Patient and Comorbid Factors

The changing spectrum of human illnesses is an important variable to consider in the outcomes of interventional studies. Recent studies of AKI have noted a trend of increasing severity of comorbid and extrarenal complications. Those patients with higher comorbidity were associated with a higher incidence of AKI, especially if they were on mechanical ventilation. In a multicenter study of 618 patients with AKI in the intensive care unit (ICU) (the Program to Improve Care in Acute Renal Disease Network [PICARD]), the incidence of comorbid conditions was high, including 30% with CKD, 37% with coronary artery disease, 29% with diabetes mellitus (DM), and 21% with chronic liver disease. AKI was accompanied by extrarenal organ system failure in most patients. These comorbid conditions are likely contributors to failed treatment regimens.

Preexisting renal disease is the most important factor in predicting AKI after exposure to radiocontrast agents, major surgery, and other medical conditions. In a recent study, 1764 patients who developed hospital-acquired AKI and were treated with dialysis were compared with more than 600,000 patients who were hospitalized but did not develop AKI requiring dialysis. In the group of patients with AKI requiring dialysis, 74% occurred among patients with an estimated GFR <60 mL/min/1.73 m ² . The more severe the baseline CKD, the greater the risk for AKI: a twofold increase among patients with estimated GFR (eGFR) 45 to 59 mL/min/1.73 m ² and a fortyfold increase among patients with eGFR <15 mL/min/1.73 m ² . These results, and results from other studies, strongly suggest that underlying CKD may be the single most important risk factor for AKI.

Pathogenesis of Acute Kidney Injury Is Complex

The pathogenesis of AKI is complex; whereas initiating events may be dissimilar (ischemia or toxins are major factors that precipitate injury), subsequent injury responses may involve similar pathways. The complexity of AKI is illustrated in the following example. AKI associated with ischemia caused by a reduction of renal blood flow (RBF) less than the limits of blood flow autoregulation leads to maladaptive molecular responses. These responses lead to endothelial and epithelial cell injury after the onset of reperfusion. Pathogenic factors such as vasoconstriction, leukostasis, vascular congestion, apoptosis, and abnormalities in immune modulators and growth factors have formed the basis of rational therapeutic interventions. However, many of these targeted therapies have failed, are inconclusive, or have yet to be performed despite the advances made in understanding the pathogenesis of AKI. Given the complexity of the pathogenesis of AKI, it may be naïve to expect that one therapeutic intervention would have success unless that intervention focuses on prevention of AKI and targets a specific initiating cause. Given the multiple overlapping pathways involved in AKI, therapies may need to simultaneously target multiple pathways to achieve success. In addition, despite the advances made in our understanding of the pathogenesis of AKI, translating this information to treat human AKI requires addressing issues such as identification of relevant targets through the analysis of human tissue biopsy and necropsy specimens, development of relevant disease models of AKI, inclusion of proper pharmacokinetic/pharmacodynamics studies and dose-response studies, and, lastly, improvement in preclinical and human clinical trial design.

Acute Kidney Injury Is a Multisystem Disease

If small changes in serum creatinine are independent predictors of increased mortality, why then do these patients with AKI die? In ICUs it is not uncommon to observe complicated medical conditions that arise from the dysfunction of one organ leading to the dysfunction of another. In a cohort of patients with AKI after radiocontrast, many developed complications after the onset of AKI, including sepsis, hemorrhage, central nervous system (CNS) manifestation, and respiratory failure. AKI in some cases is thought to contribute to distant organ dysfunction syndrome, leading to hospital mortality and long-term consequences. Experimental studies provide some insight as to the mechanism by which isolated events leading to the loss of GFR can lead to distant organ dysfunction. Many potential factors may lead to distant organ effects, including circulating factors such as cytokines and chemokines, activated leukocytes, and adhesion molecules leading to immune cell infiltration. Oxidative injury, apoptosis, and cellular necrosis contribute to the final pathway of organ dysfunction. In critically ill patients, coexistent AKI and acute lung injury is associated with high mortality of 58% to 80%. Experimental studies demonstrated increased pulmonary vascular permeability, lung edema, alveolar hemorrhage, and leukocyte circulation after ischemic AKI. These data are scientifically and clinically relevant in defining the complex cross talk between the lung and kidney and will provide insight into human AKI. Recent studies have identified α-Klotho as a circulating factor that has cytoprotective effects in distant organs after AKI. The extracellular domain of α-Klotho is cleaved and released into the circulation and has cytoprotective effects in distant organs such as the lung in part through the activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway. Circulating α-Klotho derived mainly from the kidney and ischemia-reperfusion injury (IRI) leads to systemic α-Klotho deficiency and acute lung injury. Purified recombinant α-Klotho has a direct cytoprotective effect on epithelial cells by activating an antioxidant response element reporter and increasing the Nrf2 pathway.

Klein and colleagues found that interleukin-6 (IL-6) is a direct mediator of AKI-induced increase in vascular permeability, leukocyte circulation, and increased edema after bilateral IRI or nephrectomies.

