Continuous Venovenous Hemodiafiltration Versus Standard Medical Therapy for the Prevention of Rhabdomyolysis-Induced Acute Kidney Injury: A Retrospective Cohort Study

Abstract

Aim: To determine whether continuous venovenous hemodiafiltration (CVVHDF) plus standard medical therapy (SMT) vs. SMT alone prevents rhabdomyolysis (RM)-induced acute kidney injury (AKI) and to analyze the related health economics.

Methods: This retrospective cohort study involved patients with RM without AKI, coronary heart disease, or chronic kidney disease treated with CVVHDF plus SMT (treatment group, n = 9). Matched patients with RM without AKI treated with SMT only served as controls (1:1 ratio). Baseline characteristics, biochemical indexes, renal survival data, and health economic data were compared between groups. In the treatment group, some biochemical data were compared at different time points.

Results: At 2 and 7 days after admission, serum biochemical indices (e.g., myoglobin, creatine kinase, creatinine, and blood urea nitrogen) did not differ between the two groups. Total (P = 0.011) and daily hospitalization costs (P = 0.002) were higher in the treatment group than in the control group. After 53 months of follow-up, no patient developed increased serum creatinine, except for 1 treatment-group patient who died of acute myocardial infarction. In the treatment group, myoglobin levels significantly differed before and after the first CVVHDF treatment (P = 0.008), and serum myoglobin, serum creatinine, and blood urea nitrogen decreased significantly at different time points after CVVHDF.

Conclusions: Although CVVHDF facilitated myoglobin elimination, its addition to SMT did not improve serum myoglobin or other biochemical indices or the long-term renal prognosis. Despite similar hospitalization durations, both total and daily hospitalization costs were higher in the treatment group.

1. Introduction

Rhabdomyolysis (RM) is a clinical syndrome characterized by the injury and disintegration of skeletal muscle fibers followed by the release of myoglobin, electrolytes, enzymes, and other components of the injured skeletal muscle cells into the blood circulation[1, 2]. RM can be caused by a variety of traumatic and non-traumatic factors, such as excessive exercise, crush injuries, statins, poisoning, infections, and autoimmune diseases. The main clinical manifestations of RM are muscle pain, weakness, and dark tea-colored urine. Mild RM may be asymptomatic, but as the creatine kinase level rises beyond a certain threshold, severe complications such as electrolyte imbalance/disturbances, acute kidney injury (AKI), and disseminated intravascular coagulation may occur[3]. AKI is the most common and most severe complication of RM, and is reported to occur in 10–60% of patients with RM[4]. The occurrence of AKI can significantly worsen the prognosis of patients with RM, and the reported mortality rates of RM patients who develop AKI range from 7–80%[5]. Among RM patients in the intensive care unit, the mortality rate has been reported to be 59% when AKI was present and 22% when it was not[6].

In addition to conventional drug therapy, renal replacement therapy (RRT), including continuous or intermittent hemodialysis, hemofiltration, and hemodiafiltration, plays an important role in the treatment of RM-induced AKI. For patients with AKI, especially when associated with life-threatening complications such as hyperkalemia, hypercalcemia, hyperazotemia, anuria, or hyperhydration, RRT is indispensable[7]. RRT can remove uremic toxins and excess water, regulate the stability of the internal environment, and create a good environment for the recovery of renal and other organ functions. However, it is unclear whether RRT can prevent the occurrence of AKI in patients with RM. Although it has been reported that hemofiltration can effectively remove a certain amount of myoglobin (molecular weight, 17 kDa) from the blood of patients with RM[8, 9], most of these studies were case reports without control groups, and did not use the recovery of renal function and long-term prognosis as the study end-points. Upon searching the literature, we found no well-designed cohort study or randomized controlled trial probing the preventive effects of hemofiltration or hemodiafiltration on RM-induced AKI. Therefore, in this retrospective cohort study, we compared the effectiveness of continuous venovenous hemodiafiltration (CVVHDF) combined with standard medical therapy (SMT) versus SMT alone in preventing AKI in patients with RM. In addition, we conducted a health economic analysis of the two treatment arms.

