Actin cytoskeleton in ischemic acute renal failure

Abstract

A 36-year-old African American man was evaluated in the emergency room at Wishard Memorial Hospital following a motor vehicle accident. The patient's car was hit from behind, and as he fled the scene of the accident, he fell and rolled down a hill. He was subsequently detained by police and brought to the hospital for evaluation of diffuse trauma and myalgias. In the emergency room, he was awake and alert but tachycardic, with a heart rate of 136 beats/min, a respiratory rate of 20 breaths/min, and a blood pressure of 104/57 mm Hg. The trauma team's evaluation disclosed no significant injuries. However, he was admitted for evaluation and hydration, and because of an elevated serum creatinine level. His medical history was remarkable for a solitary right kidney, excessive alcohol intake, and use of crack cocaine, but he denied illicit intravenous drug use. He was taking no prescribed medications and had no history of diabetes, hypertension, or past surgeries. He had no known allergies. The baseline serum creatinine had been 1.2 mg/dL 8 years prior to admission. A review of systems was negative, with the exception of diarrhea over the previous 48 hours. Physical examination revealed a somewhat anxious, mildly obese black man in no apparent distress. The examination was otherwise within normal limits except for diffuse mild muscle pain. Laboratory values on admission revealed: serum sodium, 139 mEq/L; potassium, 4.9 mEq/L; chloride, 103 mEq/L; bicarbonate, 9 mEg/L; creatinine, 2.0 mg/dL; total protein, 6.5 g/dL; albumin, 3.5 g/dL; calcium, 9.2 mg/dL; bilirubin, 1.7 mg/dL; hemoglobin, 14.1 g/dL; white blood cell count, 12,600/mm2 with a normal differential; platelets, 245,000; a normal peripheral smear; and lactate, 4.7 mEq/L. Urinalysis disclosed cloudy urine containing >300 mg/dL protein; pH, 5.5; 4+ hemoglobin on dipstick; 5 red blood cells/high-power field; and no casts, but the urine was qualitatively positive for myoglobin. The initial serum creatine phosphokinase (CPK) was 14,565 units/mL; aspartate aminotransferase (AST), 2470; and alanine aminotransferase (ALT), 1785 U/mL. The patient was aggressively hydrated with normal saline at 200 mL/hour. After receiving 1 L, the infusion was altered to 5% glucose with 3 ampules of bicarbonate added per liter and administered at 300 mL/hour. Twenty-four hours following admission, the patient's laboratory values were: sodium, 133 mEq/L; potassium, 4.9 mEq/L; chloride, 96 mEq/L; bicarbonate, 22 mEq/L; blood urea nitrogen (BUN), 36 mg/dL; and creatinine, 2.3 mg/dL. The CPK was 134,470 U/mL; calcium, 6.1 mg/dL; magnesium, 3.7 mg/dL; and phosphate, 6.3 mg/mL. The albumin and total protein had decreased to 2.5 g/dL and 5.0 g/dL, respectively, and the hemoglobin had decreased to 11.7 g/dL without evidence of bleeding; the level remained stable thereafter. Over the first 24 hours, the patient had received several liters of fluid and had produced 2.2 L of urine. Repeat urinalysis was unchanged, except that the pH had increased to 7.0 and numerous amorphous casts were present. Indirect immunofluorescent staining revealed fragmented and vesicular material both within casts and free floating that stained for F-actin, actin depolymerizing factor, and cofilin Figure 1. Over the course of his hospital stay, he remained nonoliguric. The CPK, AST, and ALT levels steadily declined, and the serum creatinine peaked at 6.4 mg/dL on hospital day 6. He did not undergo renal replacement therapy and was discharged on day 8 from the hospital with a serum creatinine of 4.3 mg/dL that was decreasing daily. DR. BRUCE A. MOLITORIS (Director, Nephrology Division, Professor of Medicine, and Director, Indiana Center for Biological Microscopy, Indiana University School of Medicine, Indianapolis, Indiana, USA): This case represents a typical presentation of multifactorial acute renal failure (ARF). Prerenal azotemia, cocaine-mediated vasoconstriction and trauma resulted in acute tubular necrosis (ATN) secondary to rhabodmyolysis and renal hypoperfusion. The pathophysiology and clinical aspects of rhabdomyolysis-induced ATN have recently been reviewed1 and is little changed from the excellent 1996 article by Zager2. Therefore, this case will be used as a model of renal ischemia resulting in cellular actin alterations in epithelial, endothelial, and smooth muscle cells as a mechanism of cellular injury and death mediating kidney dysfunction. The patient was treated aggressively with volume replacement and bicarbonate therapy but he remained nonoliguric for the duration of his hospital stay. Since the level of serum creatinine increased by greater than 1.5 mg/dL, but the patient did not require renal replacement therapy, I would describe this as moderate ARF. Although the initial urine analysis was nondiagnostic, the subsequent presence of hemoglobin, myoglobin, and muddy brown casts Figure 1a left little doubt as to the diagnosis and etiology of ATN in this patient. In a previous case of rhabdomyolysis, secondary to rigorous exercise, we had the highly unusual advantage of having obtained an early renal biopsy, taken within 24 hours of the initiating event, to help delineate the pathophysiology of clinical ATN. As Figure 2 illustrates, there was severe proximal tubule injury with loss of apical microvilli, accumulation of proteinaceous material within the lumen, detachment of proximal tubule cells (PTCs), and increased white blood cells within the peritubular microvascular space. Unfortunately, the biopsy material was limited to the cortical region, so the outer medullary area could not be evaluated. The pathophysiology of ischemic ARF involves a complex interplay among cell injury, inflammation, and altered renal hemodynamics. While no single overarching theme can tie the myriad of injurious consequences together, alterations in the actin cytoskeleton have been shown to affect multiple cell types and physiologic processes within the kidney during and following ischemic...