Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Abstract

Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (,1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P , 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 6 9.5% and 32.3 6 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P , 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. Conclusions: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.Keywords: sepsis; apoptosis; necrosis; autophagy; kidney Sepsis causes profound myocardial depression, and echocardiography frequently reveals severe biventricular dysfunction (1-5). Sepsis also induces renal insufficiency in 30 to 60% of patients, up to half of whom require dialysis (6-10). The mechanistic basis for cardiac and renal dysfunction occurring in sepsis is controversial (1,5,7,9,(11)(12)(13)(14)(15)(16). The degree to which apoptosis, necrosis, or autophagy contribute to cardiac and renal dysfunction in sepsis is unresolved (2,3,(16)(17)(18)(19).Although a few well controlled studies have been performed, extensive cell death in hearts or kidneys in patients dying of sepsis has not been described, leading investigators to postulate that cellular "hibernation" or metabolic suppression and not cell death is the basis of sepsis-induced organ failure (11,13,14,16,18,(20)(21)(22). Cardiac dysfunction in sepsis is reversible, and the majority of renal failure patients who survive sepsis recover baseline renal function; these observations are consistent with organ "hibernation" (1, ...

Septic acute kidney injury in critically ill patients – a single-center study on its incidence, clinical characteristics, and outcome predictors

“…18 Despite more patients with septic AKI required RRT when compared with non-septic AKI, they had better renal recovery. This finding is actually similar to that reported by Cruz et al and Bagshaw et al, 8,19 signifying a difference in the pathophysiology [20][21][22] between septic and non-septic AKI. Instead, Singer et al proposed the cell cycle arrest hypothesis and mentioned that multiorgan failure induced by critical illness is primary a functional, rather than structural abnormality.…”

Cellular and Molecular Mechanisms of AKI

“…20 Not unexpectedly, mitochondrial pathology is a shared feature across diverse forms of human AKI, ranging from renal ischemia to sepsis and nephrotoxic injury. [21][22][23][24] Ultrastructural features of mitochondrial injury include swelling with rarefaction of the cristae and mitochondrial fragmentation. With few exceptions, the spectrum of experimental rodent models of AKI demonstrates widespread mitochondrial injury, [25][26][27] and the onset of mitochondrial pathology typically precedes detectable loss of renal function.…”

Renal Hemodynamics in AKI

“…Persistent perfusion deficits and diminished tissue oxygenation have been shown to be of greater magnitude in the highly vulnerable outer medulla compared with the cortex in a variety of experimental models, including total ischemia, radiocontrast nephropathy, and nonsteroidal anti-inflammatory drugand other drug-induced AKI etiologies, including fluid therapy. 23,39 The renal cortex microcirculation is significantly compromised in sepsis models 3,40 and humans, 41 where inhomogeneous patchy areas of microischemia can occur (Figure 2). These heterogeneous areas of hypoxia and normal oxygenation define the nature of hemodynamic alterations leading to inflammation, because it is expected that there is increased reactive oxygen species production associated with hypoxia-normoxia interactions.…”