Liu and associates reported that mice with AKI exhibited increased brain vascular permeability and an increase in the level of glial fibrillary acidic protein, a marker for activated glial cells during brain inflammation, and activated microglial cells (brain macrophages) that were associated with increased numbers of pyknotic neurons. Thus CNS manifestations of AKI may be the result of distant effects of AKI-induced inflammation.

AKI promotes cardiac injury that is characterized by hypertrophy and fibrosis. AKI has been found to increase cardiac apoptosis and production of IL-1 and tumor necrosis factor (TNF), cardiac hypertrophy and fibrosis, and gene expression for the macrophage chemokine osteopontin. These effects lead to an increase in inflammation and abnormal cardiac function.

There is considerable interest in the role of volume overload after AKI, which predisposes to multiorgan dysfunction and high mortality in the critically ill patient. Salt and water overload is associated with impaired wound healing, bowel edema, pulmonary edema/acute respiratory distress syndrome, lung infection, congestive heart failure, and cerebral edema. Conservative fluid management strategies are associated with improved outcomes.

The cholinergic antiinflammatory reflex pathway, an immunomodulatory neuroimmune circuit interfacing the brain with the immune system, has been described as an endogenous homeostatic response to inflammation caused by infection, injury, and trauma. The vagus nerve and the spleen are important components of the efferent limb of the neuroimmune circuit. In experimental models of AKI, splenectomy or denervation of the spleen, which would interrupt this pathway, exacerbate kidney IRI. Importantly, distant organ effects were observed in splenectomized animals. In animals with splenectomy subjected to AKI, there was an increase in lung injury as measured by capillary leak, higher myeloperoxidase activity, and higher chemokine (C-X-C motif) ligand 1 (CXCL1) compared with animals with AKI alone. Activation of the cholinergic antiinflammatory pathway through nonpharmacological approaches attenuates IRI-induced AKI and sepsis-induced AKI and blocks systemic inflammation.

In conclusion, although AKI is an independent risk factor for mortality, in most studies of AKI renal failure per se is usually not the cause of death. The potential systemic effects of AKI involve multiple organs and lead to high mortality. Thus the complexity created by the systemic effects of isolated AKI may have contributed to ineffective treatments in past clinical trials. These observations also suggest that potential therapeutic strategies should not be limited to treatment of kidney injury alone but should be broadly based to treat systemic effects of AKI.

Diuretics

Both loop diuretics and osmotic diuretics decrease tubular oxygen demand and relieve intratubular obstruction in animals. Intratubular obstruction with debris released from injured or dead tubular epithelial cells from more proximal parts of the nephron increase proximal tubule pressure, further limiting glomerular filtration. This observation, and the belief that nonoliguric AKI predicts better outcomes, made the clinical use of diuretics (especially loop diuretics) in oliguric AKI popular until recent times. Both loop diuretics and osmotic diuretics are of limited use in attenuating the extent of the kidney injury or altering the outcomes in a positive manner. Furthermore, a prospective observational study in 17 Finnish ICUs reported diuretics as a risk factor for the development of acute kidney injury.

In a retrospective analysis of data from a cohort of 552 patients with AKI in the ICUs of a university hospital, Mehta et al. examined the effect of diuretic use on all-cause hospital mortality, nonrecovery of renal function, and the combined outcome of death or nonrecovery of renal function. In this cohort about 59% of the patients had used diuretics; after adjustments for covariates and propensity scores, this group had a significantly higher risk for death or nonrecovery of renal function (OR, 1.77; 95% CI, 1.14 to 2.76). There have been additional systematic reviews or metaanalyses concerning the role of diuretics in this setting. None of these found that diuretics were of any benefit in reducing the incidence of AKI, mortality, or need for renal replacement therapy (RRT).

Other studies have found that diuretics are not associated with higher mortality. These results may be related to the importance of volume overload and mortality, and diuretics may provide a pharmacological approach to control fluid overload. In the PICARD study, a >10% fluid accumulation was associated with mortality at the start of renal replacement therapy ; there was a 19.6% fluid overload in nonsurvivors versus 10.1% in survivors. In the Fluid and Catheter Treatment Trial (FACTT), which compared liberal versus conservative fluid management strategy using fluid restriction and diuretics to maintain lower central venous pressure in patients with acute respiratory distress syndrome, the conservative treatment led to fewer ventilatory days. These results suggest that strategies to limit volume overload may affect mortality. Beginning and Ending Supportive Therapy for Kidney (BEST) was a large, multicenter, randomized prospective epidemiological study in ICUs from 54 centers and 23 countries. In this study, 70% of the patients were treated with diuretics. Their results could not confirm findings of Mehta’s study. Instead, they found that diuretics were not associated with an increase in mortality in critically ill patients in the ICU. Analysis of the data from the FACTT for the treatment of acute lung injury revealed that higher post-AKI furosemide doses had a protective effect on 60-day mortality, but this significant effect was lost after adjustment for post-AKI fluid balance. However, the authors noted that the benefit derived from diuretics may be due to reduction in fluid balance and that adjustment for fluid balance in the statistical analysis may not be appropriate. Thus, although diuretics should not be used to prevent or treat AKI, their use should be included as part of the pharmacological management of fluid overload in AKI as well as renal replacement therapy.

