Translating advances in our understanding of the pathogenesis of acute kidney injury (AKI) to clinical trials require robust animal models for AKI, identification of targets for AKI relevant to humans, pharmacokinetic and pharmacodynamic studies, and improved preclinical and human clinical trial design. In addition, there is a growing importance of the systemic effects of AKI as well as the role of volume overload following AKI. The NIDDK-sponsored Kidney Medicine Precision Project should identify new molecular and signaling pathways in humans that will serve as the basis for drug development for the treatment of AKI. Potential therapeutic strategies should be based on the treating systemic effects of AKI and not the treatment of AKI alone. Newer drugs and nonpharmacological approaches used in innovative clinical trial designs are on the horizon and are likely to impact outcomes of AKI.
Keywordsacute kidney injury, drug development, prevention, treatment
Barriers to Successful Clinical Trials in Acute Kidney Injury, 726
Patient and Comorbid Factors, 726
Pathogenesis of Acute Kidney Injury Is Complex, 726
Acute Kidney Injury Is a Multisystem Disease, 726
Pharmacological Interventions, 727
Antioxidants: N-Acetylcysteine, Vitamin C, 728
Dopamine, Dopamine Analogs, and Natriuretic Peptides, 730
Vasopressin and Analogs, 731
Angiotensin II, 732
Adenosine Analogs, 732
Calcium Channel Antagonists, 732
What Drugs Are on the Horizon?, 733
Antiapoptotic Drugs, 733
Antisepsis Drugs, 734
Growth Factors, 735
Antiinflammatory Drugs, 736
Mitochondrial Agents, 736
Iron Metabolism Agents, 737
Mesenchymal Stem Cell Therapy, 737
Anesthetic Agents, 738
The authors are grateful to Dawn Kidd (University of Virginia) for helpful comments. This work was supported in part by funds from NIH (1R01DK105133, R01DK62324 1R01 DK085259 U18EB021787 to MDO).
Pharmacological therapy of acute kidney injury (AKI) continues to be largely unsuccessful despite proven benefits found in preclinical studies. Prevention and treatment of AKI is an important clinical issue because mortality in patients with AKI, especially in critically ill patients, remains high despite substantial advances in techniques of resuscitation and renal replacement therapy. Furthermore, there are a number of studies that suggest that those patients who survive AKI in the hospital develop chronic kidney disease (CKD) or end-stage renal disease (ESRD) (for a review, see Coca et al. ). Based on databases of US hospitalizations over the past 10 to 15 years, the incidence of AKI is increasing markedly as a result of the expansion of invasive medical and surgical procedures and the increasing expectation for aggressive medical management of critically ill patients. In critically ill patients, mortality is 40% to 60% and traditionally has been attributed to comorbid conditions. Data suggest, however, that AKI has an independent negative impact on mortality. Chertow et al. reported that even a rise of serum creatinine of 0.3 to 0.4 mg/dL was associated with an increase in mortality (multivariable odds ratio [OR], 1.7; 95% confidence interval [CI], 1.2 to 2.6). Standardization of the definition of AKI has led to advancements in the study of clinical AKI. The Acute Dialysis Quality Initiative (ADQI) classification, called RIFLE ( R isk, I njury, F ailure, L oss, E nd-stage kidney disease), and Acute Kidney Injury Network (AKIN) staging (1, 2, and 3) are based on graded levels of rise in serum creatinine or decrease in urine output. Even the least severe category, R or AKIN stage 1, was associated with a mortality rate of 30.9% or 30.7%, respectively. In 2012 the Kidney Disease Outcomes Global Initiative (KDIGO) combined the AKIN and RIFLE guidelines into a single definition of AKI. The diagnosis of AKI may be missed when using one or the other classification schemes. However, combining the two criteria into one KDIGO criteria ensured that the diagnosis is captured. KDIGO defined AKI by an absolute serum creatinine increase of ≥0.3 mg/dL occurring within 48 hours (this is similar to AKIN) and a 50% increment of serum creatinine within 7 days (similar to RIFLE). These studies highlight the important effects of a small decline in glomerular filtration rate (GFR) on the overall outcome of critically ill patients.