2. Materials And Methods

3. Results

4. Discussion

To our knowledge, the present retrospective cohort study is the first to compare the effectiveness of CVVHDF combined with SMT vs. SMT alone in preventing the occurrence of AKI in patients with RM and to analyze the related health costs. Our findings demonstrate that although a single session of CVVHDF could facilitate myoglobin elimination, its addition to SMT did not significantly improve the serum Mb level or the levels of other biochemical indices or the long-term renal prognosis. However, the addition of CVVHDF to SMT did greatly increase the hospitalization costs.

While the therapeutic effects of RRT on RM-induced AKI have been extensively studied, its usefulness as a preventive measure is yet to be determined. Currently available blood-purification techniques, such as high-flux hemodialysis, hemofiltration, hemodiafiltration, and plasmapheresis, can effectively eliminate myoglobin, which is a small protein molecule with a molecular weight of 17 kDa. Some studies have investigated the capacity of these blood-purification techniques to eliminate myoglobin. Sorrentino et al. measured the myoglobin clearance in 6 patients with RM-induced AKI, and found that high-flux hemodialysis effectively eliminated myoglobin, with a median myoglobin clearance of 90.5 mL/min (range, 52.4–126.3 mL/min) and a median myoglobin removal per treatment hour of 0.54 g (range, 0.15–2.21 g)[11]. Naka et al. reported the case of a 53-year-old woman with RM and AKI for whom hemofiltration resulted in a myoglobin clearance of 30.5–39.2 mL/min and removed 0.55–0.64 g myoglobin/treatment hour for 8 hours of treatment[12]. In a case series of 6 patients with RM-induced AKI, the mean myoglobin clearance was 81 mL/min (range, 42–131 mL/min) after hemodiafiltration with a postdilutional fluid substitution rate of 2–3 L/h[13]. A control study with a two-stage crossover design also verified that hemodiafiltration could effectively clear myoglobin[14]. Although we did not find any studies that confirmed that plasmapheresis eliminates myoglobin, we speculate that this is definitely the case because during plasmapheresis, plasma is non-selectively discarded and replaced with exogenous fresh plasma.

However, none of the above studies indicate whether these therapeutic measures can prevent the occurrence of RM-induced AKI because effective myoglobin clearance does not directly indicate a good prognosis[15]. Hence, cohort studies or randomized controlled trials with good control groups and renal survival data are required to directly investigate the ability of blood-purification techniques to prevent RM-induced AKI. We were unable to find any such studies via a literature search. We did find a systematic review that investigated the therapeutic effects of continuous renal replacement therapy (CRRT) for RM and RM-induced AKI[16]. This review included 4 studies from China, one of which contained patients without AKI and the other 3 studies contained patients with AKI. The review concluded that although CRRT may provide some benefits for RM patients, the poor methodological quality of the included studies and the lack of data on clinically important outcomes meant that there was insufficient evidence to discern any likely benefits of CRRT over conventional therapy for the prevention of RM-induced AKI[16]. A case report found that plasmapheresis did not prevent renal failure in a patient with RM-induced AKI[17]. We found no other study that explored the protective effects of plasmapheresis against RM-induced AKI. However, several studies have explored the therapeutic effects of plasmapheresis on RM-induced AKI and found that this treatment was effective[18, 19]. Nevertheless, as these studies were case reports or case analyses without a control group, Szpirt considered that the use of plasmapheresis was not justified for the treatment of RM and AKI[20].

CVVHDF is the most common CRRT technique, and combines hemofiltration and hemodialysis, so it could effectively clear both middle-molecular-weight urotoxins and micromolecular urotoxins, including myoglobin. Therefore, we conducted this retrospective cohort study to determine whether CVVHDF combined with the SMT vs. SMT only could prevent RM-induced AKI. Our study showed that although a single CVVHDF treatment facilitated myoglobin elimination, compared with SMT only, CVVHDF combined with SMT did not significantly improve the serum Mb levels or other biochemical indices or the long-term renal prognosis of patients with RM. Thus, we consider that the available clinical evidence does not show any benefit of hemodiafiltration to prevent RM-induced AKI.