Antioxidants: N-Acetylcysteine, Vitamin C

N-Acetylcysteine (NAC) is a thiol-containing antioxidant with experimental evidence of improved renal function in mouse (and rat) renal IRI. Because of positive early reports, it has been used as an intervention to prevent radiocontrast-induced AKI in high-risk populations. Several randomized controlled clinical trials have been done subsequently to investigate the role of NAC in contrast-induced CI-AKI and in the setting of prolonged hypotension (e.g., abdominal aortic surgery). Results of many of these do not support those early reports of benefit, and controversy still exists on the efficacy of NAC in this setting. A recent metaanalysis of 41 randomized controlled trials (RCTs) with 6379 patients evaluated multiple therapeutic agents in high-risk patients who received radiocontrast. This metaanalysis found that, compared with hydration alone, NAC was the most effective agent at preventing radiocontrast-induced AKI of all the agents examined (theophylline, fenoldopam, dopamine, furosemide, mannitol, and bicarbonate). However, the authors noted this conclusion to be “debatable,” with several limitations of the study, mainly the inconsistent definition of “radiocontrast-induced nephropathy” as primary outcome in most of the trials.

Recently, Hoffmann and colleagues found that in healthy volunteers without AKI, NAC can reduce serum creatinine concentration (and eGFR) independent of an effect on true GFR as assessed by cystatin C (cys-C). This effect may be accomplished through an effect of NAC affecting creatinine metabolism or altering the tubular secretion of creatinine. Despite this suggestion, not all studies support the concept that NAC alters serum creatinine independent of GFR.

The Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) randomly assigned 2308 patients to receive 1200 mg NAC twice daily or placebo for 2 days to investigate the effect of NAC on the incidence of CI-AKI after coronary angiography. There was no difference in the incidence of CI-AKI between NAC and placebo arms (12.7% vs. 12.7%, P = 0.97). Also, a subgroup analysis of 367 patients revealed no benefit of NAC in reducing 30-day mortality or the need for renal replacement therapy. The ACT trial had some shortcomings—predominantly that it included low-risk patients (only 15.7% patients had a serum creatinine of more than 1.5 mg/dL); in addition, high-risk agent (high osmolar contrast media) was used in 20% of the procedures; the baseline serum creatinine was obtained 3 months preprocedure; and periprocedural fluid management was not standardized. Although the ACT trial does not prevent small increases in serum creatinine or serious 30-day outcomes in low-risk patients, there remains clinical equipoise on the use of NAC for the prevention of CI-AKI. The results of the Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial were recently published. Using a two-by-two factorial design, the investigators randomly assigned 5177 patients at high risk for renal complications who were scheduled for angiography to receive intravenous (IV) 1.26% sodium bicarbonate or IV 0.9% sodium chloride and 5 days of oral acetylcysteine or oral placebo; of these patients, 4993 were included in the modified intention-to-treat analysis. The primary endpoint was a composite of death, the need for dialysis, or a persistent increase of at least 50% from baseline in the serum creatinine level at 90 days. Contrast-associated AKI was a secondary endpoint. Notably, the sponsor stopped the trial after a prespecified interim analysis. The primary endpoint occurred in 110 of 2511 patients (4.4%) in the sodium bicarbonate group compared with 116 of 2482 (4.7%) in the sodium chloride group (OR, 0.93; 95% CI, 0.72 to 1.22; P = 0.62) and in 114 of 2495 patients (4.6%) in the acetylcysteine group compared with 112 of 2498 (4.5%) in the placebo group (OR, 1.02; 95% CI, 0.78 to 1.33; P = 0.88). There was no interaction between sodium bicarbonate and acetylcysteine with respect to the primary endpoint ( P = 0.33). There were no significant between-group differences in the rates of contrast-associated AKI.

Evidence does not support the use of NAC to reduce mortality or renal outcomes (such as AKI or AKI requiring renal replacement therapy) without radiocontrast administration. A metaanalysis of 10 RCTs with 1193 patients cumulatively undergoing major surgery evaluated the effectiveness of NAC in reducing mortality and renal outcomes. NAC was not associated with a reduction in mortality (OR, 1.05; 95% CI, 0.58 to 1.92), AKI requiring RRT (OR, 1.04; 95% CI, 0.45 to 2.37), or increase in serum creatinine by 25% more than baseline (OR, 0.84; 95% CI, 0.64 to 1.11). In addition, use of NAC does not prevent development of AKI after off-pump cardiac surgery and new-onset hypotension. The results of the PRESERVE trial also confirmed these findings. The overall conclusion that can be reached with these studies and systematic reviews is that NAC is not of any benefit in prevention of radiocontrast- or ischemia-induced AKI.