Although many animal studies have demonstrated that different classes of pharmacological agents are effective in preclinical studies, few have been found to be beneficial in human studies of AKI. For these reasons, and because of the high morbidity and mortality associated with AKI, a better understanding of the barriers to the prevention and treatment of AKI is necessary. Significant efforts are currently being directed in an international and multidisciplinary manner to improve outcomes in such patients by finding ways to prevent AKI, establishing early diagnoses and treatments with both nonpharmacological and pharmacological interventions. With a refined and consistent definition of AKI and point-of-care use of novel biomarkers for the early identification of AKI and predictors of AKI, new and old pharmacological therapies will require testing (or retesting) in well-designed randomized clinical trials.
This chapter focuses on pharmacological agents that have been used to prevent or treat AKI clinically, with variable levels of proven success (or failures), and also those with promising data from recent experimental studies of AKI in animals and humans.
Barriers to Successful Clinical Trials in Acute Kidney Injury
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.
Pharmacological interventions can be expected to be useful when used at various points in the natural history of AKI. Theoretically these would include agents that are used to lower the risk (i.e., prevent) in patients identified with high risk for AKI, agents that are used to limit injury in established AKI, and those that improve outcomes by improving rates of recovery from AKI. More clinical information is available for the prevention of AKI and very scant information for the other categories ( Table 48.1 ).
|Not used for prevention or treatment of AKI, but is used in pharmacological management of fluid overload
|Not useful in improving mortality
|Some recommend use in radiocontrast-induced AKI along with isotonic crystalloid administration
Not recommended to prevent AKI after cardiac surgery
|Not enough evidence to support its use in the prevention of radiocontrast-induced AKI
|No proven role in prevention and treatment
|No role in prevention and treatment
|Not enough evidence for a beneficial effect in sepsis (but maybe beneficial in subgroup with less septic shock)
|May be useful in bridging for transplantation in hepatorenal syndrome
|Beneficial in animal studies
Also, improved BP in patients with vasodilatory shock
|Calcium channel antagonist
|No proven role in prevention and treatment
|Possibly useful in decompensated cardiac failure
Evidence of reduction of AKI in postterm neonates with severe perinatal asphyxia
|Atrial natriuretic peptide
|No proven role in prevention and treatment
Lower doses may be beneficial by reducing hypotensive episodes
|Intensive insulin therapy not recommended for management of AKI and is associated with severe hypoglycemia
|Not recommended for prevention of AKI
|Not recommended for prevention of AKI
|Not recommended for prevention of AKI
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 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.
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.
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.
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.
