Renal protective effects of early continuous venovenous hemofiltration in rhabdomyolysis: improved renal mitochondrial dysfunction and inhibited apoptosis. (Paden)

Artif Organs. 2013 Apr;37(4):390-400  PMID: 23441644

Rhabdomyolysis (RM) and subsequent myoglobin (Mb) deposition can lead to acute kidney injury. Continuous venovenous hemofiltration (CVVH) can remove Mb, but direct renal protection is unclear. We hypothesized that CVVH can improve renal mitochondrial dysfunction in its early stage. Twenty-four mongrel dogs were randomly divided into four groups: (A) control; (B) model; (C) model + CVVH (50 mL/kg/h); and (D) model + CVVH (30 mL/kg/h). RM was induced by glycerol via intramuscular injection. The dogs were closely monitored for urine flow and renal function. Mb, plasma tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. After 8 h of CVVH, the morphological changes of renal mitochondria were observed and mitochondrial function indicators (reactive oxygen species, malondialdehyde, and respiratory control index) were detected. Western blot analysis was used to detect the expression of Mb, TNF-α, and IL-6 in renal tubules. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay method and Western blot analysis were used to detect apoptosis and apoptosis-related proteins. In group B, the dog urine output gradually decreased with increased blood creatinine. In groups C and D, the urine output was normal and stable. CVVH effectively eliminated Mb. High-dose CVVH was significantly better for removal efficiency than low-dose CVVH. CVVH significantly reduced the deposition of circulating Mb in the kidney in a dose-dependent manner. The impact of CVVH on TNF-α and IL-6 were not observed. The morphological changes of mitochondria and function indicators were significantly improved in group C compared with groups D and B. Compared with group B, renal apoptosis and apoptosis-related protein expression were inhibited in groups C and D. Group C was significantly better for mitochondrial improvement and apoptosis inhibition than group D. At the cellular and molecular level, CVVH can improve renal mitochondrial function and inhibit cell apoptosis. Early CVVH can protect from RM-caused renal injuries in a dose-dependent manner.

© 2013, Copyright the Authors. Artificial Organs © 2013, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

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Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. (Fortenberry)

Am J Respir Crit Care Med. 2013 Mar 1;187(5):509-17. PMID: 23348975

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 ± 9.5% and 32.3 ± 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.

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