Ascorbic acid (vitamin C), a scavenger of reactive oxygen species (ROS), is another antioxidant that has shown some promise in animal experiments. Human studies using ascorbic acid to prevent radiocontrast-induced AKI are less conclusive. Spargias and associates randomly assigned 238 patients with a serum creatinine of 1.2 mg/dL and receiving nonemergent coronary angiography or intervention to receive 3 g of ascorbic acid or placebo about 2 hours before such procedures and then a second and third dose later in the day and the next morning. Mean serum creatinine concentration increased significantly in the control group versus the intervention group (difference of 0.09 mg/dL; 95% CI, 0 to 0.17; P = 0.049). These differences, however, did not seem to be clinically significant. More recently, a large trial (the REMEDIAL trial) found that the combination of ascorbic acid and NAC was no better than NAC and saline. Also, high-dose NAC was compared with ascorbic acid in an RCT of 212 CKD patients who underwent coronary angiography. The incidence of CI-AKI was greater in the ascorbic acid group compared with NAC (4.4% vs. 1.2%, P = 0.370). Notably, among patients with diabetes, NAC significantly reduced CI-AKI rates compared with ascorbic acid (0% vs. 12.5%, P = 0.039). In addition, ascorbic acid administration revisited in a metaanalysis of nine RCTs with 1536 patients suggested a 33% lesser risk for CI-AKI in patients treated with ascorbic acid compared with placebo or an alternative pharmacological treatment (relative risk [RR] by random-effects model, 0.672; 95% CI, 0.466 to 0.969, P = 0.034) However, there was heterogeneity in the route of administration of vitamin C (six orally and three intravenously) and another neutral or negative small RCT ( n = 250), which could invalidate the positive results of the metaanalysis in the future. A large RCT to address the clinical efficacy of vitamin C in CI-AKI is needed.

Thus the evidence does not support the use of ascorbic acid in the prevention of radiocontrast-induced AKI.

Insulin

Insulin resistance and hyperglycemia are common in critically ill patients, and intensive insulin therapy targeting blood glucose levels between 80 and 110 mg/dL reduced mortality and the incidence of AKI. It is well known that IRI is greater in chronic hyperglycemia and thought to be related to increased oxidative stress. Furthermore, acute hyperglycemia exacerbates myocardial and renal IRI. The effects of insulin may relate to improved glycemic control or be due to direct cellular effects of insulin. The relationship of hyperglycemia and adverse outcome in critically ill patients with AKI was also observed in subgroup analysis of the PICARD study. The mechanism for clinical benefit may relate to the direct metabolic and nonmetabolic effects of hyperglycemia. Endothelial dysfunction and subsequent hypercoagulation and dyslipidemia, commonly observed in critically ill patients, can also be partially corrected by insulin independent of its blood glucose–lowering effect. However, despite these promising results, the effect of intensive insulin treatment in the setting of critically ill patients is still controversial.

The Normoglycemia in Intensive Care Evaluation—Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study was the largest randomized control trial evaluating the question about intensive therapy or conventional therapy. The study enrolled 6100 patients to assess the risk-benefit ratio of tight glycemic control. The intensive glucose control group was associated with increased mortality compared with conventional glucose control (27.5% vs. 24.9%, P = 0.02). Also, there was no significant difference between the two groups in the incidence of RRT (15.4% vs. 14.5%).

Intensive insulin therapy is associated with an adverse event of severe hypoglycemia. The Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial was a multicenter randomized trial in 537 patients with severe sepsis who were divided into an intensive insulin therapy group and a conventional insulin therapy group; the volume resuscitation was either 10% pentastarch or a modified Ringer’s lactate solution. This trial was stopped early because of the safety signal of severe hypoglycemia in the intensive therapy group compared with the conventional treatment group (17% vs. 4.1%, P < 0.01). Intensive insulin therapy is not recommended for the management of AKI and is associated with a severe hypoglycemia.

Dopamine, Dopamine Analogs, and Natriuretic Peptides

Exogenous dopamine can bind to at least three types of receptors: the dopamine receptor, the ß-adrenoreceptor, and the α-adrenoreceptor. Differences in these receptors’ affinity for dopamine account for its distinct dose-response profile. Dopamine is a selective renal vasodilator at low doses (1 to 3 mcg/kg/min). Cardiac output and renal perfusion pressure are also improved at different doses of dopamine. The ability to improve RBF provided the rationale for its use in the prevention and treatment of AKI. Many clinical studies have been done to investigate the effect of dopamine on the natural history of AKI. The results of many of these studies have been conflicting and also complicated by the frequent use of surrogate endpoints that are sometimes not clinically relevant. A few systematic reviews and metaanalyses have also been undertaken. The overall conclusion is that low-dose dopamine has no proven role in prevention and treatment of AKI.

Why has dopamine failed in clinical trials? This has been examined in several reports. Low-dose dopamine consistently causes renal vasodilatation in healthy adults, but this effect is often attenuated or absent in ill patients. In other reports, dopamine reduced renal vascular resistance in patients without AKI but paradoxically increased resistance indices in patients with AKI. Several factors may account for this, including unpredictable pharmacokinetics in critically ill patients, hypertensive arteriopathy, or counterregulatory effects of other vasoactive hormones, such as activity of the renin-angiotensin-aldosterone system (RAAS) or sympathetic nervous system. Both extracellular volume depletion and hypoxemia have been found to abrogate the renal effects of dopamine. Based on many studies, low-dose dopamine should not be used in the prevention of AKI.

