LEADING ARTICLE

Drugs 2010; 70 (9): 1099-1114 0012-6667/10/0009-1099/$55.55/0

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Novel Aspects of Pharmacological Therapies for Acute Renal Failure

lver1 and Anja Haase-Fielitz2 Ulrich Kunzendorf,1 Michael Haase,2 Lars Ro
1 Division of Nephrology and Hypertension, University of Kiel, Kiel, Germany -University Medicine Berlin, 2 Department of Nephrology and Intensive Care Medicine, Charite Campus Virchow-Klinikum, Berlin, Germany

Abstract

Acute renal failure (ARF) comprises several syndromes that are associated with a sudden decrease in renal function. ARF is common among critically ill patients, is typically multifactorial and is of great prognostic significance. Indeed, even moderate changes in renal function significantly add to the morbidity and worsen mortality associated with ARF. Recent definitions, namely the renal Risk, Injury, Failure, Loss of renal function and End-stage kidney disease (RIFLE) classification or Acute Kidney Injury Network (AKIN) criteria, which incorporate the levels of oliguria in addition to fractional serum creatinine elevation, are important because the magnitude of kidney injury according to those definitions correlates very well with both short- and long-term patient survival. However, preventive strategies are most effective when started before oliguria or elevated serum creatinine is detectable, as those criteria already reflect established renal tubular cell injury. New biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid binding protein (L-FABP) or kidney injury molecule-1 (KIM-1) that increase prior to the serum creatinine elevation are promising and have been proven to be useful in this regard in a few clinical trials. In addition, genetic profiling may define patients at risk earlier and help to individualize preventive strategies. Well established strategies include limiting dehydration and hypotension by the use of intravenous isotonic fluids at an optimal and individualized rate, as well as avoiding exposure to nephrotoxins, which include aminoglycosides, amphotericin or non-ionic contrast. Generally accepted and evidence-based pharmacological preventive or therapeutic options have not yet been established, although many drugs (e.g. renal vasodilators, diuretics and HMG-CoA reductase inhibitors [statins]) have been tested. New promising agents interfere with the apoptotic signalling that can occur in the setting of toxin exposure or ischaemiareperfusion injury, limit inflammatory responses or modulate endothelial cell activation. In the future, these new approaches will enable us to extend our therapeutic repertoire.

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Acute kidney injury (AKI), previously referred to as acute renal failure (ARF), is a devastating disease that affects millions of patients worldwide, and contributes to high morbidity and mortality. Several recent studies have discovered that even minimal increments in serum creatinine are associated with a gradual and substantial decrease in survival.[1,2] Therefore, along with the introduction of the new AKI classification systems, a change in paradigm towards the detection of increasingly smaller loss of renal function has been recently proposed and is now widely accepted. Despite growing insight into the pathophysiology of acutely worsening renal function, there is still no effective pharmacological treatment established in our current clinical practice. Barriers to successful therapies are multifactorial and include the complexity of AKI in humans, the influence of patients co-morbidities, pathological interactions between the kidney and distant organs (i.e. organ cross-talk and injury), and the dose and timing of potentially nephroprotective treatment. Novel renal biomarkers are emerging that enable a timely diagnosis of subclinical renal tubular injury, which precedes manifest AKI characterized by a reduction in or a loss of renal function. Another tool employed to predict the risk of AKI and to improve individualized patient care focuses on the identification of genetic risk factors that might be involved in the development of the disease. This article reviews recent aspects and highlights the prospects and pitfalls of new pharmacological treatments for AKI currently being evaluated in animal experiments or in clinical studies, as well as novel biomarkers for the early diagnosis of subclinical AKI that are emerging on the horizon. We suggest several points to be considered for successful pharmacological treatment in the near future. 1. Definition of Acute Kidney Injury (AKI) Descriptions of AKI date back to the ancient Greek period,[3] when the diagnosis was possible only by observing a reduction in urine volume. Today, AKI comprises a family of syndromes
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that are characterized by an abrupt and persistent but potentially reversible reduction in or complete loss of renal function associated with a decrease in urine output and an increase in nitrogenous waste products, e.g. urea and creatinine, in the blood.[4-6] A significant limitation to advances in the development of pharmacological treatments of AKI has been the absence of a uniform definition. By 2004, more than 35 different definitions were used in the literature to describe populations with wide differences in severity and outcome,[7] making comparisons among clinical trials difficult. The Acute Dialysis Quality Initiative (ADQI)[8] and the Acute Kidney Injury Network (AKIN),[9] both international expert consortia, introduced increasingly sensitive classifications of AKI, acknowledging that even small reductions in renal function are clinically relevant (figure 1). These classification systems use two criteria, a change in serum creatinine or glomerular filtration rate (GFR) from a baseline value and urine output, whichever is worse, to define three stages of increasing severity of renal dysfunction. Meanwhile, both the Risk, Injury, Failure, Loss of renal function and End-stage kidney disease (RIFLE) and the AKIN classifications have been widely used in clinical research on AKI. The sequential organ failure assessment (SOFA) score[10] is used to monitor a patients status during the stay in an intensive care unit, and describes renal function loss by absolute changes in serum creatinine or urine output within the setting of multi-organ failure. 2. Epidemiology and Outcome AKI is a major medical problem in hospitalized patients, occurring in 5% of all patients admitted to the hospital and in up to 30% of those admitted to an intensive care unit.[11-13] It is associated with a 2- to 15-fold increased mortality, and has a separate and independent effect on the risk of death.[14] Hospital mortality for patients with AKI has been reported to vary from 28% to 90%.[15,16] In the US alone, AKI kills an estimated 4 million
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a Cr/GFR criteria Increased Cr 1.5 or GFR decreases >25% Increased Cr 2 or GFR decreases >50% UO criteria UO <0.5 mL/kg/h 6h UO <0.5 mL/kg/h 12 h

