Clinical presentation and outcomes of patients with rhabdomyolysis: A tertiary care center experience.

OBJECTIVES: To evaluate the clinical and laboratory features, complications, and outcomes of patients with rhabdomyolysis in the Saudi population. METHODS: Retrospectives descriptive study of adult patients who presented to King Abdulaziz Medical City (KAMC) withrhabdomyolysis between January 2016 and December 2022. RESULTS: Most of the participants (84.5%) were male, with a median age of 41 years and a body mass index of 26.5 kg/m2. Medications, mainly statins (22.4%) and illicit drugs (15.5%), constituted the root causes of rhabdomyolysis in the cohort (44.8%). The most common presenting complaints were myalgia (63.8%) and fatigue (37.9%). More than one-third of the participants (32.8%) developed AKI, with 3 patients requiring temporary hemodialysis, and only 8.6% developed acute liver failure (ALF). Intensive care unit (ICU) admission was required for 10 patients (17.2%), and the overall mortality rate was 8.6%. Patients who developed complications (composite outcomes of AKI, ALF, multiorgan failure, or death) had significantly reduced kidney function and higher levels of blood urea nitrogen, anion gap, and uric acid upon admission than those who did not. CONCLUSION: This study offers a thorough understanding of clinical and laboratory features, causes, complications, and outcomes of rhabdomyolysis among Saudi patients. The insights gained enhance our understanding of rhabdomyolysis within this population, providing a foundation for future research and improvements in clinical management.

D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.

D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.

Exertional rhabdomyolysis among active component members of the U.S. Armed Forces, 2019-2023.

A largely preventable condition, exertional rhabdomyolysis persists as an occupational hazard of military training and operations, especially in high heat environments among individuals exerting themselves to their physical endurance limits. During the 5-year surveillance period of this study, unadjusted incidence rates of exertional rhabdomyolysis per 100,000 person-years among U.S. active component service members fluctuated, reaching a low of 38.0 cases in 2020 and peaking at 40.5 cases in 2023. The rate in 2020 constituted a decline of 3.8% from the rate in 2019 (39.5 cases). Beginning in 2020, incidence rates per 100,000 person-years gradually increased, by 1.8% in 2021 (38.7 cases), 5.3% in 2022 (40.0 cases), and 6.6% in 2023 (40.5 cases). Consistent with prior reports, subgroup-specific crude rates in 2023 were highest among men, those less than 20 years old, non-Hispanic Black service members, Marine Corps or Army members, and those in combat-specific and 'other' occupations. Recruits experienced the highest rates of exertional rhabdomyolysis during each year, with incidence rates 6 to 10 times greater than all other service members.

Super-refractory status epilepticus, rhabdomyolysis, central hyperthermia and cardiomyopathy attributable to spinal anesthesia: a case report and review of literature.

BACKGROUND: There are only six past reports of super-refractory status epilepticus induced by spinal anesthesia. None of those patients have died. Only < 15 mg of bupivacaine was administered to all six of them and to our case. Pathophysiology ensuing such cases remains unclear. CASE PRESENTATION: A 27 year old gravida 2, para 1, mother at 37 weeks of gestation came to the operating theater for an elective cesarean section. She had no significant medical history other than controlled hypothyroidism and one episode of food allergy. Her current pregnancy was uneventful. Her American Society of Anesthesiologists (ASA) grade was 2. She underwent spinal anesthesia and adequate anesthesia was achieved. After 5-7 min she developed a progressive myoclonus. After delivery of a healthy baby, she developed generalized tonic clonic seizures that continued despite the induction of general anesthesia. She had rhabdomyolysis, one brief cardiac arrest and resuscitation, followed by stress cardiomyopathy and central hyperthermia. She died on day four. There were no significant macroscopic or histopathological changes in her brain that explain her super refractory status epilepticus. Heavy bupivacaine samples of the same batch used for this patient were analyzed by two specialized laboratories. National Medicines Quality Assurance Laboratory of Sri Lanka reported that samples failed to confirm United States Pharmacopeia (USP) dextrose specifications and passed other tests. Subsequently, Therapeutic Goods Administration of Australia reported that the drug passed all standard USP quality tests applied to it. Nonetheless, they have detected an unidentified impurity in the medicine. CONCLUSIONS: After reviewing relevant literature, we believe that direct neurotoxicity by bupivacaine is the most probable cause of super-refractory status epilepticus. Super-refractory status epilepticus would have led to her other complications and death. We discuss probable patient factors that would have made her susceptible to neurotoxicity. The impurity in the drug detected by one laboratory also would have contributed to her status epilepticus. We propose several possible mechanisms that would have led to status epilepticus and her death. We discuss the factors that shall guide investigators on future such cases. We suggest ways to minimize similar future incidents. This is an idiosyncratic reaction as well.