Fenoldopam is a selective dopamine-1 receptor (DA1) agonist that has been found, like dopamine, to cause renal arteriolar vasodilatation, leading to an increase in RBF and improvement in renal function while attenuating the decline in RBF and function in animals exposed to radiocontrast. Fenoldopam results in peripheral and renal vasodilation and diuresis and natriuresis via stimulation of vascular and renal tubular DA1 receptors. Studies in healthy, salt-replete participants have confirmed dose-dependent increases in renal plasma flow, urine flow rate, and urinary sodium excretion without changes in GFR. The lack of increase in the GFR is secondary to parallel vasodilation of both afferent and efferent renal arterioles, rendering intraglomerular pressure constant. Animal studies have demonstrated fenoldopam to be markedly more potent than dopamine in decreasing renal vascular resistance and augmenting RBF. Its relative potency, in conjunction with the absence of the potentially deleterious cardiac side effects characteristic of dopamine as a result of ß-adrenoreceptor stimulation, were the impetus for trials examining its potential to prevent and treat renal ischemia.

The clinical benefit in humans is inconclusive. Randomized controlled trials and metaanalyses of clinical trials concluded that there is no proven role for fenoldopam in prevention and treatment of AKI.

For prevention of AKI, there are several underpowered studies and metaanalyses with inconclusive results as a result of heterogeneity among participants, inconsistent definitions of AKI, and lack of placebo arms. Fenoldopam has mixed results in metaanalysis and systematic reviews.

The largest secondary prevention RCT to investigate the effect of fenoldopam in 667 patients after cardiac surgery was stopped early after a planned interim analysis revealed a safety signal of hypotension in the treatment arm compared with placebo. In addition, fenoldopam did not significantly reduce the need for RRT or risk for mortality at 30 days. Of note, this was a secondary prevention trial in which patients were randomly allocated after the development of AKI (defined by 50% rise in serum creatinine). Also, the therapeutic intervention happened after a median of 32 hours (interquartile range of 26 to 52 hours) after initiation of surgery. A rising serum creatinine represents an already decreased level of GFR, and the delay in intervention may have contributed to the adverse results of the study. Besides, this trial suggested alternative pathophysiological mechanisms (e.g., inflammation) other than renal hypoperfusion in AKI after cardiac surgery.

Finally, a systematic review and metaanalysis of six RCTs with 507 surgical patients (cardiovascular surgery, partial nephrectomy, post–liver transplant) demonstrated a significant reduction in postoperative AKI but without any benefit on reduction in RRT or hospital mortality. It is an underpowered metaanalysis with heterogeneity in the criteria of AKI. Extrapolating the data to other surgical patients would be difficult. In conclusion, clinical equipoise remains about the use of fenoldopam in the management of AKI .

Atrial natriuretic peptide (ANP) is not recommended for prevention and treatment of AKI based on the evidence, although it does exert pleiotropic effects (via guanylyl cyclase A activation) such as natriuresis, suppression of the renin-angiotensin system, vasodilation, and renoprotective effects. Multiple large and multicenter RCTs have failed to find such clinical benefit, however. A systematic review and metaanalysis of ANP in AKI found 19 RCTs (11 for prevention and 8 for treatment). The studies were described as low to moderate quality and mostly underpowered, and as such no definitive statements could be made about ANP use in AKI prevention or therapy. Also, data regarding potential confounders such as remote ischemic preconditioning and the use of isoflurane anesthesia were lacking. After this metaanalysis, a few RCTs were conducted. Sezai et al. studied the effect of low-dose ANP (carperitide) on postoperative serum creatinine in 303 CKD patients undergoing on-pump coronary artery bypass graft in a single-center RCT. The investigators reported a lower serum creatinine in the treatment group compared with placebo on the first day after surgery, and this effect persisted 1 year postoperatively ( P = 0.00665, P < 0.0001). Subsequently, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) randomly assigned 7141 patients admitted with decompensated heart failure to receive nesiritide or placebo in addition to standard of care. The study reported a moderate symptomatic benefit of dyspnea in heart failure patients treated with nesiritide compared with placebo. However, there were no differences in rehospitalization rates or 30-day mortality between the two study arms. In addition, incidence of AKI defined by 25% change in serum creatinine from baseline was not different in the two groups (31.4% vs. 29.5%; OR, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Continuous low-dose infusion of ANP needs to be performed in larger clinical trials before it can be recommended for routine use.

Norepinephrine

AKI is often associated with hypotension in patients with concurrent clinical problems like sepsis or liver failure, especially in ICUs. Attempts to maintain systemic blood pressure within limits that allow visceral organ perfusion (including autoregulation of RBF) are usually done with systemic vasoconstrictors.

