Complication Of Rhabdomyolysis Research Articles

A Series of Eight Cases of Pigment Nephropathy: An Obscured Aspect of Acute Kidney Injury.

Pigment-induced acute kidney injury (AKI) is an important and preventable complication of rhabdomyolysis or hemolysis. It is characterized by the release of free heme pigment (myoglobin or hemoglobin) in the circulation, leading to direct injury of the proximal tubuleand distal tubule obstruction by pigment cast. We are reporting eight cases of pigment-induced AKI, including six cases of myoglobin cast nephropathy and two cases of hemoglobin cast nephropathy.The causes of rhabdomyolysis were strenuous exercise, infection/febrile illness, and drug-induced neuroleptic malignant syndrome. Paroxysmal nocturnal hemoglobinuria and anti-tuberculosis treatment (rifampicin and isoniazid) had led to hemoglobin cast nephropathy each in one case. Seven cases had severe renal failure requiring dialysis.Short-term renal outcome was favorable. However, long-term follow-up is necessary to determine whether pigment-induced AKI has delayed sequelae. Therefore, clinicians should consider rhabdomyolysis or hemolysis as potential hidden causes of AKI in diverse clinical conditions, especially those of non-traumatic origin, to achieve an accurate diagnosis.

Rare and Dangerous Complication of Rhabdomyolysis in Critically Ill Patients: a Case Study

Rhabdomyolysis in critically ill patients is rare and can easily lead to serious adverse complications. We present the case of a young male patient who experienced acute liver failure resulting from closed abdominal injury, accompanied by severe complications of rhabdomyolysis and compartment syndrome. The patient underwent orthotopic liver transplantation surgery to restore liver function. Compartment syndrome of the lower legs was treated with percutaneous deep fasciotomy. Upon discharge, the patient was in a post-liver transplant state and exhibited partial dysfunction in lower limbs. Therefore, rhabdomyolysis occurs insidiously in severe patients and can easily lead to serious adverse outcomes. Clinicians should recognize symptoms of rhabdomyolysis and intervene promptly.

Protective Effect of Silymarin on Attenuating of Rhabdomyolysis -induced Acute Kidney Injury in Animal Models

Acute kidney injury is one of the most serious complications of rhabdomyolysis characterized by an acute loss of renal function. The study aims to investigate the renoprotective effect of silymarin against rhabdomyolysis-induced acute kidney injury in rats. Twenty-four healthy rats were equally divided into three groups: control, induction, and treatment groups. Rats in the control and induction groups received distilled water, while rats in the treatment group received silymarin (50 mg /kg/day p.o) for three consecutive days. On the first day, all rats (except rats of control group) received a single intramuscular injection of glycerol (10 mL/kg, 50% v/v in sterile saline) divided equally into each hind leg for induction of acute kidney injury. On the fourth day of experiment, blood and kidney,s were collected from all rats for biochemical and histopathological assay. Silymarin efficiently attenuated acute kidney injury caused by rhabdomyolysis evidenced by a significant decrease in serum creatinine and blood urea nitrogen(BUN), along with a significant reduction in renal homogenate levels of TNF-α, IL-6, NF-κB, caspase-3, and MDA with a significant increase in GSH level, which was further confirmed by improving renal histological changes when compared to that of induction group. This study found that silymarin has a potential attenuating effect on acute kidney injury due to its antioxidant, anti-inflammatory and antiapoptotic actions.

Renal Salt Wasting: Earliest Manifestation of Rhabdomyolysis, Supreet/Mehandru Syndrome