b Cr criteria Increased Cr 1.5 or 0.3 mg/dL Increased Cr 2 UO criteria UO <0.5 mL/kg/h 6h UO <0.5 mL/kg/h 12 h

Risk

Stage 1

Injury

Stage 2

Increased Cr 3 or GFR decreases >75% or Failure Cr 4 mg/dL (with acute rise of 0.5 mg/dL) Loss

UO <0.3 mL/kg/h 24 h or anuria 12 h

Stage 3

Increased Cr 3 or Cr 4 mg/dL (with acute rise of 0.5 mg/dL)

UO <0.3 mL/kg/h 24 h or anuria 12 h

Persistent ARF = complete loss of renal function for >4 wk End-stage renal disease

ESRD

Patients who receive RRT are considered to have met the criteria for stage 3 irrespective of the stage that they are in at the time of commencement of RRT

Fig. 1. (a) Risk, Injury, Failure, Loss of renal function and End-stage kidney disease (RIFLE) and (b) Acute Kidney Injury Network (AKIN) classifications for acute kidney injury (adapted from Bellomo et al.[8] and Mehta et al.,[9] with permission from BioMed Central). ARF = acute renal failure; Cr = creatinine; GFR = glomerular filtration rate; RRT = renal replacement therapy; UO = urine output.

