Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Sepsis-Induced Acute Kidney Injury
Objectives
This chapter will:
- 1.
Review the epidemiology of sepsis-induced acute kidney injury.
- 2.
Discuss the evidence supporting novel mechanisms leading to acute kidney injury in the setting of sepsis.
- 3.
Review novel approaches to the diagnosis of sepsis-induced acute kidney injury.
- 4.
Review current and potential therapies in the context of novel mechanisms of disease.
Sepsis is the most common cause of acute kidney injury (AKI) in critically ill patients, affecting 40% to 50% of cases. Importantly, the development of AKI in the setting of sepsis increases the risk of in-hospital death sixfold to eightfold, and among survivors, the risk of progression to chronic kidney disease. Despite this, the mechanisms by which sepsis causes AKI are not well understood. Therefore current therapy remains reactive rather than preventive and nonspecific. Given that the leading clinical conditions associated with AKI, namely, sepsis, major surgery, heart failure, and hypovolemia, are associated with hypoperfusion, it is tempting to attribute all AKI to ischemia. However, an increasing body of evidence suggests that at least in a portion of patients, AKI can occur in the absence of overt signs of hypoperfusion. Langenberg et al. showed, for example, that AKI developed in septic animals despite normal or increased renal blood flow. In a human study, Prowle et al. were able to demonstrate that decreased renal blood flow (RBF) was not a universal finding, even in patients with well-established sepsis-induced AKI. Furthermore, in a large-scale study, including more than 1800 patients with community-acquired pneumonia, Murugan et al. found that a fifth to a quarter of patients with nonsevere pneumonia who were never admitted to an ICU and whom never displayed overt signs of shock or hypoperfusion still developed AKI. Complementary to the insights from clinical and in vivo studies, in vitro experiments in which hemodynamics are no longer relevant have shown that incubation of human renal tubular epithelial cells with plasma from septic patients induces damage of tubular epithelial cells evidenced by the increased release of tubular enzymes, elevated permeability, and the decreased expression of key molecules for tubular functional integrity. Taken together these data provide evidence that, at least in some patients, renal injury cannot be explained solely on the basis of the classic paradigm of hypoperfusion and that other mechanisms must come into play.
Recent studies in septic animals and postmortem observations in septic humans have provided evidence of what sepsis-induced AKI actually looks like. Despite representing the latest stages of the disease, these kidneys were characterized by a strikingly bland histology with focal areas of tubular injury, which was also entirely discordant with the profound functional impairment seen premortem. In addition, and contrary to prior understanding, necrosis and apoptosis were largely absent, which not only argues in favor of the notion that sepsis-induced AKI is not equivalent to acute tubular necrosis (ATN) but also supports the hypothesis that at least in the early stages, this phenotype may represent a concerted, organized, common underlying adaptive mechanism.
A consistent observation in these studies, regardless of species, disease stage, severity, or organ examined, appears to be the presence of three main alterations: inflammation, diffuse microcirculatory flow abnormalities, and cellular bioenergetic adaptive responses to injury. The study and understanding of these three domains may provide a roadmap to unravel the mechanisms by which sepsis causes AKI and perhaps organ injury in general and may facilitate the development of more targeted therapies. In this chapter we provide an overview of the current clinical classification system and the epidemiology of sepsis-induced AKI and then focus on the roles the above-mentioned mechanisms may play in the genesis of sepsis-induced AKI and on the discussion of potential therapeutic implications.
Definition of Acute Kidney Injury in the Clinical Setting
The definition of AKI has undergone important transformations in recent years. Traditionally it was based on the assessment of renal function, and in particular, on the assessment of changes in glomerular filtration rate (GFR). Although practical at the bedside, this approach is limited by the fact that functional changes do not necessarily reflect structural alterations. An additional limitation is the interpretation of GFR through the quantification of creatinine. Although creatinine levels correlate well with GFR in steady-state conditions, AKI usually occurs in the setting of rapidly changing hemodynamic, microcirculatory, metabolic, and local conditions. Finally, the assessment of renal dysfunction based on glomerular function does not take into account the presence of tubular dysfunction, which has been recognized as an important pathophysiologic event. Despite these limitations, the standardization of two measures of glomerular function has provided the scientific community with a tool, in a common language, to assess the occurrence of AKI. These measures are serum creatinine and urine output. Using these tools, AKI has been defined as any of the following:
-
Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours
-
Increase in serum creatinine to ≥1.5 times baseline, presumed or known to have occurred in the previous 7 days
-
Urinary volume < 0.5 mL/kg/hr for 6 hours
Several classification systems have been developed, each with virtues and caveats, including the Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria, the Acute Kidney Injury Network (AKIN) criteria, and the pRIFLE (a modification for pediatrics). More recently, in an attempt to harmonize RIFLE, AKIN, and pRIFLE, the Kidney Disease: Improving Global Outcomes (KDIGO) has proposed a unified version of these classification systems, which is shown in Table 90.1 .
TABLE 90.1
KDIGO Criteria and Staging for Acute Kidney Injury
| STAGE | SERUM CREATININE | URINE OUTPUT |
|---|---|---|
| 1 | 1.5–1.9 times baseline creatinine OR ≥0.3 mg/dL (≥26.5 µmol/L) increase |
<0.5 mL/kg/hr for 6–12 hr |
| 2 | 2.0–2.9 times baseline creatinine | <0.5 mL/kg/hr for ≥12 hr |
| 3 | 3.0 times baseline creatinine OR Increase in serum creatinine ≥ 4.0 mg/dL (353.6 µmol/L) OR Initiation of renal-replacement therapy OR In patients < 18 years, decrease in eGFR to <35 mL/min/1.73 m 2 |
<0.3 mL/kg/hr for ≥24 hr; OR Anuria for >12 hr |
KDIGO, Kidney Disease: Improving Global Outcomes.
Epidemiology of Sepsis-Induced Acute Kidney Injury
Sepsis is the leading cause of AKI in acutely ill patients. Acute kidney injury occurs in as many as 40% to 50% of septic critically ill patients, which increases the risk of death sixfold to eightfold and the risk of advancing to renal fibrosis and chronic kidney disease. Importantly, a large proportion of patients who usually are considered to be less severely compromised and thus at lower risk still develop AKI. Murugan et al. showed in a large cohort of patients admitted to the emergency department with nonsevere community-acquired pneumonia that 34% of these patients developed AKI, many of whom never required admission to an ICU. This suggests that AKI is related not only to shock states or critical illness and that patients with non–life-threatening infections also may be at high risk of developing renal dysfunction and its short- and long-term consequences.
Novel Concepts in the Pathophysiology of Sepsis-Induced Acute Kidney Injury
Recent evidence suggests that the origin of most cases of AKI is multifaceted and that several concurrent mechanisms may be at play. These mechanisms include inflammation; profound, heterogeneous distortion of microvascular flow at the peritubular and glomerular levels; and tubular epithelial cell injury and impairment. Given that these three major events occur early in the course of sepsis and that cell death seldom occurs, early sepsis-induced AKI may be the clinical and biochemical manifestation of tubular cell responses to injury. Evidence from animal studies suggests that such response is, at least in part, adaptive, in that it is driven by metabolic reprogramming and by downregulation and reprioritization of energy expenditure to avoid energy imbalance favoring individual cell survival processes (e.g., maintenance of membrane potential and cell cycle arrest) at the expense of organ function (i.e., tubular absorption and secretion of solutes).
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here