RM is a syndrome characterized by rapid breakdown and leakage of skeletal muscle cell contents, such as myoglobin, CK, and other cytokines. During the past several decades, there have been multiple and diverse causes of RM, which include trauma, toxins, infections, drugs, and strenuous exercise[20–26]. The major cause of RM in our study was determined to be infections (36.2%), including Staphylococcus aureus, Streptococcus pneumoniae, and klebsiella pneumoniae.. All 86 cases presented with certain classical symptoms, such as muscle weakness, myalgia, or dark - colored urine, along with significantly higher CK levels, and without red blood cells in the urine sediment.
Among the various forms of RM, the most common pathophysiologic feature is attributed to a rise in intracellular ionized calcium from the injury muscles, which brings a loss of the transcellular calcium gradient, and this eventually leads to cell death . The result of these cellular impairments is the release of CK, myoglobin, and various electrolytes into the blood circulation, and this results in a classic clinical presentation, as well as RM – induced AKI. RM itself makes a fluid sequestration, which decreases renal perfusion, activates the Renin-Angiotensin -Aldosterone System (RAAS), and results in renal vasoconstriction. In addition, RM-associated AKI is believed to be triggered by myoglobin, which in this context is considered to be a toxin that causes renal dysfunction. Myoglobin could potentially precipitate with Tamm-Horsfall protein, which could lead to the tubular obstruction. Additionally, the heme moiety released from myoglobin could promote free radical formation, which accelerates direct and ischemic tubular injury. All of the above potentially contribute to RM – induced AKI.
According to the RIFLE classification system, all participants in our study belonged to the “Risk” “Injury” or “Failure” stages of renal function. In order to prevent the deterioration of RM-associated AKI, traditional fluid resuscitation, including crystal and colloid liquid, was applied for all patients. For those with remarkable metabolic acidosis, sodium bicarbonate therapy was used to stabilize the homeostasis. Additionally, CRRT was chosen because all patients with RM-associated AKI met at least one of the intervention criteria.
Data from several previous studies have identified the effect of CRRT on RM- associated AKI. As early as 2012, Zhang Ling et.al showed that CVVH could be employed to clear myoglobin effectively in patients with RM – induced AKI and presented oliguria. After that, Wangxin Tang et.al (2013) confirmed the renal protective effects of CVVH in a glycerol – injection – induced RM model; specifically they found that CVVH could improve mitochondrial function and reduce tubular epithelial apoptosis through a dose – effect relationship. In addition, there have been an increasing number of reports on High Cut-Off (HCO) hemodiailtration for removal of myoglobin in RM-associated AKI. Research published by Nils Heyne et al (2012) concluded that HCO CRRT was a highly effective means for elimination of myoglobin and a novel therapeutic approach to severe RM – induced AKI. Similarly, Vladimir Premru et al (2013) also supported the use of HCO hemodiafiltration for rapid initial removal of myoglobin in severe acute myoglobinuric kidney injury. In recent years, several case reports have investigated the effect of plasma exchange, as well as plasma filtration adsorption, on RM-associated AKI, and proved a successful reduction of myoglobin levels, along with preservation of renal function[11, 12, 29]. Participants in our study, had a significantly high McMahon score, as well as worse renal function on admission, which suggested a necessity for renal replacement therapy. Despite the fact that CRRT is reputedly safe and efficacious for RM – induced AKI, questions have still been raised regarding its use.
According to the British Renal Association guidelines about AKI, if the urine output is > 1,000 mL/D, and serum creatinine ≤ 265umol/L, CRRT could be considered for suspension . However, for RM-associated AKI, whether CK levels should be taken into account for CRRT termination, seems to be a common problem for therapy. For one, moderate RM with CK above 5,000 U/L, predicts an increased risk of renal injury. Additionally, severe RM, which CK > 15,000 U/L, shows a higher risk of dialysis. Further,, patients with a higher level of CK suggests a potential ongoing muscle injury or incomplete recovery after treatments.
