Current Drug Targets - Volume 10, Issue 12, 2009

Acute kidney injury (AKI) is the sudden (over hours or days) loss of kidney function, which may or may not be reversible and may lead to the need for renal replacement therapy with dialysis. AKI represents a potentially life threatening condition with a mortality as high as 80% [1]. Even in those cases that may not be directly life-threatening, the impairment in renal function has significant consequences to the patient. In the setting of AKI, procedures may be limited, drug dosing may be inaccurate, metabolic complications may occur, immune dysregulation is present and all of these may lead to poor outcomes. The therapeutic challenges associated with AKI make prevention critically important as well as prompt, accurate diagnosis and effective treatment when this complication does occur. This issue of Current Drug Targets is devoted to recent developments in the understanding of the pathogenesis of AKI as well as recent advances in the diagnosis and therapy of AKI. The issue begins with an extensive discussion of the epidemiology of AKI by Parmar and colleagues. This review sets the stage for a review of the pathophysiological aspects of AKI in sepsis by Ricci and Ronco. Kalantarinia then discusses the role of imaging and novel imaging techniques in the diagnosis of AKI. Moving into therapeutic regimens, Liu and Glidden provide an overview on why clinical trials for AKI have failed and discuss how the knowledge of past errors in design can be utilized to design an effective clinical trial in AKI patients. The last four articles discuss specific therapeutic agents and their potential in treating AKI. Three of the articles focus on pharmacological agents (the articles by Bajwa et al., Chawla et al., and Gupta et al.), while the final article by Song and Humes, discusses the bioartificial kidney. While no means comprehensive, this issue provides an overview of therapeutic targets for the prevention and therapy of AKI and highlights the movement of these therapies from the bench to the bedside. It is hoped that substantial improvements in the care of patients either at risk for the development of AKI, or in those who have developed AKI will be seen as these advances move into the clinical arena.

Acute kidney injury (AKI) associated with sepsis remains an all too common occurrence with an associated high mortality rate. However, recent developments bring hope that this scenario may be changing. This change is being brought about by a multi-pronged approach that highlights several different but inter-related aspects of AKI. These include: (1) defining a standard definition for AKI; (2) understanding the importance of early recognition of AKI; (3) improving imaging techniques for the diagnosis of AKI; (4) improved understanding of the complex pathogenesis of AKI, especially in sepsis; (5) the development of targeted strategies to prevent and treat AKI and (6) an improved understanding of the design and implementation of clinical trials in AKI. Through advances in all of these areas it is hoped that the incidence and mortality rates associated with AKI will be improved.

The incidence of sepsis and acute kidney injury (AKI) is increasing in critically ill patients and both portend a higher risk of morbidity and death. Sepsis has consistently been shown to be a key contributing factor for the development of AKI. Numerous observational studies have found septic AKI to be highly common among the critically ill. Septic AKI patients are characterized by important differences in baseline demographics, acuity of illness and treatment intensity when compared with non-septic AKI. In particular, these patients are often older, have a higher prevalence of co-morbid illnesses, and are admitted for medical or emergency surgical indications. These patients show greater aberrancy in vital signs, laboratory parameters and need for vasoactive therapy and/or mechanical ventilation. Delays in initiation of appropriate antimicrobial therapy independently predict development of AKI in septic patients. Both delays to appropriate antimicrobials and initiation of renal support are also associated with higher mortality. Survival to ICU and/or hospital discharge for septic AKI patients is significantly lower when compared to patients with either non-septic AKI or sepsis alone. However, survivors of septic AKI show trends for greater rates of renal recovery and dialysis independence compared with non-septic AKI. The burden of septic AKI continues to increase and remains associated with an unacceptably high attributable morbidity and mortality. Accordingly, there is continued need to understand its epidemiology, not only to guide in management of these patients at the bedside, but also to stimulate advances in understanding its pathophysiology and in therapeutic interventions to potentially mitigate prognosis.

Septic acute kidney injury (AKI) occurs between 15% and 20% of all intensive care unit admissions and its mortality ranges from 20% to 60%. The incidence and mortality of septic AKI has remained high throughout the last 10 years, whereas our understanding of septic AKI pathogenesis has remained limited. Current evidence about the pathophysiology of septic AKI will be reviewed and areas that require further investigation will be discussed. Improvement of knowledge about this condition seems to be most important in order to find valid diagnostic exams to exactly identify septic AKI and effective therapies to treat it: both of them are currently lacking. Finally, new preventive strategies might be experimented in order to protect critically ill patients from septic AKI.