people annually.[17] An increasing proportion of patients who have AKI require permanent renal replacement therapy (RRT) or do not fully recover renal function, and this population has an important and growing impact on the global epidemiology of chronic kidney disease and endstage renal disease requiring long-term haemodialysis.[18-20] The risk for subsequent RRT of AKI may be increased by up to 10-fold if the previous GFR is <30 mL/minute.[21] AKI is due to a variety of conditions and has serious consequences. Sepsis, major surgery, cardiogenic shock and nephrotoxins, such as contrast agents, are the most common factors contributing to AKI, as recently described in an international point-of-prevalence study in more than 1700 patients with severe AKI by Uchino et al.[11] Other causes of AKI include infections, such as HIV, malaria, leptospirosis and hantavirus nephropathy, as well as AKI secondary to haematological malignancy or solid organ transplantation-associated AKI. In developed countries, there is the notion of an at least unchanged mortality in AKI,[22] despite technical progress in the management of AKI over the last
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decades, if not a trend towards an increasing incidence[23] in hospitalized patients due to the increasing age and co-morbidities of patients, prevalence of risk factors for AKI and complexity of interventions (e.g. chemotherapy, contrast agents, immunosuppressive drugs, surgeries). Druginduced AKI is estimated to account for between 18% and 33% of inhospital cases.[24] The associated mortality rate for AKI has remained relatively static.[25] 3. AKI and Distant Organ Damage Experimental and clinical data suggest that AKI contributes to and exacerbates multi-organ failure.[26,27] Triggered by renal injury, the physiological and molecular mechanisms responsible for these interactions include leukocyte trafficking, cytokine and cell adhesion-molecule expression, and impaired membrane ion and water-channel expression in distant organs. The responses to oxidative stress after AKI are also altered, suggesting complex mechanisms of cross-talk between the injured kidney and the previously healthy or pre-morbid distant organs.
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There is evidence that isolated renal injury contributes to increased intra-alveolar haemorrhage, decreased pulmonary fluid clearance and alveolar cell apoptosis in previously healthy lungs,[27] as well as cerebral inflammation and apoptosis.[28] The complexity that is created by the distant organ effects of AKI may have contributed to the previous ineffectiveness of pharmacological treatments in achieving improved patient outcomes. These observations also suggest that potential therapeutic strategies should not be limited to the treatment of kidney injury alone, but should be broadly based to treat the systemic effects of AKI.[29] The choice of endpoints in clinical trials of AKI needs to be carefully considered. 4. Clinical Risk Factors Multiple patient-related risk factors for the development of AKI have been identified. Chronic kidney disease is one of the most important predictors of AKI.[30-32] Other important risk factors include age, peripheral vascular disease, reduced left ventricular function, diabetes mellitus (particularly when insulin-dependent), circulatory shock and the need for emergency surgery.[21,32,33] Female sex is an independent risk factor for adverse renal outcomes after open heart surgery, particularly in women of younger age (<60 years).[30,34,35] There is an independently higher incidence of AKI and mortality among those with extreme obesity or malnourishment.[36,37] The influence of race is less clear.[21,30] 5. Pathophysiology of AKI Although the pathophysiology of AKI is complex and the aetiologies diverse, subsequent injury responses are likely to involve similar mechanisms. Major contributors that precede renal injury are hypotension, ischaemia/reperfusion, inflammation and toxins. It is generally accepted that hypoperfusion, hypoxia, oxidative stress and renal vasoconstriction are common contributors in the pathogenesis of AKI, resulting in renal tubular and endothelial cell injury,
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decreased sodium reabsorption, sympathetic activation and activation of the renin-angiotensinaldosterone system leading to further renal vasoconstriction and reduced GFR. Vascular injury, vasoconstriction, apoptosis, and modulation of humoral and cellular immune function, as well as growth factors, have formed the rationale for pharmacological intervention. Many pharmacological studies on the prevention and treatment of AKI have been performed;[38-42] however, most of these studies have failed, or obtained inconclusive and inconsistent results. Other targeted therapies have yet to be performed.[43,44] Given the complex traits that contribute to the pathogenesis of AKI, it may be too simple to expect that one therapeutic intervention would have success unless that intervention focuses on the prevention of AKI and targets a specific initiating cause early in the disease process.[29] 6. Findings of Pharmacological Interventions for AKI in Clinical Studies
6.1 Preventive Approach

