Single-cell RNA sequencing identifies senescence as therapeutic target in rhabdomyolysis-induced acute kidney injury.

BACKGROUND: The role of macrophages in the development of rhabdomyolysis-induced acute kidney injury (RM-AKI) has been established, but an in-depth understanding of the changes in the immune landscape could help to improve targeted strategies. Whereas senescence is usually associated with chronic kidney processes, we also wished to explore whether senescence could also occur in AKI and whether senolytics could act on immune cells. METHODS: Single-cell RNA sequencing was used in the murine glycerol-induced RM-AKI model to dissect the transcriptomic characteristics of CD45+ live cells sorted from kidneys 2 days after injury. Public datasets from murine AKI models were reanalysed to explore cellular senescence signature in tubular epithelial cells (TECs). A combination of senolytics (dasatinib and quercetin, DQ) was administered to mice exposed or not to RM-AKI. RESULTS: Unsupervised clustering of nearly 17 000 single-cell transcriptomes identified seven known immune cell clusters. Sub-clustering of the mononuclear phagocyte cells revealed nine distinct cell sub-populations differently modified with RM. One macrophage cluster was particularly interesting since it behaved as a critical node in a trajectory connecting one major histocompatibility complex class IIhigh (MHCIIhigh) cluster only present in Control to two MHCIIlow clusters only present in RM-AKI. This critical cluster expressed a senescence gene signature, that was very different from that of the TECs. Senolytic DQ treatment blocked the switch from a F4/80highCD11blow to F4/80lowCD11bhigh phenotype, which correlated with prolonged nephroprotection in RM-AKI. CONCLUSIONS: Single-cell RNA sequencing unmasked novel transitional macrophage subpopulation associated with RM-AKI characterized by the activation of cellular senescence processes. This work provides a proof-of-concept that senolytics nephroprotective effects may rely, at least in part, on subtle immune modulation.

Telbivudine-induced rhabdomyolysis in a patient undergoing haemodialysis: A case report and review of literature.

Herein, we describe a case of acute rhabdomyolysis in a man in his early 50s undergoing haemodialysis and receiving the antiviral drug, telbivudine, for chronic hepatitis B virus (HBV) infection. Following diagnosis by electromyography (EMG), magnetic resonance image (MRI) scans and laboratory data (i.e., elevated serum creatinine kinase (CK) and myoglobin) telbivudine was discontinued and the patient was treated with methylprednisolone. While his CK and myoglobin levels decreased rapidly, his muscle weakness and pain improved slowly. Learning points include: patients undergoing haemodialysis and concomitantly receiving antiviral treatment for HBV, should have their serum levels of CK and myoglobin monitored regularly; treatment with corticosteroids maybe required; relief from rhabdomyolysis-induced muscle weakness and pain may be slow due to nerve fibre damage.

Legal Performance-enhancing Drugs Alter Course and Treatment of Rhabdomyolysis-induced Acute Kidney Injury.

INTRODUCTION: Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown. Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment. MATERIALS AND METHODS: In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort, cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours. RESULTS: Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect. Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI. CONCLUSIONS: Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.

HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.