Erythropoietin is a glycoprotein with a molecular weight of 30.4 kDa. Binding of erythropoietin to its receptor on target tissue leads to homodimerization of the receptor and initiation of complex intracellular signaling pathways. Exogenously administered erythropoietin, before or at the time of reperfusion, reduced kidney injury by reducing tubular necrosis and apoptosis. Recombinant erythropoietin has additional cell survival properties such as induction of phosphatidylinositol 3 kinase (PI3K)/Akt pathway or heat shock protein 70. Recombinant erythropoietin enhanced tubular proliferation in cisplatin-induced AKI and also mediated mobilization and proliferation of endothelial progenitor cells (EPCs) from the bone marrow, which has been reported to participate in tissue repair. The tissue-protective effects of recombinant erythropoietin appear to require a physical association between the common β-receptor chain subunit (CD131) and erythropoietin receptor. The helix B (amino acid residues 58 to 82) of erythropoietin and an 11-aa peptide composed of adjacent amino acids of helix B were found to be tissue protective and without erythropoietic activity. These results indicate that nonerythropoietic peptides of erythropoietin that simulate a portion of erythropoietin receptor’s three-dimensional structure possess tissue-protective properties. Thus recombinant erythropoietin or nonerythropoietic peptides are agents that have promise in the treatment of AKI. Early-phase clinical trials using erythropoietin in cardiac surgery have reported inconsistent results, some finding no clinical benefit and others finding some benefit. Endre and coworkers performed a double-blind placebo-controlled trial to examine the early treatment with erythropoietin to prevent the development of AKI in ICU patients. To avoid the concerns of using a late marker of AKI such as serum creatinine, these investigators used two urinary biomarkers to trigger intervention (IV erythropoietin 500 U/kg to a maximum of 50,000 U), urinary proximal tubular brush border enzymes c-glutamyl transpeptidase and alkaline phosphatase. Allocation occurred within 3.5 ± 1.6 hours after obtaining urine samples. However, 64% were randomly allocated 6.3 ± 4.2 hours after admission to the ICU. Early intervention with high-dose erythropoietin was well tolerated but did not alter the outcome. The discordance between preclinical and clinical results may in part be explained by the design of preclinical studies. De Caestecker and coworkers recently performed a careful analysis of 36 preclinical studies examining the efficacy of erythropoietin in various models of AKI, including toxin-associated, ischemic, and sepsis-associated AKI. Despite the performance of experiments in multiple models in different species (genetically inbred mice, pigs, macaques, and outbred rat strains), performance in humans have been inconclusive. Testing in models with common clinical morbidities and sex heterogeneity would improve preclinical testing, and improved clinical trial design may facilitate translation to human AKI. Thus, despite the potential for erythropoietin to prevent or treat AKI, the results remain inconclusive. An ongoing study on the use of erythropoietin in the prevention of AKI in cardiac surgery patients is near completion (NCT03007537).
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.
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.
What Drugs Are on the Horizon?
A number of novel investigational compounds and established drugs (for other indications) are being explored, some in preclinical studies and others in early-phase clinical trials ( Box 48.1 ). The goal of these agents is to either prevent AKI, treat and improve outcomes in established AKI, or halt or mitigate progression to ESRD. They have been grouped by their known main mechanism of action; some of the compounds involve more than one mechanism; for example, an agent could be an antiapoptotic and an antiinflammatory at the same time.
Alpha melanocyte stimulating hormone
Hepatocyte growth factor (HGF)
Bone morphogenic protein 7
Sphingosine 1 phosphate analogs
Adenosine 2A agonists
Inducible nitric oxide synthase (iNOS) inhibitors
MitoQ (mitoquinone mesylate)
Szeto-Schiller (SS) peptides
Iron metabolism agents
Mesenchymal stem cells
Volatile anesthetic agents
α-Melanocyte–stimulating hormone (α-MSH) is a melanocortin agonist with antiapoptotic and antiinflammatory effects. Early animal studies found that α-MSH decreased risk for AKI in IRI and sepsis and in nephrotoxin exposures. A more potent analog of α-MSH, AP214, was licensed as ABT-719. It protected against AKI in animal models of sepsis and IRI. It has advanced to phase II trials in humans, where it was used in a randomized, double-blind, placebo-controlled study to prevent AKI in high-risk cardiac surgery patients. In this phase IIb study, ABT-719 analog did not decrease the incidence of AKI using AKIN criteria or change outcomes at 90 days after cardiac surgery, nor did it reduce the increase in novel biomarkers of AKI: serum neutrophil gelatinase–associated lipocalin (NGAL) and urine NGAL, IL-18, and kidney injury molecule 1 (KIM-1).