Norepinephrine effectively raises the systemic mean arterial blood pressure to greater than 80 mmHg in many hypotensive states associated with vasodilation by stimulation of both α- and β-adrenergic receptors. This effect on mean arterial pressure is dose related, and, as such, the dosage of the drug can be titrated for desired effect. Some studies have found, however, that despite this desirable effect, there is often a less desirable decrease in splanchnic and vital organ blood flow (including kidneys). Most of these older studies, together with experimental data, indicate that norepinephrine can be used to induce a reversible model of AKI—an observation that has discouraged its clinical use for AKI. Some authors have argued that norepinephrine-induced renal hypoperfusion may not necessarily occur in sepsis or other vasodilated states, and they cite various animal experiments that support that mixed α- and β-adrenergic stimulation can increase RBF in such situations. Anderson and colleagues used infusions of norepinephrine at clinically relevant doses of 0, 0.1, 0.2, and 0.4 mcg/kg/min in conscious dogs and measured the RBF with an electromagnetic flow probe. Their findings indicated that mean arterial pressure, RBF, and GFR all increased with increasing dosage of norepinephrine, and renal vascular resistance decreased accordingly. There is a need for clinical trials in humans that will give a reliable answer to the question of whether norepinephrine and the kidneys are “friends or foes.”

Vasopressin and Analogs

Arginine vasopressin (AVP) is an endogenous peptide hormone with vasopressor and antidiuretic properties historically used to treat bleeding from esophageal varices in cirrhotic patients and for diabetes insipidus. Arginine vasopressin receptor 1A (AVPR1A), the first of three major receptor types for AVP, is found in vascular smooth muscle (and the brain, liver, and kidney). A relative deficiency of AVP has been reported in patients with septic shock. This has led to the use of low-dose AVP infusions (about 0.01 to 0.03 units/min) as adjunctive support to catecholamines for vasoconstrictor effect in sepsis-related hypotension. The Vasopressin and Septic Shock Trial (VASST), a multicenter, randomized, double-blind study, assigned patients with septic shock and who were receiving a minimum of 5 mcg/min norepinephrine (open label) to receive, in addition, either low-dose vasopressin (0.01 to 0.03 units/min) or norepinephrine (5 to 15 mcg/min) with protocol titration to maintain a target blood pressure. The study found no significant difference in the primary endpoint (mortality rate at 28 days) or any of the secondary outcomes when low-dose vasopressin (0.3 units/min) was used along with catecholamine vasopressors. In a subgroup analysis, vasopressin may have been beneficial in patients with less severe septic shock; the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P = 0.05).

Terlipressin, a glycine vasopressin, is a 12-amino acid synthetic analog of AVP that is currently being considered by the US Food and Drug Administration (FDA) as an orphan drug for the treatment of type 1 hepatorenal syndrome (HRS). Consequently, it is not yet available for clinical use in the United States (or elsewhere in North America), but it is already in use in Europe. Its major advantage is the long half-life of the drug that makes intermittent dosing (every 6 hours) possible, rather than a continuous infusion. Two recent clinical trials have had good results in cohorts of patients with AKI, specifically type 1 HRS. Sanyal and associates evaluated the safety and efficacy of terlipressin for reversal of type 1 HRS in patients with cirrhosis in a prospective, randomized, double-blind, placebo-controlled clinical trial. The treatment group ( n = 56) received terlipressin 1 mg intravenously every 6 hours (vs. placebo, n = 56) plus albumin in both groups. The results indicated that terlipressin was superior to placebo for HRS reversal (34% vs. 13%, P = 0.008), and HRS reversal significantly improved survival at day 180. Martin-Llahi and coworkers found similar results in HRS when IV terlipressin was added to IV albumin.

Angiotensin II

Septic AKI is associated with hypotension and reduced RBF. However, during the hyperdynamic phase of sepsis, RBF is increased in experimental animals and in humans, which may be due to a greater increase in dilation of the efferent arteriole compared with the increase in dilation of the afferent arteriole. When angiotensin II was infused in septic animals, arterial pressure was restored. RBF was reduced but urine output and creatinine clearance were increased, consistent with an effect to improve efferent arteriolar tone. Recently, angiotensin II was infused in patients with vasodilatory shock and increased blood pressure when conventional vasopressors failed. Whether there was an improvement in renal function was not reported.

Adenosine Analogs

Locally produced adenosine in the kidney controls renal circulation and metabolic cellular activity. Four subtypes of adenosine receptors (A ₁ , A _2A , A _2B , and A ₃ ) are characterized by having seven putative transmembrane-spanning domains, and they mediate a multitude of physiological responses. Adenosine acts on these receptors in organs such as brain, heart, and skeletal muscle and induces vasodilation to allow matching of oxygen delivery and work. Adenosine has been found to be involved in the renal hemodynamic response to radiocontrast agents and the immune response to renal IRI. Theophylline, an adenosine A1 receptor antagonist, has been used successfully in several RCTs to prevent radiocontrast-induced AKI (as reviewed in references 139 to 141). Theophylline has been used in several case-control and randomized controlled studies as a potential prophylactic agent against radiocontrast-induced AKI. A metaanalysis of these six studies indicated discordant results, with only four out of six studies finding some evidence of reduction of relative risk for radiocontrast-induced AKI. Other systemic reviews and opinions agree that the results have been discordant, mainly with some consideration that it may be more useful in the cohort of preexisting decompensated cardiac failure. There is little convincing evidence for recommending theophylline in the prevention of radiocontrast-induced AKI.