BACKGROUND: Cardiovascular disease is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), and the absolute risk of cardiovascular events is similar to people with coronary artery disease. This is an update of a review first published in 2009 and updated in 2014, which included 50 studies (45,285 participants). OBJECTIVES: To evaluate the benefits and harms of statins compared with placebo, no treatment, standard care or another statin in adults with CKD not requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 4 October 2023. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. An updated search will be undertaken every three months. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on death, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD (estimated glomerular filtration rate (eGFR) 90 to 15 mL/min/1.73 m2) were included. DATA COLLECTION AND ANALYSIS: Two or more authors independently extracted data and assessed the study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous benefits and harms with 95% confidence intervals (CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 63 studies (50,725 randomised participants); of these, 53 studies (42,752 participants) compared statins with placebo or no treatment. The median duration of follow-up was 12 months (range 2 to 64.8 months), the median dosage of statin was equivalent to 20 mg/day of simvastatin, and participants had a median eGFR of 55 mL/min/1.73 m2. Ten studies (7973 participants) compared two different statin regimens. We were able to meta-analyse 43 studies (41,273 participants). Most studies had limited reporting and hence exhibited unclear risk of bias in most domains. Compared with placebo or standard of care, statins prevent major cardiovascular events (14 studies, 36,156 participants: RR 0.72, 95% CI 0.66 to 0.79; I2 = 39%; high certainty evidence), death (13 studies, 34,978 participants: RR 0.83, 95% CI 0.73 to 0.96; I² = 53%; high certainty evidence), cardiovascular death (8 studies, 19,112 participants: RR 0.77, 95% CI 0.69 to 0.87; I² = 0%; high certainty evidence) and myocardial infarction (10 studies, 9475 participants: RR 0.55, 95% CI 0.42 to 0.73; I² = 0%; moderate certainty evidence). There were too few events to determine if statins made a difference in hospitalisation due to heart failure. Statins probably make little or no difference to stroke (7 studies, 9115 participants: RR 0.64, 95% CI 0.37 to 1.08; I² = 39%; moderate certainty evidence) and kidney failure (3 studies, 6704 participants: RR 0.98, 95% CI 0.91 to 1.05; I² = 0%; moderate certainty evidence) in people with CKD not requiring dialysis. Potential harms from statins were limited by a lack of systematic reporting. Statins compared to placebo may have little or no effect on elevated liver enzymes (7 studies, 7991 participants: RR 0.76, 95% CI 0.39 to 1.50; I² = 0%; low certainty evidence), withdrawal due to adverse events (13 studies, 4219 participants: RR 1.16, 95% CI 0.84 to 1.60; I² = 37%; low certainty evidence), and cancer (2 studies, 5581 participants: RR 1.03, 95% CI 0.82 to 1.30; I² = 0%; low certainty evidence). However, few studies reported rhabdomyolysis or elevated creatinine kinase; hence, we are unable to determine the effect due to very low certainty evidence. Statins reduce the risk of death, major cardiovascular events, and myocardial infarction in people with CKD who did not have cardiovascular disease at baseline (primary prevention). There was insufficient data to determine the benefits and harms of the type of statin therapy. AUTHORS' CONCLUSIONS: Statins reduce death and major cardiovascular events by about 20% and probably make no difference to stroke or kidney failure in people with CKD not requiring dialysis. However, due to limited reporting, the effect of statins on elevated creatinine kinase or rhabdomyolysis is unclear. Statins have an important role in the primary prevention of cardiovascular events and death in people who have CKD and do not require dialysis. Editorial note: This is a living systematic review. We will search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Protective effect of citronellol in rhabdomyolysis-induced acute kidney injury in mice.

Acute kidney injury (AKI) is a serious pathophysiological event consequent to rhabdomyolysis. Inflammatory mechanisms play a role in the development of rhabdomyolysis-induced AKI. Citronellol (CT) is a naturally occurring monoterpene in essential oils of aromatic plant species. In this study, we explored the protective effects of citronellol on AKI resulting from glycerol-induced rhabdomyolysis. Rhabdomyolysis was induced by a single intramuscular injection of glycerol 50% (10mg/kg) in the thigh caudal muscle. Four groups of mice were assigned, including a control group, a group administered with glycerol to induce AKI as a model, a group treated with glycerol plus 50mg/kg CT, and a group treated with glycerol plus 100mg/kg CT. The renal function of mice from all groups was evaluated using kidney histopathological changes and kidney injury molecule-1 (KIM-1). Myoglobin levels were measured to detect rhabdomyolysis. Apoptosis was evaluated by renal cleaved caspase-3 and BAX levels. Both doses of citronellol (50mg/kg and 100mg/kg) significantly reduced KIM-1 mRNA expression and myoglobin levels compared to the glycerol group. In addition, citronellol resulted in lower cleaved caspase-3 and BAX in the renal tissue, indicating that citronellol exerted an anti-apoptotic effect in AKI. Citronellol showed a reno-protective effect against rhabdomyolysis-induced AKI, which may be attributed to its anti-apoptotic effects.