Recommendations for the prevention of AKI include intravenous isotonic hydration,[45,46] avoidance of nephrotoxins such as NSAIDs, glycopeptide and aminoglycoside antibacterials,[47] and maintenance of adequate systemic blood pressure and cardiac output.[48] Restrictive medical indications for the use of contrast agents (type and dose),[49-51] calcineurin inhibitors and ACE inhibitor/angiotensin receptor antagonists in patients at risk of developing AKI are also recommended. Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery.[52] In addition to hydration, the best evidence for the prevention of contrast-induced nephropathy (CIN) is via the use of N-acetylcysteine (at high doses)[53-55] and sodium bicarbonate.[56-58] Given the multiple overlapping pathways that are involved in AKI, therapies may need to
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target multiple pathways simultaneously to realise success.[59] For example, the use of N-acetylcysteine and sodium bicarbonate more effectively prevents the development of CIN than the combination of normal saline with N-acetylcysteine alone or with the addition of ascorbic acid.[60] Furthermore, numerous pharmacological interventions have been tested in randomized controlled trials (RCTs) with regard to their nephroprotective effects in patients at risk for AKI. The investigated drugs might act via multiple mechanisms and are aimed at increasing natriuresis (e.g. furosemide, and atrial and brain natriuretic peptide), increasing renal blood flow (e.g. dopamine, fenoldopam, pentoxyfylline and theophylline, which is a phosphodiesterase inhibitor that blocks neutrophils), inhibiting inflammatory or oxidative stress (e.g. dexamethasone, sodium bicarbonate and N-acetylcysteine, which is a thiol group-containing antioxidant and vasodilator), and inhibiting renal vasoconstriction induced, for example, by sympathetic nervous system activation (e.g. clonidine). Table I[61-83] lists the pharmacological interventions that are undergoing further evaluation as well as those that have failed, sorted for AKI following cardiac surgery or the administration of contrast media. Even though some of these drugs are promising, no known drugs have demonstrated conclusive renal protection with a high grade of evidence. The failure of many of these interventions in reliably preventing AKI may be due, in part, to the fact that AKI may have a more complex pathophysiology than originally considered. It may also be due to the following: (i) interventions that target only single pathways are unlikely to succeed; (ii) uncertainty about when to begin and when to stop the intervention; (iii) no clear evidence for the dosing of specific drugs; and (iv) most RCTs performed to date in this setting have been underpowered. Until positive findings of large multicentre studies that are sufficiently powered to detect important patient outcomes, there is no internationally acknowledged consensus regarding any pharmacological intervention designed to prevent AKI.
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Table I. Pharmacological interventions for acute kidney injury (AKI) in clinical studies For further evaluation Anti-inflammatories and antioxidants sodium bicarbonate (prevention of CSA-AKI)[40] HMG-CoA reductase inhibitors (statins) [prevention of CIN][61] Growth factor erythropoietin (prevention of CSA-AKI)[62] Vasoactive drugs natriuretic peptides (prevention of CIN[63] and CSA-AKI[38,64]) fenoldopam (at low doses to prevent septic AKI and CSAAKI)[65,66] nitroprusside sodium (prevention of CSA-AKI)[67] pentoxyfylline (prevention of CSA-AKI)[68,69] diltiazem (prevention of CSA-AKI)[70,71] clonidine (prevention of CSA-AKI)[72] Extracorporeal blood purification with antimicrobial-coated membranes/columns polymyxin B/ofloxacin (for septic AKI)[73,74] Failed pharmacological interventions Vasoactive drugs dopamine (for septic AKI and CSA-AKI)[42,75,76] fenoldopam (for CIN and CSA-AKI)[39,77] theophylline (for CSA-AKI)[78] Anti-inflammatories and antioxidants dexamethasone (for CSA-AKI)[79,80] N-acetylcysteine (for CSA-AKI)[41,81,82] loop diuretics (for CSA-AKI)[76,83] CIN = contrast-induced nephropathy; CSA-AKI = cardiac surgeryassociated AKI.

6.2 Therapeutic Approach

Against the background of emerging novel renal biomarkers for the very early detection of relevant subclinical tubular injury (see section 8), medications that have previously been clinically tested and found unsuccessful might deserve a re-evaluation when applied in a timely manner. Therefore, it seems worthwhile to briefly discuss the potential rationale for such interventions for AKI therapy before new and innovative drugs targeting newly discovered pathophysiological mechanisms are highlighted. In this section, in a strict sense, we focus on the treatment of established and clinically manifest AKI when significant damage has occurred and a loss of renal function is evident. Basic treatment of AKI includes avoidance or discontinuation of