Interestingly, an animal experiment was performed to explore the direct renal protective effect of continuous venovenous hemofiltration (CVVH) in the early stage of RM[21]. In this study, the 2 hind legs of mongrel dogs were intramuscularly injected with 50% hypertonic glycerol to establish RM, and 2 h after the injection, CVVH was performed for 8 h. The study confirmed that at the cellular and molecular levels, CVVH treatment mitigated myoglobin-induced mitochondrial damage by inhibiting the mitochondrial apoptotic pathway and cell apoptosis; the treatment also delayed the occurrence of oliguria and protected the renal function during the early stage of RM development[21]. However, we consider that this single animal experiment cannot accurately represent the actual clinical condition due to the following reasons: First, in clinical practice, patients generally receive blood-purification treatments 1–2 days or even longer after the occurrence of RM, rather than being treated 2 h after the pathogenic onset like in the animal experiment; by the time blood-purification treatment is initiated, myoglobin has already caused some renal damage at the molecular level. Second, the CRRT regimen in most dialysis centers is 6–12 h daily or every other day for several days, so the observation period should be longer; however, in the animal experiment, observations were performed before and after a single treatment. Third, even with extracorporeal circulation therapy, the kidneys are still the main organs responsible for removing myoglobin.

In our study, we also conducted a health economic analysis, and found that although the total duration of hospitalization did not differ between the treatment and control groups, both the total and daily hospitalization costs were significantly higher in the former than in the latter. Although few studies conduct health economic analyses, the cost of healthcare is a problem that cannot be ignored. CRRT, especially, is an expensive treatment requiring more medical insurance funds and patients’ financial resources, especially in less-developed areas.

The present study has certain limitations. First, this was a retrospective study with a small sample size. More large-scale prospective studies are required to explore this issue, including cohort studies and randomized controlled trials. Second, the ability of high-flux hemodialysis and plasmapheresis to prevent RM-induced AKI is also worth exploring.

5. Conclusion

In summary, although a single CVVHDF treatment could facilitate myoglobin elimination, CVVHDF combined with SMT as compared to SMT only did not significantly improve the serum Mb levels or other biochemical indices or the long-term renal prognosis. Although the total hospitalization duration did not differ between the two groups, CVVHDF combined with SMT obviously increased the total and daily hospitalization costs.

Abbreviations

Declarations

Acknowledgments

The abstract of this article was presented by post in the Blood Purification Forum of the Chinese Society of Nephrology in 2021.

Authors’ Contributions

YM, DS, and JZ were responsible for the study concept and design. YM, MZ, CW, and DW were responsible for the acquisition, analysis, and interpretation of the data. YM and JZ were responsible for drafting the manuscript. MZ was responsible for the statistical analysis. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors interpreted the findings, contributed to writing the manuscript, and approved the final version for publication. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (nos., 81960143, 81960130), the Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region (no., NJYT-19-B34), the “Going far” Talent Program of Inner Mongolia Medical University (no., ZY0130015), the Trinity College Students Innovation and Entrepreneurship Cultivation Project of Inner Mongolia Medical University (no., SWYT2020008), the Head Start Program of the Affiliated Hospital of Inner Mongolia Medical University (no., FYQMJH2020026), and the Project of Hebei Provincial Health and Family Planning Commission (no., 20181078).

Availability of data and materials

Data are available on request.