Minocyclines are second-generation tetracycline antibiotics with proven human safety data. Minocycline is known to have antiapoptotic and antiinflammatory effects. When administered 36 hours before renal ischemia, minocycline reduced tubular cell apoptosis and mitochondrial release of cytochrome C, p53, and Bax. Furthermore, minocycline reduced kidney inflammation and also microvascular permeability. Minocycline has been used in clinical trials for rheumatoid arthritis and amyotrophic lateral sclerosis. Minocycline has been tested in treatment of AKI after cardiac surgery, acute spinal cord injury, and acute stroke (see www.clinicaltrials.gov ). In a randomized, double-blind, and placebo-controlled trial to prevent AKI after cardiac surgery in 40 patients, minocycline or placebo was given in at least 4 doses (200 mg initially, then 100 mg every 12 hours until surgery) with a maximum of 14 doses. In this small underpowered study, the primary outcome, AKI (a 0.3 mg/dL or more rise in serum creatinine concentration within 5 days after surgery), was no different in both groups.
p53 Small Interfering RNA
The tumor suppressor protein p53 is a homotetrameric transcription factor and regulates cell cycle and apoptosis by inducing cell cycle arrest or apoptosis in response to DNA damage. A variety of factors induce activation of p53, including irradiation, hypoxia, and nucleotide depletion. Additional activities regulated by p53 are supported by studies, including regulation of autophagy, glycolysis, repair of genotoxic damage, cell survival, regulation of oxidative stress, motility, cellular senescence, and differentiation. Once activated, p53 induces apoptosis by activating proapoptotic Bax, which triggers apoptosis via the intrinsic pathway. Pharmacological inhibition of p53 downregulates activation of Bax and inhibits the translocation of p53 to mitochondria, decreases tubule cell apoptosis, and preserves renal function. In p53-deficient mice, AKI was attenuated in cisplatin-induced AKI but not in a model of renal IRI.
QPI-1002 targeted at p53 is a synthetic antiapoptotic agent that has received “orphan drug” designation from the US Food and Drug Administration, the first small interfering RNA (siRNA) drug to be administered to humans (NCT00554359); after preclinical studies, siRNA for p53 showed a dose-dependent attenuation of apoptotic signaling in IRI, delayed graft function, and nephrotoxic (cisplatin)–related AKI. Using two-photon microscopy, Cy3-labeled siRNA is rapidly filtered and taken up by proximal tubules, significantly reducing p53 gene expression for up to 24 to 48 hours. Subsequent clinical studies are in phase II (NCT02610283) to examine the efficacy and safety of QPI-1002 in patients at high risk for AKI after cardiac surgery and in phase II (NCT00802347) and III (NCT02610296) targeting delayed graft function after kidney transplantation.
The endocannabinoids are an endogenous signaling system that modulates a variety of functions, including the immune system. Cannabinoid 1 (CB1) and cannabinoid 2 (CB2) are linked to the G-protein–coupled receptors Gi, which inhibit adenylyl cyclase and intracellular cyclic adenosine monophosphate (cAMP) accumulation. CB2 receptors are expressed on leukocytes and regulate the immune system. CB2 receptor agonists decrease leukocyte endothelial cell interaction and inflammation and increase microcirculatory flow by intravital microscopy. CB2 receptor–deficient mice had increased mortality, lung injury, and neutrophil recruitment at the site of infection after sepsis. A highly selective CB2 receptor agonist, N -(piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno[1,2- c ]pyrazole-3-carboxamide (GP1a), reduced inflammation and bacterial colony count and improved survival time.
The thrombomodulin–protein C system is important for healthy endothelial cells that maintain regional microcirculation and prevent thrombosis. Thrombomodulin (TM), a 557–amino acid glycoprotein expressed broadly on the surface of endothelial cells, exerts thromboresistance resulting in anticoagulation. On the cell surface, cleavage of protein C by thrombin requires TM as a cofactor generating activated protein C (APC). APC is an important modulator of coagulation and inflammation associated with sepsis by inactivating factor Va and VIIIa, thereby promoting fibrinolysis and inhibiting thrombosis. In addition, soluble thrombomodulin (sTM) independent of its ability to generate APC reduced ischemia-reperfusion injury. In this study an aortic clamp model was used; sTM not only attenuated the rise in creatinine after reperfusion, but it also improved microvascular erythrocyte flow, reduced microvascular endothelial leukocyte adhesion, and minimized endothelial permeability. A mutant, F376L, in which a point mutation was made in sTM, reduced IRI, suggesting that the protective effect of sTM is independent of its ability to generate APC.