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nephrotoxins, such as radiocontrast agents, NSAIDs, or glycopeptide and aminoglycoside antibacterials, a switch to drugs that are preferentially metabolized in the liver, or adjustment of the drug dosing schedule and dosages according to renal function or RRT intensity.[84] The use of noradrenaline (norepinephrine) in intensive care patients with hypotensive vasodilatation despite fluid resuscitation and evidence of AKI remains the subject of much debate and controversy. At present, the experimental and human data strongly suggest that, in these patients, vasopressor therapy is safe and likely to be beneficial from a renal and, perhaps, a general point of view. On the basis of the currently available evidence, in hypotensive vasodilated patients with AKI, the restoration of blood pressure should occur promptly with noradrenaline and be sustained until such vasodilatation dissipates. The additional role of other vasopressors in these situations remains unclear. The addition of vasopressin may be helpful in individual patients not responding sufficiently to noradrenaline.[85] Terlipressin appears to be useful in patients with AKI secondary to hepatorenal syndrome. Whether it is superior to noradrenaline in this setting remains uncertain; more studies are needed before recommendations can be made.[86] Drugs that increase renal blood flow, promote natriuresis and block inflammation have been investigated for the treatment of AKI.[87] In general, few RCTs have been performed to investigate such strategies and, therefore, the evidence to date is very limited. In a small uncontrolled trial in post-cardiac surgical patients, renal-dose dopamine improved creatinine clearance in patients with established AKI.[88] Conversely, renal-dose dopamine worsened renal perfusion in critically ill patients with AKI, which raises questions concerning the routine use of renal-dose dopamine as a treatment option.[89] In a multicentre, placebo-controlled RCT that investigated renal-dose dopamine, the treatment was not able to improve renal function or any other outcome in critically ill patients.[42] Fenoldopam mesylate, a selective dopamine receptor-1 agonist, has been shown to reduce
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systemic vascular resistance in a dose-dependent manner. It is able to augment renal blood flow in patients with normal renal function and chronic renal failure. Fenoldopam is used in the belief that improving renal blood flow and oxygen delivery will disrupt the progression toward dialysis-dependent AKI. Despite early success in the prevention of AKI,[90-92] no convincing evidence for the treatment of established AKI after cardiopulmonary bypass using fenoldopam has yet been reported. In a pharmacological dose-effect study, atrial natriuretic peptide increased the GFR in a cohort of patients with established AKI after cardiac surgery.[93] A small RCT demonstrated that lowdose atrial natriuretic peptide, administered after the development of postoperative AKI, improved the dialysis-free survival of patients with AKI following cardiac surgery.[94] In a multicentre trial, activated protein C failed to demonstrate a benefit for the mortality of critically ill patients with severe sepsis and a low risk of death,[95] whereas a previous singlecentre study[96] demonstrated increased survival for patients with severe sepsis and an Acute Physiology and Chronic Health Evaluation (APACHE) II score >25 points. Diuretics are used to regulate the daily fluid balance; however, they do not appear to help the kidney recover faster from injury.[97] In another RCT that enrolled patients with oliguric AKI after cardiac surgery, the combined use of furosemide, mannitol and dopamine improved renal function after cardiac surgery compared with intermittent use of furosemide alone.[98] Various other therapeutic agents, such as insulin-like growth factor and erythropoietin, have shown promising results.[99,100] The effect of such therapies remains to be confirmed prior to their administration in clinical routine in the early postoperative period for AKI. In summary, no pharmacological interventions designed to revert established AKI have consistently resulted in improved outcomes. Therefore, to date, the treatment of patients with AKI is essentially supportive, and consists mainly of different modalities and doses of RRT. Currently, data for the dosage of antibacterials
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in patients with RRT-dependent AKI are insufficient. Underdosage of antibacterials may often occur during modern high washout continuous RRT. Future studies should focus on this important issue and measure plasma antibacterial concentrations in these patients.
6.3 Why Pharmacological Interventions for AKI Failed in Clinical Trials