A single dose of theophylline may be given in postterm neonates who are at high risk for AKI. There is evidence of a reduction in AKI in postterm neonates with severe perinatal asphyxia in a recent metaanalysis of RCTs of 197 patients comparing theophylline to placebo. The pooled RR reduction of AKI = 0.38; 95% CI, 0.25 to 0.57, P < 0.001. However, we have to be cautious with the clinical use of theophylline because the long-term renal outcomes, neurodevelopmental outcomes, and adverse effects related to theophylline levels were not reported.

Calcium Channel Antagonists

Calcium channel antagonists relieve afferent arteriolar vasoconstriction, among other actions, and have been found to be protective against radiocontrast-associated AKI in animals. Calcium channel blockers have been used in different randomized controlled studies to assess ability to prevent AKI from radiocontrast and in renal allografts. The preservation of GFR by day 2 in patients treated with nitrendipine versus placebo and exposed to radiocontrast study seems promising ; however, the others do not indicate any benefit of calcium channel blockers in this setting.

Identification of effective pharmacological agents for the prevention and treatment of AKI remains a subject of intense focus for many investigators. None of the agents discussed have had enough impact to be considered sole and effective intervention for the prevention or treatment of AKI. Further, large clinical trials may give more information on these agents.

Statins

Statins are not recommended for the prevention of AKI. A recent single-center RCT of 199 patients demonstrated no difference in the incidence of AKI among postoperative patients when high-dose atorvastatin was compared with placebo (RR, 1.06; 95% CI, 0.78 to 1.46). In addition, subgroup analysis in patients with CKD (eGFR <60 mL/min/1.73 m ² ) noted a higher incidence of AKI in atorvastatin group compared with placebo. Hence, we do not recommend the use of statins for the prevention of AKI.

Corticosteroids

Steroids have diminished the inflammatory response to cardiopulmonary bypass in a small-scale RCT. However, methylprednisone was ineffective compared with placebo in decreasing the incidence of new renal failure, one of the composite primary outcomes, in a large-scale RCT of patients undergoing cardiac surgery (4% vs. 4%; RR, 0.87; 95% CI, 0.69 to 1.08).

The proven preventive clinical strategies of good hydration and volume expansion with isotonic saline before exposure to radiocontrast agents; discontinuation of nonsteroidal antiinflammatory agents, metformin, and angiotensin-converting enzyme (ACE) inhibitors; limitation of nephrotoxin exposure; and efforts to maintain renal perfusion still remain very useful clinical strategies.

Antiapoptotic Drugs

Antisepsis Drugs

Growth Factors

Vasodilators

The traditional concept that global ischemia is a major cause of AKI formed the basis for vasodilator therapy. The absence of benefit from dopamine, fenoldopam, and natriuretic peptides (see earlier) suggests that therapeutic interventions must consider the complexity of glomerular hemodynamics and its variability in response to different mechanisms of AKI. For example, prerenal azotemia from volume depletion leads to decrease in renal plasma flow, single-nephron GFR, and ultrafiltration coefficient (Kf). On the other hand, in sepsis, RBF may be decreased, unchanged, or increased. The decrease in GFR, primarily caused by a decrease in intraglomerular pressure, is governed by pressure in Bowman space as a result of a decrease in renal plasma flow, balance of afferent and efferent tone, downstream tubule obstruction, and decreased K _F . Furthermore, in addition to factors that govern RBF and GFR, it is important to determine the contribution of peritubular microcirculation and tissue oxygenation. The peritubular microcirculation may be altered by glycocalyx, adhesion molecule expression, leukostasis, inflammation, complement, and others. The inability to measure continuously human RBF and GFR, as well as tissue microcirculatory flow, is a barrier to advancement of therapies targeting renal hemodynamics.

Antiinflammatory Drugs

Inflammatory cells, including polymorphonuclear cells, monocytes, macrophages, and T cells, have received considerable attention as important contributors to ischemic acute renal failure. Several new compounds appear to be effective in reducing injury for ischemia-reperfusion through direct action on leukocytes.

Mitochondrial Agents

Mitochondria are dynamic organelles that have a critical role in cellular energy production, metabolism, calcium homeostasis, and programmed cell death. Mitochondria are abundant in proximal tubules and supply ATP from oxidative phosphorylation (OXPHOS) necessary for tubular function. During renal ischemia, mitochondrial function diminishes ; during reperfusion, ultrastructural analysis reveals fragmented mitochondria associated with mitochondrial dysfunction, ATP depletion, generation of mitochondrial-derived ROS, and activation of cell death pathways. These morphological and functional changes that occur contribute to AKI, and evidence supports the concept that preserving the integrity of mitochondria and enhancing mitochondrial biogenesis may promote recovery from AKI.