Oral Dantrolene Reduces Myalgia and Hyperckemia in a Child with RYR1-Related Exertional Myalgia/Rhabdomyolysis.

RYR1-related exertional myalgia/rhabdomyolysis (ERM) is an underrecognized condition, which can cause limiting muscle symptoms, and may account for more than one-third of undiagnosed rhabdomyolysis cases. Dantrolene has shown promising results in controlling muscle symptoms in individuals with ERM, however, its use in children remains poorly documented. This case report presents the successful treatment of a 5-year-old patient with ERM using oral dantrolene. The patient experienced notable improvements, including a reduction in the frequency and intensity of myalgia episodes, no hospitalizations due to rhabdomyolysis, a substantial decrease in creatine phosphokinase (CPK) levels, and enhanced performance on the 6-minute walk test. The use of dantrolene was well-tolerated, and no significant adverse effects were observed. This report adds to the existing evidence supporting the effectiveness of oral dantrolene in managing ERM, and, to the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms.

Aripiprazole-Associated Rhabdomyolysis in a 17-Year-Old Male.

Rhabdomyolysis is a rare serious side effect of antipsychotic medication use. There are cases of rhabdomyolysis due to the use of clozapine, risperidone, olanzapine, and haloperidol in the literature. In this report, we describe a rhabdomyolysis case developed on the 13th day of using 2.5 mg /day aripiprazole in a 17-year-old male patient with a diagnosis of somatic symptom disorder. This case is one of the youngest in the literature to develop rhabdomyolysis after the use of aripiprazole. Moreover, this case is distinguished from the others with its low-dose, short-term and single antipsychotic use. In the child and adolescent age group, routine blood tests should be done before starting medication. Symptoms that appear to be nonspecific and that may be overlooked or may be thought to be caused by an existing psychiatric complaint should be carefully and thoroughly considered during follow-up.

Precision engineered peptide targeting leukocyte extracellular traps mitigate acute kidney injury in Crush syndrome.

Crush syndrome induced by skeletal muscle compression causes fatal rhabdomyolysis-induced acute kidney injury (RIAKI) that requires intensive care, including hemodialysis. However, access to crucial medical supplies is highly limited while treating earthquake victims trapped under fallen buildings, lowering their chances of survival. Developing a compact, portable, and simple treatment method for RIAKI remains an important challenge. Based on our previous finding that RIAKI depends on leukocyte extracellular traps (ETs), we aimed to develop a novel medium-molecular-weight peptide to provide clinical treatment of Crush syndrome. We conducted a structure-activity relationship study to develop a new therapeutic peptide. Using human peripheral polymorphonuclear neutrophils, we identified a 12-amino acid peptide sequence (FK-12) that strongly inhibited neutrophil extracellular trap (NET) release in vitro and further modified it by alanine scanning to construct multiple peptide analogs that were screened for their NET inhibition ability. The clinical applicability and renal-protective effects of these analogs were evaluated in vivo using the rhabdomyolysis-induced AKI mouse model. One candidate drug [M10Hse(Me)], wherein the sulfur of Met10 is substituted by oxygen, exhibited excellent renal-protective effects and completely inhibited fatality in the RIAKI mouse model. Furthermore, we observed that both therapeutic and prophylactic administration of M10Hse(Me) markedly protected the renal function during the acute and chronic phases of RIAKI. In conclusion, we developed a novel medium-molecular-weight peptide that could potentially treat patients with rhabdomyolysis and protect their renal function, thereby increasing the survival rate of victims affected by Crush syndrome.