injury, and include inhibitors of apoptosis, antiinflammatory substances, modulators of ischaemiareperfusion injury, vasodilators and inhibitors of Toll-like receptors (TLRs), as well as modulators of endothelial cells, the coagulation pathway and mesenchymal stem cells. The majority of new pharmacological therapies for AKI were tested in animal models.
7.1 Inhibitors of Apoptosis

Failure of pharmacological interventions for AKI in clinical trials may be due to the delay in the diagnosis of AKI, as current clinical practices rely on markers of glomerular filtration that are neither sensitive nor specific. Serum creatinine is a functional marker of GFR, which is dependent on numerous non-renal factors. The main limitation is its late increase, often 2448 hours after the injurious event to the kidney, a time window which, therefore, cannot be used for early intervention. Early identification of kidney injury will be critical for future developments in the treatment or prevention of AKI. Advances in the care of patients with stroke, myocardial infarction and sepsis have been made possible by early intervention, which is, in turn, only possible with early diagnosis. In future clinical trials, AKI biomarkers that reflect important consequences of the injury (e.g. death, need for RRT and length of hospital stay) should be considered. Additional reasons for the lack of success in clinical trials of AKI include inappropriate endpoints, low statistical power, administration of the drug at a dose too low or for a duration too short to reverse AKI, adverse effects of the drug, patient heterogeneity and, last but not least, the complexity of AKI pathophysiology requiring a multi-target pharmacological approach. Furthermore, difficulties in patient recruitment and randomization that control for illness severity have proven to be barriers to successful clinical trials. 7. New Pharmacological Therapies for AKI Promising agents that are currently in development address multiple pathways of renal
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Caspases are a family of proteases that are involved in the initiation and execution phase of apoptosis. Nonselective and selective caspase inhibitors are effective in attenuating renal injury in ischaemia- or endotoxaemia-induced AKI when administered before or at the time of injury. Caspase activation has been implicated in the development of ischaemia-reperfusion injury when administered as a preventive measure.[101,102] A caspase-1 inhibitor significantly reduced biochemical and histological evidence of renal dysfunction and injury.[102] Furthermore, caspase-3 was found to contribute to renal injury under hypoxic conditions.[103] A caspase-3 inhibitor produced a significant improvement in renal (glomerular) function (reduced serum creatinine levels), but it was not able to reduce tubular dysfunction and injury.[102] Although short-term use of caspase inhibitors has been well tolerated in liver transplant patients, long-term use may be associated with increased tumour risk.[104,105] Minocyclines are second-generation tetracycline antibacterials with proven human safety data. Minocyclines are known to have antiapoptotic and anti-inflammatory effects. In an ischaemia-reperfusion model in which rats received either minocycline or saline for 36 hours before ischaemia, minocycline was found to reduce tubular cell apoptosis.[106] In another experimental model of ischaemia-reperfusion, minocycline mitigated the renal microvascular permeability defect.[107] Heat shock protein 72 kDa (HSP72) is a molecular chaperone that might improve cell-cell junctions and enhance cell-matrix interactions. HSP72 is induced by an emulsion containing
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tocopherol and gum arabic, and ameliorates renal tubulointerstitial fibrosis in obstructive nephropathy by inhibiting renal tubular epithelial cell apoptosis and the epithelial-to-mesenchymal transition.[108] Proteasome inhibitors block cisplatin-induced activation of executioner caspases and apoptosis, and prevent the mitochondrial release of apoptosis-induced factors.[109] Other anti-apoptotic medications are guanosine and pifithrin-alpha, both of which are agents that are currently being investigated in clinical trials for cancer. Guanosine-triphosphate salvage by exogenous administration of guanosine reduced renal tubular cell apoptosis, an effect that was associated with inhibition of p53 expression.[110] Pifithrin-alpha, a novel p53 inhibitor, led to decreased tubule cell apoptosis and preserved renal function.[111] Despite some success in preclinical studies, anti-apoptotic medications also have the potential to cause harm, as demonstrated in a model of tumour necrosis factor (TNF)-induced shock in mice.[112] Indeed, in this experiment, caspase inhibition was associated with increased oxidative stress, kidney failure and death. Even worse, in a case series, patients who received minocycline therapy for acne or rheumatoid arthritis developed severe pauci-immune crescentic and necrotizing glomerulonephritis associated with positive cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA) titres and proteinase 3 levels.[113] Therefore, the complexity of the balance of factors involved in apoptosis and the response to sepsis or ischaemia-reperfusion appears not to be fully understood and requires further investigation.
7.2 Anti-Inflammatory Agents

HMG-CoA inhibitors (statins) have multiple mechanisms of action and exert anti-inflammatory properties. In a clinically relevant model of sepsis-induced AKI using cecal ligation and puncture (CLP) in elderly mice, simvastatin improved sepsis-induced AKI via direct effects on the renal vasculature and reversal of tubular hypoxia, and also had a systemic anti-inflammatory effect.[114]
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Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate glucose and lipid metabolism, which play an important role in inflammation and immunity.[115] Pretreatment of animals with fibric acid derivatives (fibrates) [PPAR-ligand] ameliorates cisplatin-induced renal dysfunction accompanied by suppression of nuclear factor-kB activation, cytokine/chemokine expression and neutrophil infiltration. Thus, the protective effect of fibrates may be mediated through their anti-inflammatory effects.[116] Interleukin (IL)-10 modulates the expression of cytokines and plays an important role in late septic AKI. In a murine CLP model of sepsis, a single administration of liposomal IL-10-carrying plasmid DNA significantly reduced kidney dysfunction.[117] Septic AKI is often caused by lipopolysaccharide (LPS), which induces nitric oxide (NO) synthase (NOS) and the subsequent generation of reactive nitrogen species. Inducible NOS (iNOS) contributes to injury to renal proximal tubules. In a mouse model of LPS challenge, an iNOS inhibitor prevented kidney injury.[118] This inhibitor completely blocked the increase in reactive nitrogen species and prevented the capillary defects at 6 hours after LPS administration.[118] A nonselective NOS inhibitor (Nmethyl-l-arginine or tilarginine) was studied in a phase III clinical trial in septic patients.[119] This study was stopped prematurely by the data safety monitoring board because of an excess of mortality in the treatment group. Numerous studies have shown that ethyl pyruvate decreases the levels of pro- and antiinflammatory cytokines in animal models of septic AKI.[120,121] It is also a potent endogenous antioxidant and free radical scavenger. In a polymicrobial model of sepsis by CLP in mice, ethyl pyruvate significantly attenuated tubular damage and accelerated renal recovery.[120] This renoprotective effect was also observed when its administration was delayed until 12 hours after surgery. Adenosine binds to receptors that are members of the G protein-coupled receptor family, which includes four subtypes: A1, A2A, A2B and A3 receptors.[122] The selective A2A receptor agonist ATL146e (apadenoson) is highly protective
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against ischaemia-reperfusion injury of the kidney and reduces injury by 7080%.[123] The use of A1 or A3 modulators may be effective in AKI.[124,125] Other agents with anti-inflammatory capacity are anti-CD147 antibody[126] and a-melanocyte stimulating hormone.[127]
7.3 Modulators of Ischaemia-Reperfusion Injury