APC, in addition to its effect on coagulation, has been found to have direct cellular effects via endothelial cell protein C receptors (EPCRs), including antiinflammatory and antiapoptotic activities, leukocyte activation, and stability of barrier function. Through genetic engineering of wild-type APC, mutants have been created that have the cytoprotective effects of APC and anticoagulant activity. After endotoxemia, these molecules with preserved cytoprotective properties are effective in preserving RBF, attenuating acute kidney injury, and reducing mortality. On the other hand, an APC mutant with potent antithrombotic activity but minimal cytoprotection was less effective in reducing endotoxin-induced murine mortality. Although the data suggest that the protective effect is independent of its anticoagulant effect, sTM may exert its effect by several means. sTM may have antiinflammatory effects; studies using N -terminal lectin-like domain of TM, which lacks anticoagulant function, have found that it blocks leukocyte adhesion to endothelial cells. In addition, sTM may have cytoprotective and antiinflammatory effects through activating EPCR/protease activated receptor (PAR) signaling. Lastly, sTM inactivates C3a or C5a and blocks inflammation. Thus additional studies are necessary to delineate the mechanism of action of sTM while clinical studies are ongoing to demonstrate its efficacy in sepsis (see Box 48.1 ).
Hepatocyte Growth Factor
Hepatocyte growth factor (HGF) is a mesenchyme-derived polypeptide that is a potent mitogen for hepatocytes (reviewed in Brines et al. 222 ). Mature HGF is a heterodimeric molecule consisting of a 69-kDa α chain and a 34-kDa β chain. HGF is synthesized and secreted as a 728-aa single-chain precursor processed by specific serine proteases to generate a biologically active form that is made up of two chains. HGF can promote cell growth, motility, and morphogenesis and act as a cell survival factor. Renal expression of HGF and its receptor, c-Met, increases after IRI, and exogenous administration of HGF reduces renal injury and accelerates renal regeneration in a murine model of AKI. The mechanism of protection includes a decrease in leukocyte–endothelial interaction with reduced inflammation; promoting tubular regeneration; upregulating cell survival proteins, including Bcl-2; and decreasing in tubular cell apoptosis. , , , , , BB3 is a small molecule with hepatocyte-like growth factor activity that has been found to be effective in focal cerebral ischemia and renal IRI. BB3 was administered to rats 24 hours after IRI and improved survival and renal function, while decreasing KIM-1, NGAL, and apoptosis. BB3 enhanced phosphorylation of cMET and Akt and upregulated Bcl-2. BB3 is being tested in a phase II study (Guard Against Renal Damage [GUARD]), a multicenter, randomized, placebo-controlled, double-blind study of ∼100 patients in the United States with risk factors for AKI (NCT02771509). BB3 was also tested in a phase II study in renal transplant patients for delayed graft function (NCT01286727). The interim analysis found that BB3 increased urine output, lowered serum creatinine, reduced the need for dialysis, and shortened length of hospitalization. A phase III study (Graft Improvement Following Transplantation [GIFT]) is being conducted in which BB3 or placebo is administered within 30 hours of transplantation to determine its effect on duration of dialysis or other measure of kidney function (NCT02474667).