Time-to-onset Analysis of Rhabdomyolysis due to Different Proton Pump Inhibitors Using a Pharmacovigilance Database.

BACKGROUND/AIM: Recent research has increasingly demonstrated an association between proton pump inhibitors (PPIs) and serious adverse events. This study aimed to evaluate the association between PPI and rhabdomyolysis (RM), examining its time-to-onset profiles using the Japanese Adverse Drug Event Report (JADER) database. PATIENTS AND METHODS: Data spanning from April 2004 to March 2022 were used. The association between PPIs and RM was evaluated using the reporting odds ratio (ROR), adjusted for sex and age. Subsequent analyses were conducted after excluding cases involving concomitant use of statins or fibrates. Furthermore, the onset time of RM and Weibull distribution parameters were calculated to evaluate the expression profile of RM, and the outcomes were examined. RESULTS: RM was associated with the use of esomeprazole, omeprazole, and rabeprazole, even in the absence of concomitant statin or fibrate use. The median time to RM onset varied among PPIs, ranging from 6.5 to 127 d. The Weibull distribution parameters indicated that the hazard types of nearly all orally administered PPIs were classified as early failure or close to random failure. Regarding outcomes, cases of death were reported for all PPIs except vonoprazan. CONCLUSION: The findings suggest the need for vigilant monitoring of RM during PPI administration, particularly in the early stages, considering the varying onset times.

Advancing Adverse Drug Reaction Prediction with Deep Chemical Language Model for Drug Safety Evaluation.

The accurate prediction of adverse drug reactions (ADRs) is essential for comprehensive drug safety evaluation. Pre-trained deep chemical language models have emerged as powerful tools capable of automatically learning molecular structural features from large-scale datasets, showing promising capabilities for the downstream prediction of molecular properties. However, the performance of pre-trained chemical language models in predicting ADRs, especially idiosyncratic ADRs induced by marketed drugs, remains largely unexplored. In this study, we propose MoLFormer-XL, a pre-trained model for encoding molecular features from canonical SMILES, in conjunction with a CNN-based model to predict drug-induced QT interval prolongation (DIQT), drug-induced teratogenicity (DIT), and drug-induced rhabdomyolysis (DIR). Our results demonstrate that the proposed model outperforms conventional models applied in previous studies for predicting DIQT, DIT, and DIR. Notably, an analysis of the learned linear attention maps highlights amines, alcohol, ethers, and aromatic halogen compounds as strongly associated with the three types of ADRs. These findings hold promise for enhancing drug discovery pipelines and reducing the drug attrition rate due to safety concerns.

Genome-Wide Analysis of Exertional Rhabdomyolysis in Sickle Cell Trait Positive African Americans.