Renal injury induced by aortic ischaemiareperfusion is an important factor in the development of postoperative AKI. For example, endothelin (ET) is a potent vasoconstrictor and is involved in the development of ischaemic renal injury. Tezosentan is a specific ET-1 receptor A and B antagonist that decreases tissue levels of malondialdehyde, superoxide dismutase, catalase and myeloperoxidase in rats after induction of renal ischaemia-reperfusion. Treatment with tezosentan significantly decreases focal glomerular necrosis, dilatation of Bowmans capsule, degeneration of tubular epithelium, necrosis in tubular epithelium and tubular dilatation in renal tissue.[128] Another ET-1 receptor A and B antagonist, bosentan, showed a harmful effect on experimental post-ischaemic AKI, probably due to disturbed autoregulatory renal function. On the other hand, ET receptor blockade in mild NO blockade associated with reperfusion injury improved the most haemodynamic, biochemical and morphological parameters.[129] Of interest, an ET-1 receptor A antagonist reduced iNOS and ET-1 concentrations, preserved the GFR and improved liver, lung and myocardial function when given preoperatively in a porcine model of renal recovery after the use of cardiopulmonary bypass.[130] Sildenafil is the first commercially available selective inhibitor of phosphodiesterase-5 and appears to attenuate experimental cisplatin-induced nephrotoxicity by preventing apoptosis.[131] Neutrophil gelatinase-associated lipocalin (NGAL) is a siderophore-binding lipocalin involved in ischaemic renal injury and repair processes. Its role in human physiology or pathophysiology is not entirely clear, but it does seem to act as a growth and differentiation factor for epithelia,
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possibly through its ability to transport iron to and from cells.[132,133] Recently, NGAL was described as an early, highly sensitive and specific renal biomarker in animals and humans that are developing AKI.[134-136] NGAL was nephroprotective when administered concomitantly with renal ischaemia-reperfusion.[132,133] Midkine, a heparin-binding growth factor, is involved in the migration of inflammatory cells. Intravenous injection of midkine antisense oligodeoxyribonucleotide was rapidly incorporated into proximal tubular epithelial cells and inhibited midkine synthesis, leading to the reduced migration of inflammatory cells to the injured epithelial layer. Treated animals exhibited less severe renal damage than untreated animals 2 days after ischaemia-reperfusion, pointing to midkine as a candidate for a novel therapeutic strategy against ischaemic acute tubulointerstitial injury.[137]
7.4 Inhibitors of Toll-Like Receptors

TLRs are a family of receptors that are positioned as a first line of innate defence by recognizing pathogen-associated molecular patterns, as well as endogenous signals of tissue injury.[138] TLR4 is present on monocytes and other cell types and mediates inflammatory events, such as the release of TNF after exposure to LPS. Renal epithelial cells bind complement and express TLRs, while resident and infiltrating cells produce cytokines/chemokines. In TLR4 knockout mice, Cunningham et al.[139] identified renal neutrophil infiltration and renal cell apoptosis, as well as TLR4 modulation per se, as potential mechanisms by which endotoxaemia leads to AKI. Pulskens et al.[140] found TLR4 as a cellular sentinel for acute renal damage that subsequently controls the induction of an innate immune response in TLR4-/-, MyD88-/- and TRIF-mutant mice that were subjected to renal ischaemiareperfusion injury.
7.5 Modulators of Endothelial Cells and the Coagulation Pathway

Sharfuddin et al.[141] found that soluble thrombomodulin administered 2 hours after reperfusion
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protects against ischaemia-induced renal dysfunction at 24 hours and improves survival in a renal ischaemia-reperfusion animal model. Soluble thrombomodulin may have therapeutic potential for ischaemic AKI.[141]

In the future, it might be possible to adjust the differential therapy for AKI according to kidney tissue-specific and, therefore, aetiologyindicative biomarkers.