Two retrospective reviews of 30 and 41 cases about exertional RM-associated AKI, found discharged CK values ranging from 1,410 to 94,665 U/L and 10 to 61,617 U/L[30, 31]. Mario Pezzi et.al (2017) reported case series about the use of coupled plasma filtration adsorption (CPFA) in traumatic RM, and the lowest CK level was 9,000 U/L, and the highest level was 20,000 U/L when CPFA stopped. Olcay Dilken et.al (2019) presented a successful reduction of CK levels to 40,000 U/L in severe RM using extracorporeal blood purification (CytoSorb) after termination. Recently, an article published by Eka Laksmi Hidayati et al (2020) displayed a progressive reduction of CK levels to 61 U/L for multiple wasp stings-induced RM through continuous plasma exchange. To our knowledge, there is still no consensus on the confirmed CK levels that should be reduced by CRRT.
In our study, we investigated whether CK levels should also be considered in CRRT therapy for patients with RM-associated AKI. Patients were divided into two groups, and those with CK > 5,000 U/L after termination were assigned to the experimental group. Laboratory examinations, such as routine blood tests, CK levels, myoglobin, renal function indicators, and inflammatory biomarkers, were comparable between the two groups on admission. After CRRT termination, the APACHEII score, as well as McMahon score, revealed differences. The average McMahon score for all patients was below six, which predicted a lower requirement for renal replacement therapy again. The result of our study also found that serum myoglobin was significantly higher in the experimental group, except for an obvious high level of CK. The renal function indicators, such as urine output, creatinine, urea nitrogen, and eGFR, along with inflammatory biomarkers, were consistent between patients after CRRT. Although in-hospital mortality showed no difference, the slength of stay for in-hospital, as well as ICU, was significantly lower, and the CRRT period was significantly shorter for the higher CK level group. Another important finding was a positive correlation between CK and myoglobin after CRRT treatment, but there was no evidence that CK had any relationship to renal function indicators.
To the best of our knowledge, there is an accumulation of CK and myoglobin in the blood after muscle damage. CK reaches its maximum value after around 24 hours, and then is eliminated by oxidation in the blood; this process is independent from liver and kidney function. Myoglobin reaches its maximum value within 12h and is rapidly cleaned up by the kidneys, if kidney function is unrestricted CK and myoglobin are sensitive indicators for striated muscle injury. For patients with RM-associated AKI, a large amount of myoglobin is released into the blood, which exceeds renal excretion capacities and causes nephrotoxic effects. In this case, the levels of CK and myoglobin may show a consistent exponential growth with respect to each other, along with persistent muscle damage. CRRT, an approach to aggressively remove the serum uremia-related molecules (such as creatinine and urea nitrogen), mainly aims to protect renal function, while its effect on sustained muscle injury is limited. Our study found that there was no relationship between CK and renal function markers after CRRT by linear correlation analysis.
Lastly, we performed a subgroup analysis for patients with CK > 5,000 U/L, since it included those with severe RM at the end of CRRT. It is interesting to note that neither in-hospital mortality nor length of stay showed any difference among subgroups. These results suggest that if renal functions are significantly improved by CRRT, CK levels could be gradually returned to normal through traditional supportive treatments, such as fluid resuscitation and alkalization of urine. Importantly, on the premise of improved renal functions, a higher CK level might not be an independent risk factor for in-hospital mortality.
There were several potential limitations associated with the research presented here that need to be highlighted. First, our study only divided patients into two groups according to CK levels after CRRT termination. We could not identify an appropriate range that CK should be decreased to that would guarantee low recurrence of RM - induced AKI. Second, since there was a positive correlation between CK and myoglobin at the end of CRRT, it is unlcear whether high levels of myoglobin would lead to a poor prognosis, and this requires further investigation.. Lastly, as this was a single center and retrospective analysis, selection bias cannot be ruled out. In addition, with the development of new and more advanced therapeutics over the past decade,, relative biases cannot be ruled out. It is possible that a larger, randomized and controlled trial over an extended period of time could help to override these limitations.