Targeting Labile Iron-Mediated Ferroptosis Provides a Potential Therapeutic Strategy for Rhabdomyolysis-Induced Acute Kidney Injury.

Acute kidney injury (AKI) is a global health problem that occurs in a variety of clinical settings. Despite some advances in supportive clinical care, no medicinal intervention has been demonstrated to reliably prevent AKI thus far. Therefore, it is highly necessary to investigate the pathophysiology and mechanisms involved in AKI for the discovery of therapeutics. In the current study, a robust change in the level of renal malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and elevated renal iron levels were observed in murine rhabdomyolysis-induced AKI (RM-AKI), which supports a pathogenic role of labile iron-mediated ferroptosis and provides a chance to utilize iron chelation for RM-AKI prevention. Given that the existing small molecule-based iron chelators did not show promising preventative effects against RM-AKI, we further designed and synthesized a new hydroxypyridinone-based iron chelator to potently inhibit labile iron-mediated ferroptosis. Lead compound AKI-02 was identified, which remarkably protected renal proximal tubular epithelial cells from ferroptosis as well as showed excellent iron chelation ability. Moreover, administration of AKI-02 led to renal function recovery, a result that was substantiated by the decreased contents of BUN and creatinine, as well as the reduced labile iron level and improved histopathology. Thus, our studies highlighted that targeting labile iron-mediated ferroptosis could provide therapeutic benefits against RM-AKI.

Disseminated Bacillus Calmette-Guérin Infection with Rhabdomyolysis, Acute Kidney Injury, and Interstitial Pneumonia after Bacillus Calmette-Guérin Intravesical Instillation Therapy.

A 79-year-old man experienced a fever and immobility after receiving 6 doses of Bacillus Calmette-Guérin (BCG) intravesical instillation therapy for bladder tumor. Rhabdomyolysis and acute kidney injury occurred; therefore, hemodialysis was performed. His kidney function was restored. However, he exhibited an inflammatory reaction that was resistant to broad-spectrum antibiotics and eventually developed interstitial pneumonia. Corticosteroid treatment partially relieved the symptoms of interstitial pneumonia, although disuse syndrome persisted. He was diagnosed with disseminated BCG infection through sputum culture. BCG infection shows various symptoms and is difficult to diagnose microbiologically. It should be suspected when systemic symptoms occur after BCG intravesical instillation therapy.

[Severe rhabdomyolysis associated with atorvastatin. Case report]. / Rabdomiólisis severa asociada a atorvastatina. Reporte de caso.

Background: Dyslipidemia is a risk factor for the development of atherosclerosis and ischemic heart disease. Statins are safe drugs that are part of the routine treatment in patients with Acute Myocardial Infarction (AMI), however, rhabdomyolysis associated with severe myonecrosis due to statins can occur and associated complications such as acute kidney injury increase mortality. The main objective of this article is to report the case of a critically ill patient with AMI who presented severe statin-associated rhabdomyolysis documented with muscle biopsy. Description of the case: A 54-year-old man who presented with AMI, cardiogenic shock, and cardiorespiratory arrest requiring cardiopulmonary resuscitation, fibrinolysis, and successful salvage coronary angiography. However, he presented severe rhabdomyolysis associated with atorvastatin that required suspension of the drug and multi-organ support in a Coronary Care Unit. Conclusions: The prevalence of statin-associated rhabdomyolysis is low, however, the late elevation of CPK above 10 times its upper normal value in those patients with successful percutaneous coronary angiography should promptly draw attention, generate a diagnostic approach towards non-traumatic acquired causes of rhabdomyolysis and assess the suspension of statins.