Acute kidney injury is a feared and common complication of rhabdomyolysis, occurring in 10-40% of hospitalized patients with mortality rate as high as 59% in critically ill patients. However, there is a lack of information in the literature on renal salt wasting in rhabdomyolysis. We report 3 cases of rhabdomyolysis who developed renal salt wasting in presence of normal glomerular filtration rate. To the best of our knowledge, this is the first case report in humans displaying this phenomenon. Authors noted that all the three patients had urine pH of over 7.0. Literature reveals, patients with rhabdomyolysis and urine pH<6.5 develop acute kidney injury whereas urine pH>7.0 experienced renal salt wasting in presence of normal glomerular filtration rate. All 3 cases, previously not known to have hypertension, were noted to have elevated blood pressure during acute phase of rhabdomyolysis. Animal studies have shown that increase in blood pressure causes increase in renal interstitial pressures that results in naturesis and diuresis. All 3 cases had increased levels of plasma renin activity and aldosterone. There is a direct proportionality between increased blood pressure and naturesis. Clinicians should be aware of salt wasting as an early renal manifestation in patients with rhabdomyolysis

Rhabdomyolysis aggravates renal iron accumulation and acute kidney injury in a humanized mouse model of sickle cell disease

Individuals with sickle cell disease (SCD) are at greater risk of rhabdomyolysis, a potentially life-threatening condition resulting from the breakdown of skeletal muscle fibers. Acute kidney injury (AKI) is one of the most severe complications of rhabdomyolysis. Chronic kidney and cardiovascular disease, which account for SCD mortality, are long-term consequences of AKI. Although SCD elevates the risks of rhabdomyolysis-induced sudden death, the mechanisms that underlie rhabdomyolysis-induced AKI in SCD are unclear. In the present study, we show that, unlike their control non-sickling (AA) counterparts, transgenic homozygous SCD (SS; Townes model) mice exhibited 100% mortality 8–24 h after intramuscular glycerol injection. Five hours after glycerol injection, SS mice showed a more significant increase in myoglobinuria and plasma creatine kinase levels than AA mice. Basal plasma heme and kidney tissue iron levels were significantly higher in SS than in AA mice. In contrast to AA, glycerol-induced rhabdomyolysis aggravated these parameters in SS mice. Rhabdomyolysis also amplified oxidative stress in SS compared to AA mice. Glycerol-treated SS mice exhibited worse renal function, exemplified by a reduction in GFR with a corresponding increase in plasma and urinary biomarkers of early AKI and renal tubular damage. The free radical scavenger and Fenton chemistry inhibitor, TEMPOL, ameliorated rhabdomyolysis-induced AKI in the SS mice. These findings demonstrate that oxidative stress driven by renal iron accumulation amplifies rhabdomyolysis-induced AKI in SCD mice.

Clinical and Epidemiological Characteristics of Rhabdomyolysis: A Retrospective Study.

Rhabdomyolysis (RM) refers to a clinical syndrome in which muscle cells are damaged by various causes and the clinical manifestations are mainly muscle pain, weakness, and dark urine. Acute kidney injury (AKI) is a serious complication of RM with complex mechanisms and high mortality. Therefore, understanding the pathogenesis and clinical manifestations, early diagnosis and treatment of RM are crucial to improve its prognosis. Analysis of medical records of RM patients admitted to Tianjin Medical University General Hospital from October 2019 to October 2022. Statistical software SPSS 25.0 was used to analyze the data. The risk factors of RM-complicated AKI were analyzed by logistic regression. The receiver operating characteristic (ROC) curve was plotted, the area under the curve (AUC) was calculated, and the optimal cutoff value was determined by the Youden index. P < 0.05 indicates a statistically significant difference between the groups. Among the 71 patients, the median age of the patients was 53.0 (30.0, 71.0) years and was 2.5 times higher in men than in women. Infection was the most common etiology. History of alcohol consumption, CK, and creatinine were independent influencing factors for AKI due to RM. Logistic regression analysis showed that CK combined with creatinine had a better predictive value than the single index. Our study revealed the clinical and laboratory characteristics of RM in the population attending the Tianjin Medical University General Hospital in the last three years, which is a reference for future multicenter, prospective studies.

