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A rhabdomyolysis protocol (RP) with mannitol and bicarbonate to prevent acute renal dysfunction (ARD, creatinine >2.0 mg/dL) remains controversial. Patients with creatine kinase (CK) greater than 2,000 U/L over a 10-year period were identified. Shock, Injury Severity Score, massive transfusion, intravenous contrast exposure, and RP use were evaluated. RP was initiated for a CK greater than 10,000 U/L (first half of the study) or greater than 20,000 U/L (second half). Multivariable analyses were used to identify predictors of ARD and the independent effect of the RP. Seventy-seven patients were identified, 24 (31%) developed ARD, and 4 (5%) required hemodialysis. After controlling for other risk factors, peak CK greater than 10,000 U/L (odds ratio 8.6, P = .016) and failure to implement RP (odds ratio 5.7, P = .030) were independent predictors of ARD. Among patients with CK greater than 10,000, ARD developed in 26% of patients with the RP versus 70% without it (P = .008). Reduced ARD was noted with RP. A prospective controlled study is still warranted. •The 2 major treatments for rhabdomyolysis are alkaline diuresis and crystalloid.•The use of a rhabdomyolysis protocol with mannitol and bicarbonate remains debated.•Use of a rhabdomyolysis protocol was supported for creatinine kinase greater than 10,000 U/L.•Evaluation of rhabdomyolysis strategies in a prospective randomized trial is needed.

Background Crush syndrome (consisting of hyperkalemia, acidosis, hypocalcemia, and acute kidney injury), is the second-most common cause of death in earthquakes, and a frequent cause of critical illness after burn, blast, and prolonged immobility. No specific treatment exists; supportive treatment is burdensome, contributing to deaths in austere environments, especially disasters and conflicts. There is urgent need for specific treatment which reduces burden of care. Crush syndrome is dependent on the renal megalin-dependent endocytic system. We investigated whether cilastatin sodium, a megalin inhibitor which is US Food and Drug Administration-approved for another purpose, has efficacy as a crush syndrome treatment in a highly translational large animal trauma model. Methods Anesthetized 40 kg female pigs received blunt muscle injury and 48 h protocolized critical care management. Cilastatin sodium or vehicle was administered 30 minutes after injury in randomized, blinded fashion. Renal function and injury were assessed by repeated quantification of iohexol clearance, serial plasma assessment, and histopathologic analysis. Linear mixed models and Kaplan-Meier analysis were used to assess differences. A power estimate for a clinical trial was performed. Results Here we show that cilastatin has efficacy to reduce kidney impairment from crush syndrome, resulting in increased measured glomerular filtration rate and reduced creatinine, histopathologic kidney damage, and need for treatment of hyperkalemia. Animals receiving cilastatin excrete more myoglobin in the urine and are more likely to recover from acute kidney injury. The effect size suggests feasibility of future clinical trials. Conclusions Cilastatin sodium has efficacy to ameliorate crush syndrome in a translational large animal model These results support further efforts to translate this potential therapy. Munhall et al. perform a large-animal trial of a repurposable specific drug treatment for crush syndrome, the second-most common cause of death in earthquakes. Cilastatin sodium is effective to ameliorate kidney injury and reduces the lethal elevation of blood potassium, suggesting strong potential for further steps toward translation. Plain language summary Crush syndrome occurs when people are crushed under rubble, or by explosions. It is the second-most common cause of death in earthquakes, and frequent in war. Crushing muscle releases a toxin which causes kidney failure and death from excessive blood potassium, which stops the heart. Treatment requires intensive care, which is often not available in disasters and war zones. Using anesthetized pigs with experimental crush syndrome, we found that the drug cilastatin reduced kidney failure and excessive blood potassium, and increased the likelihood of kidney recovery. Because cilastatin is already approved for another purpose, the path to use for treatment is less challenging than for new drugs. These results may pave the way for human trials of a new treatment.

Cardiorenal syndrome type 1 (CRS‐1) acute kidney injury (AKI) is a critical complication of acute cardiovascular disease but is poorly understood. AKI induces acute albuminuria. As chronic albuminuria is associated with worsening kidney disease and albumin has been implicated in tubular epithelial injury, we investigated whether albumin participates in CRS‐1, and whether CRS‐1 alters renal albumin handling. We report the role of albumin in in vivo and in vitro CRS‐1 models. An established translational model, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) induced severe acute albuminuria which correlated with tubular epithelial cell death. In vivo microscopy demonstrated CA/CPR‐induced glomerular filtration of exogenous albumin, while administration of exogenous albumin after CA/CPR worsened AKI compared to iso‐oncotic control. Increased albumin signal was observed in the proximal tubules of CA/CPR mice compared to sham. Comparison of albumin flux from tubular lumen to epithelial cells revealed saturated albumin transport within minutes of albumin injection after CA/CPR. In vitro, HK2 cells (human kidney tubular epithelial cells), exposed to oxygen‐glucose deprivation were injured by albumin in a dose dependent fashion. This interference was unchanged by the tubular endocytic receptor megalin. In conclusion, CRS‐1 alters albumin filtration and tubular uptake, leading to increased tubular exposure to albumin, which is injurious to tubular epithelial cells, worsening AKI. Our findings shed light on the pathophysiology of renal albumin and may guide interventions such as albumin resuscitation to improve CRS‐1 outcomes. This investigation may have important translational relevance for patients that receive exogenous albumin as part of their CRS‐1 treatment regimen. Administered albumin worsens AKI in cardiorenal syndrome type 1; this is associated with increased albumin filtration and altered tubular albumin uptake.

In this study of three strategies — hypothermia, machine perfusion, or both — for pretransplantation preservation of kidneys from brain-dead donors, hypothermia was found to be inferior to machine perfusion.