8. Novel Renal Biomarkers: Pharmacological Treatment of Subclinical Injury to Prevent Manifest AKI While recent advances have suggested new and successful therapeutic approaches in animal models, translational efforts in humans have yielded disappointing results. A barrier to timely pharmacological intervention is the lack of early, sensitive, specific and prognostically relevant renal biomarkers. As previously mentioned (sections 1 and 6.3), in clinical practice the diagnosis of AKI is based mostly on an increase in serum creatinine. This surrogate parameter of renal function is affected by several non-renal factors as well as the hydration status of the patient. It is considered as a late indicator of AKI, as it typically increases only when the GFR has decreased to <50% of the normal rate. There has been increasing interest in the identification and validation of novel biomarkers of AKI that can detect tubular damage earlier, and thus permit a more timely and accurate diagnosis. Newer biomarkers under consideration aim to identify cellular injury. Several novel tubular markers have emerged as biomarkers that predict the development of clinically manifest AKI in heterogeneous groups of patients, 13 days earlier than serum creatinine, e.g. NGAL,[136] kidney injury molecule-1 (KIM-1)[142] or liver-type fatty acid binding protein (L-FABP).[143] An extended therapeutic window may allow for timely intervention in subclinical renal injury where reversal of AKI might still be possible using potentially nephroprotective medications or the early withdrawal of nephrotoxic medications. For example, in the case of relevant hypotension with a positive result for the presence of a reliable biomarker, it might be beneficial to begin vasopressor or inotropic drugs earlier and to adjust haemodynamic goals.
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9. Predisposition/Individual Risk: From Renal Risk to Drug Response Clinical predictors and biochemical markers identified for the development of AKI can only explain a part of this individual risk. Another tool to predict the risk of AKI and to improve individualized patient care focuses on the identification of genetic risk factors that might be involved in the development of the disease.[144] There is limited, but growing, evidence for an important role of genetic polymorphisms in the pathogenesis of AKI.[85,144-146] Most genetic polymorphisms that influence the susceptibility to and the severity of AKI appear to involve genes that participate in the control of inflammatory or vasomotor processes.[144,145] For example, polymorphisms in the genes coding for apolipoprotein E e2/e3/e4,[147] TNFa,[148] IL-6,[148,149] IL-10,[150] nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase p22phox/catalase[146] or the angiotensinogen 842C allele,[151] or genetic variants coding for catechol-O-methyl transferase (COMT) enzyme activity[85] have been associated with an increased incidence, duration or severity of AKI. The use of genetic epidemiology could stratify those who might benefit from preventive or therapeutic pharmacological measures from those who will not, depending on the individual genetic variant. Genotyping may prove to be a routine pharmacogenomic tool in an individualized risk-tailored patient care model that is clinically useful and cost effective.

10. Conclusions A vast number of pharmacological interventions have been tested in animal studies of AKI. Many substances have shown preventive abilities in pilot animal studies; however, most of them
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did not reach the level of larger clinical trials, or if they did, they did not achieve convincing results. The best possible explanation for this discrepancy is the relatively late application of potentially nephroprotective drugs in clinical practice. Therefore, at this stage there appears to be evidence that the next logical step should be novel biomarker-guided application of these substances in animal experiments and clinical trials. Future animal experiments designed to test AKI therapeutics should resemble most common clinical situations of subclinical kidney injury. It is unlikely that targeting events that occur late in AKI or even a single pathway will be effective. It is possible that the development of novel biomarkers for the characterization of phases of subclinical AKI (e.g. hypoxia/vasoconstriction, oxido-inflammation and apoptosis) and the identification of the location of renal injury would contribute to improved pharmacotherapy, thus leading to improved outcomes. Acknowledgements
Dr Haase holds a postdoctoral Feodor-Lynen Research Fellowship from the Alexander von Humboldt-Foundation, Bonn, Germany and A. Haase-Fielitz is a Fellow of the Jacksta dt-Foundation, Essen, Germany. The Alexander von Humboldt Foundation is a non-profit foundation established by the Federal Republic of Germany for the promotion of international research cooperation. Dr Haase has received an honorarium for speaking for Abbott Diagnostics and Biosite Incorporated. Both companies are involved in the development of NGAL assays to be applied in clinical practice. The other authors have no conflicts of interest to declare that are relevant to the content of this article.

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Correspondence: Professor Dr Ulrich Kunzendorf, Klinik fu r Nieren- und Hochdruckkrankheiten, Universita t Kiel, Schittenhelmstrasse 12, D24105 Kiel, Germany. E-mail: kunzendorf@nephro.uni-kiel.de

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