Introducción: la dislipidemia es un factor de riesgo para el desarrollo de ateroesclerosis y cardiopatía isquémica. Las estatinas son fármacos seguros que forman parte del tratamiento de rutina en el paciente con infarto agudo de miocardio (IAM). Sin embargo, la rabdomiólisis asociada a mionecrosis severa por estatinas puede presentarse y las complicaciones asociadas como la lesión renal aguda incrementan la mortalidad. El objetivo principal de este artículo es reportar el caso de un paciente críticamente enfermo con IAM que presentó rabdomiólisis severa asociada a estatinas documentada con biopsia muscular. Caso clínico: hombre de 54 años que presentó IAM, choque cardiogénico y paro cardiorrespiratorio, que ameritó reanimación cardiopulmonar, fibrinólisis y angiografía coronaria de rescate exitosa. Sin embargo, presentó rabdomiólisis severa asociada a atorvastatina que requirió de suspensión del fármaco y soporte multiorgánico en una unidad de cuidados coronarios. Conclusiones: la prevalencia de la rabdomiólisis asociada a estatinas es baja, sin embargo, la elevación tardía de la CPK por arriba de 10 veces su valor superior normal en aquellos pacientes con angiografía coronaria percutánea exitosa debe llamar la atención, generar un abordaje diagnóstico hacia causas adquiridas no traumáticas de rabdomiólisis y valorar la suspensión de estatinas.

Alpha-Mangostin ameliorates acute kidney injury via modifying levels of circulating TNF-α and IL-6 in glycerol-induced rhabdomyolysis animal model.

Alpha mangostin (AM), isolated from G. mangostana, showed beneficial effects in several disorders due to its antioxidant and anti-inflammatory properties. Acute kidney injury (AKI) due to different etiologies can develop into severe complications, resulting in high mortality rates. In this work, AM is tested for its ability to alleviate AKI in glycerol-induced AKI rat model, where 30 Male Sprague-Dawley rats were assigned to a healthy group, glycerol-treated group and AM-treated group. Glycerol- and AM groups received a single dose of glycerol (per IM, 50% glycerol in saline, 8 ml/kg), whereas control group was injected with saline. AM treatment (a single daily dose, per IP, 175mg/kg) was accomplished for three days. Animals were executed to collect blood samples and kidney tissue for biochemical and histological examination. It was found that glycerol induced increase in serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, serum magnesium, TNF-α and IL-6. It also induced renal edema and hypocalcemia along with histopathological renal damage. AM treatment improved renal histological features and alleviated increase in serum creatinine, BUN, serum magnesium, TNF-α and IL-6 levels, as well as renal edema and lipid peroxidation but did not affect serum calcium levels. This suggests AM as a potential therapeutic agent for treating AKI mainly via its antioxidant and anti-inflammatory properties.

Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.

Early-onset long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is a fatty acid ß-oxidation disorder with a poor prognosis. Triheptanoin, an anaplerotic oil with odd-chain fatty acids can improve the disease course. The female patient presented here was diagnosed at the age of 4 months, and treatment was started as fat restriction, frequent feeding, and standard medium-chain triglyceride supplementation. In follow-up, she had frequent rhabdomyolysis episodes (∼8 per year). At the age of six, she had 13 episodes in 6 months, and triheptanoin was started as part of a compassionate use program. Following unrelated hospital stays due to multisystem inflammatory syndrome in children and a bloodstream infection, she had only 3 rhabdomyolysis episodes, and hospitalized days decreased from 73 to 11 during her first year with triheptanoin. Triheptanoin drastically decreased the frequency and severity of rhabdomyolysis, but progression of retinopathy was not altered.

[A Case of Rhabdomyolysis Caused by Oxaliplatin during Postoperative Adjuvant Chemotherapy].

