences between the two groups in patient survival, renal recovery rates, number of dialysis sessions required, and time on dialysis.
A similar lack of benefit on these hard endpoints was noted in an earlier trial, in which high-dose diuretic therapy (3 g/day) led, in a few patients, to hearing loss that can be permanent [107].
The dissociation between the diuretic-induced increase in urine output and lack of effect on renal recovery probably reflects the ability of the diuretic to enhance the urine output in the few nephrons that are still functioning but inability to recruit previously nonfunctioning nephrons.
Diuretics may be given for a limited time for volume control but such use should not postpone the initiation of dialysis (if required) [112]. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Urgent indications'.)
Dosing related to loop diuretics is available in a separate topic review. (See "Loop diuretics: Dosing and major side effects".)
Experimental measures for the treatment of established ATN — There are conflicting data concerning the benefit of other pharmacologic agents in the treatment of patients with established ischemic ATN. Selected agents are discussed here.
Dopamine, fenoldopam, and atrial natriuretic peptide — We agree with the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines that dopamine, fenoldopam, and atrial natriuretic peptide (ANP) not be used to treat established ATN, as there is no convincing evidence for a benefit [34]. These agents are discussed here.
●Dopamine – Despite an increase in natriuresis, low-dose dopamine is ineffective in the treatment of established ATN. The best data are from a meta-analysis of 61 trials that randomly assigned 3359 patients with, or at risk for, ATN to low-dose dopamine (≤5 mcg/kg per minute) or to either placebo or no therapy [45]. Low-dose dopamine had no effect on mortality or need for kidney replacement therapy (KRT), although urine output increased by 24 percent.
There are potential risks associated with low-dose dopamine. These include tachycardia, arrhythmias (particularly among cardiac surgery patients), myocardial ischemia, and intestinal ischemia.
●Fenoldopam ─ Fenoldopam does not appear to provide any benefit to patients with established ATN [61,113]. The best data are from a multicenter, randomized trial that compared fenoldopam with placebo in 667 patients admitted to an intensive care unit (ICU) with AKI following cardiac surgery [61]. AKI was defined as a greater than 50 percent increase in serum creatinine from baseline or oliguria for more than six hours [61]. Compared with placebo, there was no decrease in the need for KRT or in 30-day mortality in patients who received fenoldopam. Hypotension occurred more frequently in the fenoldopam group compared with placebo (26 versus 15 percent, respectively).
●Atrial natriuretic peptide ─ ANP has been evaluated in several major trials with variable results [114-116]. In one large, multicenter, randomized trial, there was no overall difference in dialysis-free survival between ANP- and placebo-treated groups [115]. However, whereas patients who were nonoliguric appeared to do worse with anaritide (48 versus 59 percent dialysis-free survival with placebo), oliguric patients did better with anaritide (27 versus 8 percent dialysis-free survival with placebo). As in other studies, the outcome was worse in patients with oliguric versus nonoliguric ATN. (See "Nonoliguric versus oliguric acute kidney injury".)
Given the observation that oliguric patients may have had a better outcome than nonoliguric individuals when administered anaritide, a randomized, prospective trial was performed that evaluated anaritide in oliguric ATN [116]. Among 222 such patients, a 24-hour infusion of anaritide (200 ng/kg per minute) provided no benefit compared with placebo.
Low-dose ANP may provide some benefit. The prolonged administration of low-dose ANP (50 ng/kg per minute) was suggested to provide benefit in a study of 61 patients with postoperative ATN [117]. ANP or placebo was continued until KRT was required or the serum creatinine concentration had decreased below the study inclusion value. Prior to, or at, day 21, ANP resulted in a decreased frequency of KRT (6 versus 14 patients, hazard ratio [HR] 0.28, 95% CI 0.10-0.73).
Despite these positive results, the study was small and underpowered.
Subgroup analysis of a meta-analysis and Cochrane review that included patients from eight trials who had established ATN following surgery suggested that low-dose ANP may reduce dialysis requirements [64,65]. However, study heterogeneity, design weaknesses, and small numbers limit any conclusions that can be drawn regarding the use of natriuretic peptide as a treatment of ATN.
Others — A variety of other agents have been used to reduce the duration or severity of ATN, including thyroid hormone [118], alkaline phosphatase [119-125], and insulin growth factor (IGF) [126]. There is no convincing evidence for a benefit of these agents in the treatment of established ATN.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●Acute kidney injury (AKI) is defined by a rise in the serum creatinine concentration or a decline in urine output that develops within hours to days. AKI is commonly, though not always, caused by acute tubular necrosis (ATN), particularly among critically ill hospitalized patients. (See 'Acute kidney injury (AKI) versus acute tubular necrosis (ATN)' above.)
●Procedures and conditions that are more commonly associated with ATN include major surgery (particularly cardiac surgery, abdominal aortic aneurysm surgery, surgery to correct obstructive jaundice, emergent surgery, or re-exploration surgery), sepsis, marked hypovolemia, severe pancreatitis, cardiogenic shock, and hemorrhagic shock. (See 'Identification of high-risk patients' above.)
●Patients at high risk for AKI should be identified early. Comorbidities that are associated with increased AKI risk include chronic kidney disease (CKD; either reduced estimated glomerular filtration rate [eGFR] or proteinuria with normal eGFR), severe atherosclerosis, diabetes mellitus, advanced malignancy, obesity and/or poor nutrition, and heart failure. (See 'Identification of high-risk patients' above.)
●Patients who are at high risk for ischemic ATN should have interventions to prevent AKI. Interventions include optimizing volume status and avoiding or stopping nephrotoxins, if possible. We do not administer any pharmacologic agent (such as diuretics or dopamine/fenoldopam) for the prevention of ischemic ATN. (See 'Interventions to decrease risk' above.)
●Early measures to treat established ischemic ATN include the maintenance of adequate hemodynamic status to ensure renal perfusion and the avoidance of potential nephrotoxins to prevent further kidney injury. We do not use diuretics or any other pharmacologic agents to treat ATN, although diuretics may be used to manage volume status. (See 'Our approach' above.)
●Multiple pharmacologic agents and methods are under evaluation to assist in the prevention and treatment/recovery of AKI. (See 'Experimental and unproven measures for the prevention of ischemic ATN' above and 'Experimental measures for the treatment of established ATN' above.)
