By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.
SYNOPSIS: Rhabdomyolysis can be a life-threatening condition that often triggers a neurology consultation during an investigation for cause. However, in this recent study, the majority of cases (79%) were triggered by external, non-neuromuscular causes, and the others, although suspicious for an intrinsic muscular or genetic cause, rarely had a specific diagnosis confirmed.
SOURCE: Kruijt N, van den Bersselaar LR, Kamsteeg EJ, et al. The etiology of rhabdomyolysis: An interaction between genetic susceptibility and external triggers. Euro J Neurol 2020; Sep 25. doi:10.1111/ene.14553. [Online ahead of print].
Muscle pain, weakness, and dark urine comprise the triad of symptoms of rhabdomyolysis, a medical emergency characterized by muscle necrosis and the release of intracellular muscle components into the circulation, including creatine kinase (CK), aldolase, myoglobin, lactic dehydrogenase, and electrolytes. Patients may be asymptomatic, demonstrating only elevations in serum muscle enzymes, or may experience life-threatening disease, including acute kidney injury and renal failure. External environmental triggers are central to initiating rhabdomyolysis and predisposing genetic factors may increase susceptibility. What are these triggers and genetic factors?
A retrospective review of all patients admitted to the Radboud University Medical Center, Nijmegen, The Netherlands, between January 2014 and January 2019 was undertaken. Inclusion criteria for study selection required a discharge diagnosis of rhabdomyolysis, and a CK > 2,000 IU/L, since a normal CK may run as high as 1,001 IU/L. Patients referred to the neurology department for evaluation of rhabdomyolysis, following prior hospitalization, also were included. For primary trigger analysis, presumed triggers were divided into neuromuscular and non-neuromuscular causes, with the latter further subdivided into ischemic, traumatic, long-lie (on the ground for more than an hour post-fall), endocrine, convulsions, post-operative, acquired myopathic, and other. Patients were considered to have a presumed neuromuscular disorder if they had muscular dystrophy; congenital, metabolic, mitochondrial or other inherited myopathy; neuroleptic malignant syndrome; serotonin syndrome; or heat-related illness (heat stroke, heat exhaustion, or heat cramps).
In a secondary analysis, the investigators extracted data regarding genetic testing, including whole-exome sequencing, and for genes in which variants were found, comparing them to genes previously reported as associated with rhabdomyolysis. Statistical analysis included the chi-squared test, Fisher’s exact test, and the Mann–Whitney U-test.
Among 1,302 patient records selected, 934 (72%) were men, 368 (28%) were women, median age was 53 years (range 0 to 98 years), and median peak CK was 4,423. Men predominated in all categories except for the long-lie group. Non-neuromuscular causes were responsible in 1,025 (79%) patients, most commonly resulting from ischemia/anoxia (42%), followed by trauma (20%). Genetic susceptibility was proven, or neuromuscular condition suspected, in 277 (21%) patients. Recurrent episodes of rhabdomyolysis, positive family history, and a 50-fold increase or persistently elevated levels of CK raised the possibility of genetic susceptibility. Among those 277 patients, 193 were so identified, in which 72 (37%) were found to have an unequivocal genetic defect among 22 genes, including 56 variants, that explained the increased susceptibility to rhabdomyolysis. With increasing use of next-generation sequencing, it is expected that more genetic defects will be uncovered in the future as being relevant to rhabdomyolysis susceptibility.
Acute renal failure is a characteristic accompaniment of severe rhabdomyolysis, yet its mechanism of injury remains unclear. Renal tubules and vessels from patients and mice with rhabdomyolysis and acute kidney injury were examined to determine if complement activation played a role. Activation of the lectin complement pathway was found, while the alternative pathway was activated by myoglobin-derived heme, indicating a double-trigger mechanism for complement activation, via both the lectin and alternative pathways. Kidney function was preserved in C3 knock-out mice, supporting a direct pathological role for complement in renal failure associated with rhabdomyolysis. Heme and complement play a direct role in rhabdomyolysis-induced acute kidney injury.1
- Boudhabhay I, Poillerat V, Grunenwald A, et al. Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. Kidney Int 2020; Oct 30:S0085-2538(20)31244-8. doi: 10.1016/j.kint.2020.09.033. [Online ahead of print].