Mitoquinone mesylate (MitoQ) is a mitochondria-targeted antioxidant that selectively accumulates in the mitochondrial matrix because of its positive charge. In the mitochondrial matrix, MitoQ is reduced to the active antioxidant form, ubiquinol, by the respiratory chain, preventing oxidative damage–lipid peroxidation. MitoQ given to mice intravenously 15 minutes before ischemia protected mouse kidneys from injury.

SS-31 is a member of the Szeto-Schiller (SS) peptides. It selectively targets the inner mitochondrial membrane. SS-31 carries a positive charge and binds to anionic phospholipid cardiolipin (CL). CL-phospholipid expressed on the inner mitochondrial membrane has an important structural role in the organization of the respiratory complexes for optimal OXPHOS. The interaction between CL and cytochrome c is vital for mitochondrial function because it dictates whether cytochrome c acts as an electron carrier or peroxidase. CL peroxidation is associated with energy deficiency. SS-31 protects electron carrying function by cytochrome c by preventing CL from converting cytochrome c into a peroxidase. SS-31 protects the structure of mitochondrial cristae and promotes OXPHOS. Remarkably, in a study of rats subjected to 45 minutes of bilateral renal ischemia and followed for 9 months, SS-31 arrested progression of kidney disease. In control animals, glomerular and peritubular capillary rarefaction, macrophage infiltration, and fibrosis were observed, and there were marked morphological abnormalities of mitochondria. In animals treated with SS-31 for 6 weeks, beginning 1 month after ischemia, there was preserved glomerular capillary, podocyte, and mitochondrial structure with attenuated kidney fibrosis.

Iron Metabolism Agents

Mesenchymal Stem Cell Therapy

AKI resulting from toxins, ischemia, or sepsis is characterized by complex series of overlapping pathways that may necessitate a broad approach in combining multiple targets. For example, in severe sepsis, critically ill patients require multiple vasopressors and fluid regimens because of marked hypotension and multiorgan dysfunction. Marked dysregulation of innate immunity contributes to the pathophysiological events in sepsis. Mesenchymal stem cells (MSCs), derived from bone marrow, can differentiate into osteocytes, chondrocytes, and adipocytes. In preclinical studies, infused MSCs demonstrate protection and enhanced recovery in cisplatin- and glycerol-induced AKI and ischemia-reperfusion injury and reduce inflammation and AKI in experimental sepsis.

MSC-mediated tissue protection likely is due to paracrine mechanisms, including growth factors, cytokines that modulate mitogenesis, apoptosis, inflammation, and vasculogenesis and angiogenesis, rather than transdifferentiation. MSCs have been found to enhance proliferation of tubule epithelial cells through growth factors and cytokines. MSC microvesicles have been found to shuttle mRNA to injured cells to enhance survival. The use of pulsed ultrasound improved MSC homing to diseased organs and enhanced the protection observed with MSCs alone.

Because of their pluripotency, hypoimmunogenicity, easy accessibility from bone marrow, and rapid ex vivo expansion, MSCs have been used in clinical trials. AC607 are expanded bone marrow–derived MSCs obtained from healthy adult donors, and their efficacy and safety have been tested in a phase II study in at-risk patients undergoing cardiac surgery, but trials were terminated because of the lack of efficacy (NCT01602328). MSCs are in use in a pilot study examining the feasibility and safety of ex vivo expanded MSCs to repair kidneys and improve function in patients with solid organ cancer who develop AKI from cisplatin (NCT01275612). In another study, SBI0-101 is a combination product that combines MSCs with a blood-filtration device used for continuous renal replacement therapy (CRRT). This phase I/II study seeks to determine the safety and tolerability of combining MSCs with CRRT in patients with AKI necessitating renal replacement therapy (NCT03015623). In donor after cardiac death transplantation, allogeneic bone marrow–derived MSCs are being examined in a phase I/II study to determine their efficacy and safety. Renal allograft function, patient/graft survival, and adverse events within 12 months will be monitored (NCT02561767).

Anesthetic Agents

Studies have demonstrated that volatile anesthetic agents have important protective effects on multiple organs in ischemic and inflammatory conditions. Both in vitro and in vivo results indicate that volatile anesthetic agents attenuate IRI and inflammation. In ischemic AKI, volatile anesthetic agents have protective effects by decreasing inflammatory cell infiltration and proinflammatory cytokines and through effects on endothelial and epithelial cells. Importantly, the newer volatile anesthetic agents such as sevoflurane, isoflurane, desflurane, and halothane possess a triflourocarbon (CF3) molecule, which appears to exert immunomodulatory effects. Of these new volatile anesthetic agents, desflurane is the least lipid soluble and is less potent in kidney protection in rats subjected to IRI compared with the other agents with greater lipid solubility (sevoflurane, isoflurane, and halothane). A prospective randomized study compared the effect of sevoflurane versus desflurane on kidney function after living donation transplantion. On postoperative days 1 and 7 there was no difference in creatinine, estimated GFR, NGAL, or IL-18 between the two groups. In a related study, sevoflurane versus propofol on the incidence of acute rejection in recipients of living donation after circulatory death and donation after brain death, donor kidneys will be examined (NCT02727296). Additional studies will be necessary to establish whether certain volatile anesthetic agents confer greater kidney protection.