Sickle cell trait (SCT), although generally a benign carrier state of hemoglobin S (HbAS), is a risk factor for exertional rhabdomyolysis (ERM), a rare but potentially fatal consequence of highly intense physical exercise, particularly among active-duty military personnel and high-performance athletes. The association between SCT and ERM is poorly understood. The objective of this study was to elucidate the genetic basis of ERM in an SCT-positive African American cohort. SCT-positive African Americans with a personal history of ERM (cases, n = 30) and without history of ERM (controls, n = 53) were enrolled in this study. Whole-genome sequencing was performed on DNA samples isolated from peripheral white blood cells. Participants' demographic, behavioral, and medical history information was obtained. An additional 131 controls were extracted from SCT-positive subjects of African descent from the 1000 Genomes Project. SCT carriers with ERM were characterized by myotoxicity features, significant muscle involvement dominated by muscle weakness, and severe pain and substantial increase in serum creatine kinase, with a mean value of 50,480 U/L. A distinctive feature of the SCT individuals with ERM was exertional collapse, which was reported in 53.3% of the cases in the study cohort. An important factor for the development of ERM was the duration and frequency of strenuous physical activity in the cases compared to the controls. Whole-genome sequencing identified 79,696 protein-coding variants. Genome-wide association analysis revealed that the p.C477R, rs115958260 variant in the SLC44A3 gene was significantly associated with ERM event in SCT-positive African Americans. The study results suggest that a combination of vigorous exercise and a genetic predisposing factor is involved in ERM.

Acute lumbar paraspinal compartment syndrome after radical cystectomy.

Lumbar paraspinal compartment syndrome (LPCS) is a rare diagnosis, seen in patients chronically after repeated lumbar trauma or acutely in a postoperative setting. Only a dozen cases are documented worldwide, and to date no clinical guidelines exist for the diagnosis nor the treatment.We describe the case of a 44-year-old man with excruciating lower back pain following a radical cystectomy. The postoperative laboratory values were compatible with acute rhabdomyolysis. The lumbar spine MRI showed necrosis of lumbosacral paraspinal muscles, making the diagnosis of acute LPCS. After seeking advice from different specialists, the conservative approach was chosen with combined pain treatment and physiotherapy. The patient is currently still disabled for some tasks and needs chronic pain medication.

Venlafaxine-Associated Rhabdomyolysis: A Literature Review.

PURPOSE: This systematic review aimed to investigate the clinical manifestations and characteristics of venlafaxine-associated rhabdomyolysis. METHODS: A systematic search was conducted in PubMed, Elsevier, Science Direct, Embase, Springer Link, Wiley Online Library, CNKI, and Wanfang databases from the date of database inception to January 2023. Previously reported cases of venlafaxine-associated rhabdomyolysis were identified, and relevant data from these cases were collected for descriptive statistical analysis. Cases that met the inclusion criteria were evaluated to determine the correlation between adverse reactions and venlafaxine. RESULTS: A total of 12 patients with venlafaxine-associated rhabdomyolysis were included. None of these patients had a history of muscle pain or discomfort. Of the 12 patients, 5 patients received venlafaxine at doses of ≤225 mg/d, whereas the remaining 7 patients received doses exceeding 225 mg/d. The main clinical symptoms included myalgia, muscle weakness, and renal injury. All 12 patients discontinued venlafaxine and received symptomatic care. CONCLUSIONS: Venlafaxine, used either as a monotherapy or in combination with other drugs, may be associated with rhabdomyolysis. Creatine kinase levels may normalize or significantly decrease after discontinuation of venlafaxine and symptomatic treatment.

Incidence, characteristics, and risk factors of drug-associated muscle adverse reaction: a retrospective real-world study of inpatients.

OBJECTIVE: To analyze the clinical characteristics, incidence, and distribution of drug-associated muscle adverse reactions (DAMAR) in real-world inpatients, to provide valuable references for clinical medication use. METHODS: We conducted an automatic retrospective monitoring of inpatients from May 1, 2022, to April 30, 2023, to collect information on adverse drug reactions (ADR) of patients and conducted subsequent analyses. RESULTS: Among 102,430 hospitalizations, 1106 cases of DAMARs were identified, yielding an incidence of 1.08%, including 125 cases of rhabdomyolysis at an incidence of 0.12%. Seventy-five percent of the patients experienced muscle adverse reactions within 5 days after taking medication, with a median elevated creatine kinase (CK) value of 420.4 IU/L. Risk factors of DAMAR include age ≥ 65, male sex, obesity, hypertension, hepatic and renal insufficiency, and anemia. No significant correlation was observed between the duration of surgery and CK elevation, while the surgical procedure itself had an impact. The 114 drugs associated were predominantly nervous system drugs, anti-infectives for systemic use, and cardiovascular system drugs, with levofloxacin, pregabalin, and parecoxib being the most frequently associated drugs. CONCLUSION: Healthcare professionals should be vigilant with patients exhibiting the identified risk factors. Monitoring creatine kinase and related indices when using myotoxic drugs is crucial to preventing serious adverse reactions, ultimately preserving patients' quality of life.

