Recent advances in the pharmacological management of sepsis-associated acute kidney injury

ABSTRACT

Introduction

Acute kidney injury is a common occurrence in patients with sepsis and portends a high mortality as well as increased morbidity with numerous sequelae including the development of chronic kidney disease. Currently, there are no specific therapies that either prevent AKI or hasten its recovery. Thus, clinicians typically rely on management of the underlying infection, optimization of hemodynamic parameters as well as avoidance of nephrotoxins to maximize outcomes.

Areas covered

Recent advances in understanding the mechanisms of sepsis as well as how these pathways may interact to lead to acute kidney injury have opened the door to the development of new, targeted therapies. This review focuses on the operative pathways in sepsis that have been identified as critical in leading to acute kidney injury and associated therapeutic agents that target these pathways.

Expert opinion

Despite increased understanding of the pathogenesis of sepsis, development of effective therapeutics to decrease the incidence of AKI have lagged. This is likely due to the complex pathophysiology with overlapping pathways and need for multiple therapies guided by specific biomarkers. Biomarkers that detail operative pathways may be able to guide the institution of more specific therapies with the hope for improved outcomes.

KEYWORDS:

• Acute kidney injury
• sepsis
• infection
• inflammation
• drugs
• management

Article highlights

• Sepsis is the leading cause of acute kidney injury (AKI) among critically ill patients. Occurrence and severity of AKI among septic patients is associated with higher mortality.

• Few, if any preventive or therapeutic interventions are currently available for AKI.

• Pathophysiology of sepsis associated AKI is complicated and involves several pathways.

• While systemic hemodynamic changes may play a role, increased concentration of inflammatory and anti-inflammatory cytokines and their effect on microcirculation and cell metabolism, as well as maladaptive cellular response appear to be the major contributors to the pathophysiology of sepsis associated AKI.

• Sepsis is associated with both an inflammatory and an anti-inflammatory response. Depending on the severity and phases of sepsis different sets of cytokines contribute to kidney damage.

• Up- and downregulation of certain subsets of immune cells and their apoptosis is evident in different stages of sepsis and contribute to development of AKI.

• Local production of cytokines and growth factor by the kidney cells also contribute to alterations in circulation, tubular flow, and tissue damage.

• Unlike many other causes of acute tubular injury in which tubular cells develop necrosis, apoptosis of tubular epithelial cells is the dominant finding in sepsis-induced AKI.

• Alkaline phosphatase provides kidney protection in sepsis through dephosphorylation of both toxins such as LPS and extracellular ATP and thereby reducing inflammation and inducing vasodilation.

• Human recombinant alkaline phosphatase is the only compound currently in human clinical trials of sepsis-induced AKI.

• Norepinephrine, vasopressin and angiotensin II have been associated with better outcomes in patients with septic shock and in the case of angiotensin II, sepsis-induced AKI.

Declaration of interest

The author(s) have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.