Imaging of the kidneys can provide valuable information in the work up and management of acute kidney injury. Several different imaging modalities are used to gather information on anatomy of the kidney, to rule out obstruction, differentiate acute kidney injury (AKI) and chronic kidney disease and to obtain information on renal blood flow and GFR. Ultrasound is the most widely used imaging modality used in the initial work up of AKI. The utility of contrast enhanced computerized tomography and magnetic resonance imaging is limited because of toxicities associated with contrast agents used. In this review the basics of ultrasonography are reviewed with an emphasis on findings in AKI. The new developments in different imaging modality and their potential uses in AKI are reviewed as well.

Acute kidney injury is associated with significant morbidity and mortality in hospitalized patients. Clinical trials for acute kidney injury have been hampered not only by a paucity of appropriate potential therapeutic agents, but also by several clinical trial design challenges. First, for novel therapies to have the best chance at efficacy, early patient identification is critical. Second, for certain novel therapies with a mechanism of action directed at the underlying disease state (e.g., sepsis) or a specific pathogenic process, careful disease phenotyping may be required. Third, even among patients with AKI, risk stratification may be required to select a higher-risk subset for clinical trials. Finally, clinical endpoints for clinical trials must be considered carefully, as patients may die for reasons unrelated to AKI, including withdrawal of support. However, these challenges are not unique to AKI; some possible solutions including alternative endpoints used in other clinical trial settings are reviewed here.

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and both innate and adaptive immunity contribute to the pathogenesis. Kidney resident cells promote inflammation after IRI by increasing endothelial cell adhesion molecule expression and vascular permeability. Kidney epithelial cells bind complement and express tolllike receptors and resident and infiltrating cells produce cytokines/chemokines. Early activation of kidney dendritic cells (DCs) initiates a cascade of events leading to accumulation of interferon-γ-producing neutrophils, infiltrating macrophages, CD4+ T cells, B cells and invariant natural killer T (NKT) cells. Recent studies from our laboratory now implicate the IL23/IL17 pathway in kidney IRI. Following the initial early phase of inflammation, the late phase involves infiltration of anti-inflammatory cells including regulatory T cells, alternatively activated macrophages and stem cells leading to attenuation of inflammation and initiation of repair. Based upon these immune mechanisms of injury, recent studies hold promise for novel drug therapies. These pharmacological agents have been shown to reduce inflammation or cytotoxicity in rodent models of AKI and some show early promise in clinical trials. This review summarizes recent advances to further our understanding of the immune mechanisms of AKI and potential pharmacological therapies.

Sepsis associated Acute Kidney Injury (SA-AKI) is the leading cause of AKI in the hospital setting and its incidence is increasing. Although the exact pathophysiology and phenotype of SA-AKI are not known, it is widely accepted that SA-AKI has a multi-injury pathway. This form of AKI has components of ischemia-reperfusion injury, direct inflammatory injury, coagulation and endothelial cell dysfunction, and apoptosis. As such, multiple agents have been shown in pre-clinical studies to ameliorate SA-AKI, but there are no interventions currently available for the treatment of SA-AKI. Promising agents that are in development include toll-like receptor inhibition, IL-10 augmentation, modulators of the protein C pathway, and mesenchymal stem cell mediated therapeutics. The aim of this review is to review the pathophysiology of SA-AKI and the therapeutic interventions that are under development to treat this complex and morbid disease.

Protein C is a plasma serine protease that when activated plays a central role in modulating the function of the vascular endothelium and its interface with the innate immune system. Activated protein C (APC) has a dual mechanism of action via the feedback inhibition of thrombin generation, and as an agonist of protease activated receptor-1 (PAR-1). Through different cofactor interactions, this dual mechanism of antithrombotic and cytoprotective activity results in the ability of APC to modulate endothelial dysfunction by blocking cytokine signaling, functional cell adhesion expression, vascular permeability, apoptosis, and modulating leukocyte migration and adhesion. Deficiency in protein C, which occurs during systemic inflammatory activation, is highly associated with organ dysfunction. APC has shown efficacy in a number of preclinical models of thrombosis and ischemia, and the recombinant human APC drotrecogin alfa (activated), reduces mortality in patients with high-risk severe sepsis. The ability of APC to suppress pro-inflammatory pathways and enhance cellular survival suggests that APC plays a key role in the adaptive response to protect the vessel wall from insult and to enhance endothelial, cellular, and organ survival. The focus of this review will be to summarize the emerging data suggesting the potential therapeutic benefit of APC and related members of the pathway in the prevention and treatment of acute kidney injury.