The patient was a 50-year-old male. At the age of 48 years, he had undergone total gastrectomy and right hemicolectomy simultaneously for gastric and ascending colon cancers. Since adjuvant chemotherapy has become common practice for patients with ascending colon cancer, capecitabine was administered for 6 months. One year and 6 months after the surgery, he was diagnosed with recurrence of the ascending colon cancer at the anastomotic site and underwent local colectomy. Considering he was pathologically diagnosed as pT4a, mFOLFOX6 therapy was prescribed as postoperative adjuvant chemotherapy. On the day the 11th course of treatment was initiated, the patient complained of weakness; however, his blood test results showed no abnormalities; therefore, he was followed-up as an outpatient. Three days later, he presented to the hospital with exacerbated symptoms and was diagnosed with rhabdomyolysis due to a marked increase in CK(2,031 U/L). Rhabdomyolysis was determined to be the adverse effect of oxaliplatin because out of all the drugs prescribed to the patient, this condition is listed as a side effect only in oxaliplatin's package insert. Fortunately, outpatient treatment was enough to alleviate rhabdomyolysis. Subsequently, adjuvant chemotherapy was completed without oxaliplatin. The patient has been followed-up without recurrence for 9 months after the surgery.

Administration of a single dose of lithium ameliorates rhabdomyolysis-associated acute kidney injury in rats.

Rhabdomyolysis is characterized by muscle damage and leads to acute kidney injury (AKI). Clinical and experimental studies suggest that glycogen synthase kinase 3ß (GSK3ß) inhibition protects against AKI basically through its critical role in tubular epithelial cell apoptosis, inflammation and fibrosis. Treatment with a single dose of lithium, an inhibitor of GSK3ß, accelerated recovery of renal function in cisplatin and ischemic/reperfusion-induced AKI models. We aimed to evaluate the efficacy of a single dose of lithium in the treatment of rhabdomyolysis-induced AKI. Male Wistar rats were allocated to four groups: Sham, received saline 0.9% intraperitoneally (IP); lithium (Li), received a single IP injection of lithium chloride (LiCl) 80 mg/kg body weight (BW); glycerol (Gly), received a single dose of glycerol 50% 5 mL/kg BW intramuscular (IM); glycerol plus lithium (Gly+Li), received a single dose of glycerol 50% IM plus LiCl IP injected 2 hours after glycerol administration. After 24 hours, we performed inulin clearance experiments and collected blood / kidney / muscle samples. Gly rats exhibited renal function impairment accompanied by kidney injury, inflammation and alterations in signaling pathways for apoptosis and redox state balance. Gly+Li rats showed a remarkable improvement in renal function as well as kidney injury score, diminished CPK levels and an overstated decrease of renal and muscle GSK3ß protein expression. Furthermore, administration of lithium lowered the amount of macrophage infiltrate, reduced NFκB and caspase renal protein expression and increased the antioxidant component MnSOD. Lithium treatment attenuated renal dysfunction in rhabdomyolysis-associated AKI by improving inulin clearance and reducing CPK levels, inflammation, apoptosis and oxidative stress. These therapeutic effects were due to the inhibition of GSK3ß and possibly associated with a decrease in muscle injury.

Rhabdomyolysis: A Rare Presentation of Hashimoto Thyroiditis in an Adolescent Boy and Review of the Literature.

INTRODUCTION: Hypothyroidism-induced rhabdomyolysis without precipitating factors is extremely rare, particularly in pediatric patients. We describe a previously healthy adolescent boy who came to our institution with vague symptoms and was found to have rhabdomyolysis secondary to hypothyroidism due to Hashimoto thyroiditis. We also summarize previously published cases in children and adolescents. CASE PRESENTATION: A 16-year-old boy presented to the emergency department at Riley Hospital for Children with a 2-week history of bilateral eye and lip swelling, fatigue, and slowing of speech initially attributed to angioedema. His laboratory studies were significant for acute kidney injury secondary to rhabdomyolysis. Additional evaluation revealed profound primary hypothyroidism and positive TPO antibodies. Although his free T4 was undetectable, his TSH was only 32.2 mcU/mL. He received IV hydration and thyroid replacement, and his symptoms improved after several months of treatment. DISCUSSION: Rhabdomyolysis without any risk factors is very rare, especially in children. Our patient was not on any medications, had no family history of neuromuscular disorders, and no history of trauma, infection, or strenuous exercise. The reason behind the disproportionately mild elevation of TSH in the setting of an undetectable free T4 is unclear. CONCLUSION: It is important for clinicians to be aware that rhabdomyolysis may be a presenting sign of severe hypothyroidism, as delay in diagnosis and treatment can be detrimental.