Bone Morphogenic Protein
Bone morphogenetic proteins (BMP-7) are members of the transforming growth factor β superfamily, which has been found to be essential for cell growth, migration, and differentiation during development skeletal, kidney, and ocular development. Renal IRI leads to decreased levels of BMP-7 messenger RNA in the rat kidney, primarily in the outer medulla and glomeruli at 6 hours, which is more pronounced at 16 hours. Administration of exogenous BMP-7 at 1 hour and 16 hours after onset of reperfusion attenuates the severity of the injury. BMP-7–treated proximal tubule cells block basal and TNF-α–stimulated expression of the proinflammatory cytokines IL-6 and IL-1β, the chemokines monocyte chemotactic protein 1 (MCP-1) and IL-8, and endothelin 2 (ET-2). A phase II multicenter clinical trial using THR-184 in the prevention of AKI in at-risk patients undergoing cardiac surgery has been completed (NCT01830920). This study randomly allocated 140 patients undergoing high-risk cardiac surgery to either placebo or one of three THR-184 doses, given intravenously before surgery (and repeated postoperatively) and examined outcome of AKI in 7 days. There was a decrease in incidence of AKI in patients treated with the highest dose of THR-184. The drug was well tolerated and deemed safe and most effective in patients with CKD.
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.
Adenosine Triphosphate–Sensitive K Channel Agonists
Adenosine triphosphate–sensitive K (K ATP ) channels are expressed on vascular smooth muscle, are characterized by a single channel conductance of 15 pS to 258 pS, and are inhibited by intracellular ATP and activated by adenosine diphosphate (ADP). In vitro studies on isolated rabbit afferent arterioles constricted by K ATP channel inhibitor glibenclamide were dilated by the K ATP channel opener diazoxide. K ATP channels also contribute to the myogenic response, and this response is attenuated in renal hypoxia, which may be important in controlling medullary circulation where oxygen tension is low. Levosimendan is an K ATP channel opener and myocardial sensitizer and has antiinflammatory properties that may improve myocardial dysfunction and renal perfusion while reducing inflammation during sepsis. In a sepsis model, levosimendan conferred complete protection, had no effect on inflammation, and attenuated mesangial cell contraction in response to angiotensin II, suggesting that its vasoactive properties led to tissue protection. Furthermore, the lack of direct effect on hypoxic tubules suggest its potential role in sepsis or cardiorenal syndrome. Levosimendan is in a phase III study examining the effect of levosimendan versus dobutamine on renal function in patients with cardiorenal syndrome (NCT02133105), a phase IV study examining the effect of levosimendan versus placebo in patients with AKI after cardiac surgery (NCT02531724), and a phase II study examining the effect of levosimendan to reduce postoperative AKI in pediatric patients undergoing cardiac surgery (NCT02232399).
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.
Sphingosine 1 Phosphate Analogs
Sphingosine 1 phosphate (S1P) is a specific ligand for a family of G-protein–coupled endothelial differentiation gene receptors (also referred to as S1PRs 1 to 5) that evoke diverse cellular signaling responses. S1PRs regulate different biological processes depending on their pattern of expression and the diverse G proteins present. S1P binds to receptors or acts as a second messenger to stimulate cell survival, inhibit cell apoptosis, and inhibit cell adhesion and movement. An S1P analog, FTY720, acts as an agonist at four S1P receptors, which leads to sequestration of lymphocytes in secondary lymphatic tissue. In studies of kidney IRI, FTY720 or similar compounds produced lymphopenia and renal tissue protection. Activation of S1P1 on endothelial cells improves vascular integrity to protect from AKI and permit recovery. Furthermore, activation of S1P1 on proximal tubule cells improves mitochondrial function to protect kidneys from IRI. FTY720 reduced the number of lesions detected on magnetic resonance imaging and clinical disease activity in patients with multiple sclerosis, and in 2010, FTY720 was approved by the FDA to treat relapsing forms of multiple sclerosis. With discovery of new S1P analogs, more potent and selective agents will be available for preclinical and clinical studies.