Black Cohosh Interactions with Prescription Medications Associated with Serotonin Toxicity and Rhabdomyolysis: A Case Report.

BACKGROUND: Serotonin toxicity is a well-described phenomenon that is commonly attributed to a variety of drug-drug combinations. Some unregulated herbal supplements have been implicated in the onset of serotonin toxicity, however, there is currently minimal literature available on the potential for black cohosh to contribute to rhabdomyolysis and serotonin toxicity, in spite of its known serotonergic properties. CASE REPORT: A middle-aged woman presented to the emergency department with serotonin toxicity and rhabdomyolysis shortly after taking black cohosh supplements in the setting of long-term dual antidepressant use. The serotonin toxicity and rhabdomyolysis resolved with IV fluids, benzodiazepines, and discontinuation of the offending drugs. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients are sometimes not aware of how over-the-counter supplements might interact with their prescription medications. Female patients taking black cohosh to manage hot flashes and menopausal symptoms could be at risk for developing rhabdomyolysis and serotonin toxicity if they are also taking other serotonergic agents.

Uric acid in predicting the traumatic rhabdomyolysis induced acute kidney injury; a systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to assess the value of uric acid in predicting acute kidney injury caused by traumatic rhabdomyolysis. METHODS: The search was conducted in MEDLINE, Scopus, Embase and Web of Science until November 1, 2023. Based on the inclusion and exclusion criteria, the articles were included by two independent researchers. Data regarding study design, patient characteristics, number of patients with and without AKI, mean and SD of uric acid and prognostic characteristics of uric acid were extracted from relevant studies. STATA version 17.0 was used to compute pooled measures of standardized mean differences, odds ratios, and diagnostic accuracy. I2 and chi-square tests were used to assess heterogeneity between studies. RESULTS: We found 689 non-redundant studies, 44 of them were potentially relevant. Six articles met the inclusion criteria and were included in the review. The results of the meta-analysis confirmed that there was a significant correlation between serum uric acid levels and the occurrence of AKI (SMD = 1.61, 95% CI = 0.69 to 2.54, I2 = 96.94%; p value = 0.001). There were no significant publication biases. CONCLUSION: According to this meta-analysis, uric acid levels could be considered as a predictor of acute kidney injury following traumatic rhabdomyolysis.

Major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States: Results from LC-FAOD Odyssey program.

Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU). Thirty-four patients were analyzed of which 21 and 29 patients had received triheptanoin and/or medium chain triglycerides (MCT), respectively. 36% experienced MCEs while receiving triheptanoin versus 54% on MCT. Total mean annualized MCE rates on triheptanoin and MCT were 0.1 and 0.7, respectively. Annualized disease-related inpatient and ER events were lower on triheptanoin (0.2, 0.3, respectively) than MCT (1.2, 1.0, respectively). Patients were managed more in an outpatient setting on triheptanoin (8.9 annualized outpatient visits) vs MCT (7.9). Overall, this shows that those with LC-FAOD in the Odyssey program experienced fewer MCEs and less HRU in inpatient and ER settings during triheptanoin-treated periods compared with the MCT-treated periods. The MCE rate was lower after initiation of triheptanoin, consistent with clinical trials.

Perioral Paresthesia, Generalize Muscle Cramps, and Rhabdomyolysis After a Socotra Island Blue Baboon Tarantula (Monocentropus Balfouri) Bite.