Ethics approval and consent to participate

The study was approved by the ethics committee of the Affiliated Hospital of Inner Mongolia Medical University (no., WZ2021029) and performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The investigators verbally informed the patients or their legal representatives about the study, and obtained written informed consent before the participants’ entry into the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1. Chavez LO, Leon M, Einav S, et al. Beyond muscle destruction: a systematic review of rhabdomyolysis for clinical practice. Critical Care. 2016; 20(1):1–11.
2. Cabral BMI, Edding SN, Portocarrero JP, et al. Rhabdomyolysis. Disease-a-Month. 2020; 66(8):1–18.
3. Huerta-Alardín A, Varon J, Marik PE. Bench-to-bedside review: Rhabdomyolysis – an overview for clinicians. Critical Care. 2005; 9(2):158–169.
4. Delaney KA, Givens ML, Vohra RB. Use of RIFLE criteria to predict the severity and prognosis of acute kidney injury in emergency department patients with rhabdomyolysis. Journal of Emergency Medicine. 2012; 42(5):521–528.
5. Chatzizisis YS, Misirli G, Hatzitolios AI, et al. The syndrome of rhabdomyolysis: Complications and treatment. European Journal of Internal Medicine. 2008; 19(8):568–574.
6. Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. New England Journal of Medicine. 2009; 361(14):62–72.
7. Petejova N, Martinek A. Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review. Crit Care. 2014; 18(3):224–231.
8. Naka T, Jones D, Baldwin I, et al. Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: a case report. Crit Care. 2005; 9(2):R90-95.
9. Premru V, Kovač J, Buturović-Ponikvar J, et al. High cut-off membrane hemodiafiltration in myoglobinuric acute renal failure: a case series. Ther Apher Dial. 2011; 15(3):287–291.
10. Kidney Disease Improving Global Outcomes (KDIGO). Acute Kidney Injury Work Group: KDIGO clinical practice guideline for acute kidney injury. Kidney international Supplement. 2012; 2(1):1–138.
11. Sorrentino SA, Kielstein JT, Lukasz A, et al. High permeability dialysis membrane allows effective removal of myoglobin in acute kidney injury resulting from rhabdomyolysis. Critical Care Medicine. 2011; 39(1):184–186.
12. Naka T, Jones D, Baldwin I, et al. Myoglobin clearance by super high-flux hemofiltration in a case of severe rhabdomyolysis: a case report. Critical Care. 2005; 9(2):1–6.
13. Premru V, Kova J, Buturovi-Ponikvar J, et al. High Cut-off Membrane Hemodiafiltration in Myoglobinuric Acute Renal Failure: A Case Series. Therapeutic Apheresis and Dialysis. 2011; 15(3):287–291.
14. Peltonen S, Åhlström A, Kylävainio V, et al. The effect of combining intermittent hemodiafiltration with forced alkaline diuresis on plasma myoglobin in rhabdomyolysis. Acta Anaesthesiologica Scandinavica. 2010; 51(5):553–558.
15. Cruz DN, Bagshaw SM. Does continuous renal replacement therapy have a role in the treatment of rhabdomyolysis complicated by acute kidney injury? Semin Dial. 2011; 24(4):417–420.
16. Zeng X, Zhang L, Wu T, et al. Continuous renal replacement therapy (CRRT) for rhabdomyolysis. Cochrane Database Syst Rev. 2014; 15(6):1–40.
17. Cornelissen JJ, Haanstra W, Haarman HJ, et al. Plasma exchange in rhabdomyolysis. Intensive Care Med. 1989; 15(8):528–529.
18. Swaroop R, Zabaneh R, Parimoo N. Plasmapheresis in a patient with rhabdomyolysis: a case report. Cases J. 2009; 2:8138.
19. Maccario M, Fumagalli C, Dottori V, et al. The association between rhabdomyolysis and acute renal failure in patients undergoing cardiopulmonary bypass. J Cardiovasc Surg (Torino). 1996; 37(2):153–159.
20. Szpirt WM. Plasmapheresis is not justified in treatment of rhabdomyolysis and acute renal failure. J Cardiovasc Surg (Torino). 1997; 38(5):557.
21. Tang W, Chen Z, Wu W, et al. Renal protective effects of early continuous venovenous hemofiltration in rhabdomyolysis: improved renal mitochondrial dysfunction and inhibited apoptosis. Artif Organs. 2013; 37(4):390–400.