A 2A Agonists and Other Adenosine Analogs
Adenosine binds to receptors that are members of the G-protein–coupled receptor family, which includes four subtypes: A 1 R, A 2A R, A 2B R, and A 3 R. Selective activation of A 2A Rs reduces parenchymal injury in nonrenal tissue, including heart, liver, spinal cord, lung, and brain. The selective A 2A agonist, ATL146e, is highly protective against IRI of kidney and reduces injury by 70% to 80%. After administration either before or immediately at the onset of reperfusion, ATL146e alone or in combination with a phosphodiesterase inhibitor reduced renal injury. ATL146e is in human clinical studies for cardiac imaging, and efforts are directed toward human clinical studies in AKI. Additional studies demonstrate that strategies using A 1 agonists or A 3 blockers may be effective in AKI. Although there are no trials in AKI, A 2A R agonists (regadenoson) are being studied in a phase II study examining the effectiveness in reducing inflammation by its ability to reduce invariant natural killer T-cell activation (NCT0108520). Furthermore, a phase I trial will soon be underway to examine its tolerability in patients undergoing transplantation (NCT03072589). Both these studies are supported by preclinical studies demonstrating the potent effect of A 2A R agonists in blocking inflammation in models of kidney and lung ischemia-reperfusion and occlusive vascular disease in sickle cell crises.
In preclinical and clinical studies, systemic alkaline phosphatase administration as an antiinflammatory strategy demonstrated protection in sepsis-associated AKI. The mechanism by which alkaline phosphatase protects from inflammation and tissue injury is thought to be due to direct dephosphorylation of endotoxin and neutralization of endotoxin activity. Alkaline phosphatase may also act as a nonselective phosphatase and catalyzes the conversion of ATP into adenosine. Adenosine may then act on adenosine receptors, of which there are four subtypes (A 1 , A 2a , A 2b , and A 3 ). Activation of A 2a receptors has potent antiinflammatory actions, and selective adenosine 2a analogs attenuate AKI and improve survival in sepsis. In phase IIa studies, administration of bovine alkaline phosphatase resulted in reduced inflammation and decreased sepsis-associated AKI, although there were no changes in mortality. Recombinant human alkaline phosphatase was tested in a phase I study and found to be safe and tolerable while demonstrating favorable pharmacological properties and enzyme activity. A large phase II study is ongoing to test the safety, tolerability, efficacy, and quality of life in patients with sepsis-associated AKI (STOP-AKI) (NCT02182440).
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
Deferoxamine and Hepcidin
Catalytic iron (or labile) iron damages cells through its ability to induce oxidative radicals, and, in addition, mitochondrial function, and cell cycle and DNA repair are iron dependent. Iron chelation with deferoxamine decreases injury after bleomycin- or cisplatin-induced nephrotoxicity. Iron sequestration can be achieved through the release of hepcidin, an antimicrobial peptide released from the liver. Hepcidin is an endogenous acute-phase hormone that downregulates iron export protein, ferroportin, to induce reticuloendothelial iron sequestration. Swaminathan and coworkers tested whether hepcidin, by blocking iron export, can protect kidneys from IRI. Hepcidin administration decreased kidney injury, which was associated with decreased kidney ferroportin expression and increased expression of H-ferritin. H-ferritin has been found to play a cytoprotective protective role in the proximal tubule after AKI. These results suggest that a novel compound hepcidin through targeting ferroportin holds promise as a novel therapeutic target in the treatment of AKI.
Hypoxia-Inducible Factor 1 Inducing Agents
Hypoxia-inducible factor 1 (HIF1) is an evolutionary conserved transcription factor that consists of an oxygen-sensitive α subunit and a constitutively expressed β subunit that allows cellular adaption to hypoxia. Prolyl hydroxylase hydroxylates HIF and targets the protein for degradation. HIF prolyl hydroxylase inhibitors contribute to organ protection, including brain, heart, liver, and kidney. Analogs of oxoglutarate inhibit prolyl hydroxylase and stabilize HIF. Prolyl hydroxylase uses oxoglutarate as a cosubstrate, and 2-oxoglutarate analogs have been found to protect kidneys from IRI. Daprodustat (GSK1278863) is an orally available prolyl hydroxylase inhibitor in clinical trials for other indications.
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).
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.