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases.

BACKGROUND: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis. OBJECTIVE: To clarify whether use of PPIs increases the risk of rhabdomyolysis. METHODS: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher's exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher's exact test and multiple logistic regression analysis were performed. RESULTS: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin. CONCLUSION AND RELEVANCE: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients.

Mutations in the LPIN1 gene constitute a major cause of severe rhabdomyolysis (RM). The TLR9 activation prompted us to treat patients with corticosteroids in acute conditions. In patients with LPIN1 mutations, RM and at-risk situations that can trigger RM have been treated in a uniform manner. Since 2015, these patients have also received intravenous corticosteroids. We retrospectively compared data on hospital stays by corticosteroid-treated patients vs. patients not treated with corticosteroids. Nineteen patients were hospitalized. The median number of admissions per patient was 21 overall and did not differ when comparing the 10 corticosteroid-treated patients with the 9 patients not treated with corticosteroids. Four patients in the non-corticosteroid group died during a RM (mean age at death: 5.6 years). There were no deaths in the corticosteroid group. The two groups did not differ significantly in the number of RM episodes. However, for the six patients who had RM and occasionally been treated with corticosteroids, the median number of RM episodes was significantly lower when intravenous steroids had been administered. The peak plasma creatine kinase level and the area under the curve were or tended to be higher in patients treated with corticosteroids-even after the exclusion of deceased patients or focusing on the period after 2015. The median length of stay (10 days overall) was significantly longer for corticosteroid-treated patients but was similar after the exclusion of deceased patients. The absence of deaths and the higher severity of RM observed among corticosteroid-treated patients could suggest that corticotherapy is associated with greater survival.

Pentoxifylline and thiamine ameliorate rhabdomyolysis-induced acute kidney injury in rats via suppressing TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis.

Acute kidney injury (AKI) is a common complication of rhabdomyolysis (RM), a syndrome characterized by skeletal muscle damage resulting in renal tubular oxidative stress, inflammation, and activated toll like receptor-4 (TLR-4) and NOD-like receptor protein-3 (NLRP-3) inflammasome. Pyroptosis is a programmed cell death mediated by NLRP-3 leading to the activation of caspase-1 and gasdermin D (GSDMD), the hallmark of pyroptosis. This study aims to investigate the renoprotective effects of two antioxidants; pentoxifylline (PTX) and thiamine (TM) via targeting the aforementioned pathways. RM-AKI was induced in male Albino Wistar rats by intramuscular injection of glycerol (50% v/v, 10 ml/kg). PTX (100 mg/kg, oral) and TM (25 mg/kg, i.p) were administered for 12 days prior glycerol injection and continued for 3 days following induction of RM-AKI. Serum creatinine, blood urea nitrogen (BUN), creatin kinase, lipid peroxides, total antioxidant activity, inflammatory markers (tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa B), TLR4, NLRP-3, caspase-1, GSDMD and c-myc (an apoptotic marker) were estimated. Compared to AKI model, co-administered drugs revealed a significant improvement in renal function and pathology as indicated by the reduction in serum creatinine, BUN and protein cast accumulation. The elevations of oxidative stress, and inflammatory markers as well as the over-expression of c-myc were alleviated. Protein levels of TLR4, NLRP3, cleaved caspase-1, and GSDMD were significantly elevated in RM-AKI model, and this elevation was attenuated by the tested drugs. In conclusion, PTX and TM could be a potential renoprotective approach for patients with RM through targeting TLR4/NF-κB and NLRP-3/caspase-1/gasdermin mediated-pyroptosis pathways.