Acute kidney injury (AKI) continues to have an exceedingly high mortality rate, despite advances in dialysis technology. Current dialysis therapies replace only the filtration function of the kidney, not the critical transport, metabolic, and endocrine functions of renal tubule cells. Replacement of these additional functions would provide more complete AKI therapy and thereby change the natural history of this disease process. A renal tubule assist device (RAD) containing living renal proximal tubule cells has been successfully engineered and has demonstrated differentiated absorptive, metabolic, and endocrine functions of normal kidney in vitro and ex vivo in animal experiments. The addition of the RAD containing human cells to conventional continuous renal replacement therapy has been shown in preclinical and clinical studies to have the potential to advance AKI treatment, from enhancing renal clearance to providing more complete renal replacement therapy. This “bioartificial kidney” demonstrates metabolic activity with systemic effects and improvement of survival in patients with AKI and multiorgan failure. It also appears to influence systemic leukocyte activation and the balance of inflammatory cytokines, suggesting that cell therapy by use of the RAD may improve morbidity and mortality by altering the proinflammatory state of patients with renal failure. In addition to providing cellular metabolic function, technologies directed toward disrupting systemic inflammatory response may well enhance the clinical outcome of critically ill patients in the future. Innovative approaches to intensive renal care such as the RAD may break the mold of current institutional dialysis therapies and provide numerous opportunities to develop lifesaving technologies.

Malignant mesothelioma is an aggressive tumour of the serosal surfaces with poor prognosis and increasing incidence due to widespread previous asbestos exposure. Relative chemotherapeutic and radiotherapeutic resistance makes malignant pleural mesothelioma (MPM) difficult to manage, even though encouraging results were achieved with multimodality treatment. Better knowledge of angiogenesis and molecular pathways involved in MPM seems to be the right way to define new targets for systemic treatment. Neoangiogenesis may be considered as a critical step in the development of mesothelioma. Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are autocrine growth factors in MPM and epidermal growth factor receptor (EGFR) appears highly expressed in this tumour. Tyrosine kinase inhibitors (TKIs) targeting growth factors like vandetanib, dasatinib, and angiogenesis inhibitors like bevacizumab, are among the most promising agents under evaluation in clinical trials. Mesothelioma is a malignancy which owes its chemoresistance to an apoptotic defect. Thus the introduction of new biologic drugs like vorinostat, bortezomib, everolimus and temsirolimus, in the treatment of MPM finds a strong rationale. This review focuses on the current target therapies and evaluates future biologic approaches for the systemic management of MPM.

The matrix metalloproteinases (MMPs) and their endogenous regulators, the tissue inhibitors of MMPs (TIMPs) are responsible for the physiological remodelling of the extracellular matrix (ECM) in healthy connective tissues. MMPs are also involved in the regulation of cell behaviour via the release of growth factors and cytokines from the substrates they cleave, increasing the magnitude of their effects. Excess MMP activity is associated with ECM destruction in various inflammatory conditions, such as osteoarthritis (OA), while MMP under-activity potentially impairs healing by promoting fibrosis and preventing the effective removal of scar tissue. Both direct (TIMPs, small molecule MMP inhibitor drugs, blocking antibodies and anti-sense technologies) and indirect (glucocorticoids and non-steroidal anti-inflammatory drugs, statins, anti-sense technologies and various phytochemicals) strategies for MMP inhibition have been proposed and investigated. The strategy of MMP inhibition for degenerative and neoplastic diseases has been relatively unsuccessful due to undesired sequelae, often caused by non-selectivity of the MMP inhibition method. Therapeutic strategies for MMP-related conditions ideally should regulate MMP activity in order to maintain the optimum balance between MMPs and TIMPs. By avoiding complete inhibition it may be possible to prevent the complications of MMP over- and underactivity. Furthermore, MMP sub-type specificity is critical for minimising detrimental off-target effects that have been observed with broad-spectrum MMP inhibitors. Any potential MMP inhibitor or modulator must be subjected to rigorous pharmacokinetic, toxicity and safety studies and data obtained using in vitro models must be verified in clinically relevant animal models before therapeutic use is considered.

After several decades of controversies, allergen specific immunotherapy (SIT) was recognized as an effective treatment for respiratory and hymenoptera allergy by the World Health Organization in 1998. SIT involves the administration (usually subcutaneous) of increasing doses of allergen in order to achieve a hyposensitization. Moreover, SIT is the only allergen-specific treatment capable of modifying the natural history of the disease. During the last 25 years, there was an impressive development of basic and clinical research in the field of SIT, with the goal of improving the safety, the efficacy and ameliorating the knowledge on the mechanisms of action. In this regard, the sublingual route (SLIT) was extensively studied and, recently, validated. SLIT can be considered a milestone in the history of SIT, since it is expected to change the clinical practice. In parallel, the growing detailed knowledge of the immunological mechanisms of SIT has provided the opportunity to explore new forms of specific hyposensitization, such as the use of adjuvants (bacterial and DNA-based), recombinant and engineered allergens, allergenic peptides and chimeric molecules. The last frontier seems to be the manipulation of genoma with replicons and allergen-encoding plasmids.