BACKGROUND: Literature on systemic envenomation caused by tarantula bites, particularly from the Theraphosidae family, is relatively scarce. This case report provides a formal description of the first known instance of systemic envenomation caused by the Socotra Island Blue Baboon Tarantula (Monocentropus balfouri). CASE REPORT: In this case, a 23-year-old employee of an exotic pet shop suffered from perioral paresthesia, generalized muscle cramps, and rhabdomyolysis because of a Monocentropus balfouri bite. His symptoms were successfully relieved with oral benzodiazepines. EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the potential for serious complications resulting from the bite of Monocentropus balfouri, a species gaining popularity among global exotic pet collectors.

Rhabdomyolysis caused by Botrychium ternatum intoxication: Case report and literature review.

RATIONALE: Botrychium ternatum ((Thunb.) Sw.), a traditional Chinese medicine, is known for its therapeutic properties in clearing heat, detoxifying, cough suppression, and phlegm elimination. It has been extensively used in clinics for the treatment of many inflammation-related diseases. Currently, there are no documented cases of rhabdomyolysis resulting from Botrychium ternatum intoxication. PATIENT CONCERNS: A 57-year-old male presented with a complaint of low back discomfort accompanied by tea-colored urine lasting for 4 days. The patient also exhibited markedly increased creatine phosphate kinase and myoglobin levels. Prior to the onset of symptoms, the patient consumed 50 g of Botrychium ternatum to alleviate pharyngodynia. DIAGNOSES: The patient was diagnosed with rhabdomyolysis due to Botrychium ternatum intoxication. INTERVENTIONS: The patient underwent a substantial volume of fluid resuscitation, diuresis, and alkalization of urine, as well as correction of the acid-base balance and electrolyte disruption. OUTCOMES: Following a 10-day treatment plan involving massive fluid resuscitation, diuresis, and alkalization of urine, the patient showed notable improvement in his lower back pain and reported the absence of any discomfort. Following reexamination, the levels of creatine phosphate kinase and myoglobin were restored to within the normal ranges. Additionally, no abnormalities were detected in liver or renal function. As a result, the patient was considered eligible for discharge and was monitored. CONCLUSIONS: Botrychium ternatum intoxication was associated with the development of rhabdomyolysis. To manage this condition, it is recommended that patients provide massive fluid resuscitation, diuresis, alkalization of urine, and other appropriate therapeutic interventions. LESSON: Currently, there are no known cases of rhabdomyolysis resulting from Botrychium ternatum intoxication. However, it is important to consider the potential occurrence of rhabdomyolysis resulting from Botrychium ternatum intoxication when there is a correlation between the administration of Botrychium ternatum and the presence of muscular discomfort in the waist or throughout the body, along with tea-colored urine. Considering the levels of creatine phosphate kinase and myoglobin, the diagnosis or exclusion of rhabdomyolysis caused by Botrychium ternatum intoxication should be made, and suitable treatment should be administered accordingly.

Kidney replacement and conservative therapies in rhabdomyolysis: a retrospective analysis.

BACKGROUND: Toxic renal effects of myoglobin following rhabdomyolysis can cause acute kidney injury (AKI) with the necessity of kidney replacement therapy (KRT). Fast elimination of myoglobin seems notable to save kidney function and intensify kidney repair. Clinical data regarding efficacy of KRT in critical care patients with rhabdomyolysis and AKI are limited. This retrospective analysis aimed to identify differences between conservative therapy and different modalities of KRT regarding myoglobin elimination and clinical outcome. METHODS: This systematic, retrospective, single-center study analyzed 328 critical care patients with rhabdomyolysis (myoglobin > 1000 µg/l). Median reduction rate of myoglobin after starting KRT was calculated and compared for different modalities. Multivariate logistic regression models were established to identify potential confounder on hospital mortality. Filter lifetime of the various extracorporeal circuits was analyzed by Kaplan-Meier curves. RESULTS: From 328 included patients 171 required KRT. Health condition at admission of this group was more critical compared to patient with conservative therapy. Myoglobin reduction rate did not differ between the groups (KRT 49% [30.8%; 72.2%] vs. conservative treatment (CT) 61% [38.5%; 73.5%]; p = 0.082). Comparison between various extracorporeal procedures concerning mortality showed no significant differences. Hospital mortality was 55.6% among patients with KRT and 18.5% with CT (p < 0.001). Multivariate logistic regression model identified requirement for KRT (OR: 2.163; CI: 1.061-4.407); p = 0.034) and the SOFA Score (OR: 1.111; CI: 1.004-1.228; p = 0.041) as independent predictive factors for hospital mortality. When comparing specific KRT using multivariate regression, no benefit was demonstrated for any treatment modality. Life span of the extracorporeal circuit was shorter with CVVH compared to that of others (log-Rank p = 0.017). CONCLUSIONS: This study emphasizes that AKI requiring KRT following rhabdomyolysis is accompanied by high mortality rate. Differences in myoglobin reduction rate between various KRTs could not be confirmed, but CVVH was associated with reduced filter lifetime compared to other KRTs, which enable myoglobin elimination, too.

Impact of newborn screening for fatty acid oxidation disorders on neurological outcome: A Belgian retrospective and multicentric study.

Fatty acid oxidation (FAO) disorders are autosomal recessive genetic disorders affecting either the transport or the oxidation of fatty acids. Acute symptoms arise during prolonged fasting, intercurrent infections, or intense physical activity. Metabolic crises are characterized by alteration of consciousness, hypoglycemic coma, hepatomegaly, cardiomegaly, arrhythmias, rhabdomyolysis, and can lead to death. In this retrospective and multicentric study, the data of 54 patients with FAO disorders were collected. Overall, 35 patients (64.8%) were diagnosed after newborn screening (NBS), 17 patients on clinical presentation (31.5%), and two patients after family screening (3.7%). Deficiencies identified included medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (75.9%), very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (11.1%), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency (3.7%), mitochondrial trifunctional protein (MTP) deficiency (1.8%), and carnitine palmitoyltransferase 2 (CPT 2) deficiency (7.4%). The NBS results of 25 patients were reviewed and the neurological outcome of this population was compared with that of the patients who were diagnosed on clinical presentation. This article sought to provide a comprehensive overview of how NBS implementation in Southern Belgium has dramatically improved the neurological outcome of patients with FAO disorders by preventing metabolic crises and death. Further investigations are needed to better understand the physiopathology of long-term complications in order to improve the quality of life of patients and to ensure optimal management.

Proteomic analysis of multiple organ dysfunction induced by rhabdomyolysis.

Rhabdomyolysis (RM) leads to dysfunction in the core organs of kidney, lung and heart, which is an important reason for the high mortality and disability rate of this disease. However, there is a lack of systematic research on the characteristics of rhabdomyolysis-induced injury in various organs and the underlying pathogenetic mechanisms, and especially the interaction between organs. We established a rhabdomyolysis model, observed the structural and functional changes in kidney, heart, and lung. It is observed that rhabdomyolysis results in significant damage in kidney, lung and heart of rats, among which the pathological damage of kidney and lung was significant, and of heart was relatively light. Meanwhile, we analyzed the differentially expressed proteins (DEPs) in the kidney, heart and lung between the RM group and the sham group based on liquid chromatography-tandem mass spectrometry (LC-MS/MS). In our study, Serpina3n was significantly up-regulated in the kidney, heart and lung. Serpina3n is a secreted protein and specifically inhibits a variety of proteases and participates in multiple physiological processes such as complement activation, inflammatory responses, apoptosis pathways, and extracellular matrix metabolism. It is inferred that Serpina3n may play an important role in multiple organ damage caused by rhabdomyolysis and could be used as a potential biomarker. This study comprehensively describes the functional and structural changes of kidney, heart and lung in rats after rhabdomyolysis, analyzes the DEPs of kidney, heart and lung, and determines the key role of Serpina3n in multiple organ injury caused by rhabdomyolysis. SIGNIFICANCE: This study comprehensively describes the functional and structural changes of kidney, heart and lung in rats after rhabdomyolysis, analyzes the DEPs of kidney, heart and lung, and determines the key role of Serpina3n in multiple organ injury caused by rhabdomyolysis.

Tracer-based lipidomics enables the discovery of disease-specific candidate biomarkers in mitochondrial ß-oxidation disorders.

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid ß-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.