#4392 TWEAK/FN14 SYSTEM IS INVOLVED IN RHABDOMYOLYSIS-INDUCED ACUTE KIDNEY INJURY

Abstract Background and Aims Rhabdomyolysis is a pathological syndrome associated with massive and severe skeletal muscle injury. A common complication of rhabdomyolysis is acute kidney injury (AKI), a process that increases mortality of these patients. In rhabdomyolysis, myoglobin (Mb) is released from muscle cells and subsequently absorbed by the renal tubular epithelium causing a series of deleterious effects. TWEAK/Fn14 axis regulates renal inflammation and tubular cell death, pathogenic mechanisms involved in AKI. However, the role of this pathway in rhabdomyolysis-AKI has not been previously analyzed. In this study we analyzed the role of TWEAK/Fn14 axis in AKI associated with rhabdomyolysis and the AKI to chronic kidney disease (CKD) transition. Method We performed an experimental model of AKI associated to rhabdomyolysis by the intramuscular injection of 50% glycerol (10mg/Kg of weight) in Wild Type C57BL/6 (WT), TWEAK deficient (TWEAK -/-) and Fn14 deficient (Fn14 -/-) mice (male, 12 weeks old). In another set of experiments, C57BL/6 mice were intraperitoneally injected with anti-TWEAK mAb (10 mg/kg) or irrelevant isotype control IgG (10 mg/kg) every 48 hours. Blood and renal samples were taken 3 and 6 hours or 1, 3, 7 and 30 days after glycerol administration to perform gene expression studies by Real Time-PCR, immunohistochemistry analysis, protein expression studies by Western Blot and cell death assays (TUNEL). In vitro studies in murine tubular cells (MCTs) were also conducted to determine the effects of Mb on TWEAK/Fn14 expression, and the intracellular pathways involved in Mb-mediated regulation of TWEAK/Fn14 system. Results Fn14 renal expression was increased at earlier stages of rhabdomyolysis, correlating with decline of renal function. In MCTs cells, Mb induced Fn14 expression in a time- and dose-dependent manner, whereas TWEAK expression remained unchanged. The use of general antioxidants (N-Acetylcysteine) or Nrf2 inducers (curcumin or Sulforaphane) reduced Mb-mediated Fn14 upregulation in vivo and in cultured renal cells, whereas the opposite effect was observed with the HO-1 inhibitor tin protoporphyrin IX (SnPP). Furthermore, MAPK p38 and ERK1/2 inhibitors, such as SB203580 and PD98059 respectively, diminished Mb effects on Fn14 expression. Moreover, Mb enhanced pro-inflammatory effects of TWEAK in vitro. In the animal model, we observed that genetic TWEAK or Fn14 deficiency ameliorated rhabdomyolysis-related loss of renal function, reduced histological damage, tubular cell death, lipid peroxidation, and decreased the expression of inflammatory mediators (Ccl2, Tnf, Il6, Tlr4 and Ccl5), tubular injury markers (Havcr1 and Lcn2) and endothelial dysfunction (Edn1 and Icam1). TWEAK or Fn14 knockout mice also showed decreased long-term renal fibrosis (Collagen content and Fn1 expression) and inflammation (F4/80 macrophage infiltration and Ccl2 expression) 30 days after rhabdomyolysis induction. Treatment with a blocking anti-TWEAK monoclonal antibody reduced expression of Lcn2 and cell death at early stages of rhabdomyolysis and decreased long-term consequences, mainly fibrosis and inflammation. Conclusion Our data suggest that TWEAK/Fn14 axis is involved in AKI-rhabdomyolysis, as well as in the transition from AKI to CKD. TWEAK/Fn14 may be a potential therapeutic target to decrease harmful effects of rhabdomyolysis.

Abstract #1408127: A Case of Rhabdomyolysis Resulting in Fulminant Acute Kidney Injury in a Patient with Severe Hypothyroidism

Rhabdomyolysis is characterized by muscle necrosis and the release of intracellular muscle contents into circulation. Hypothyroidism is known to be associated with musculoskeletal problems, rarely rhabdomyolysis. We report a case of severe hypothyroidism due to a prior thyroidectomy with poor medication adherence, who presented with rhabdomyolysis resulting in severe acute kidney injury requiring urgent dialysis. A 65-year-old male with a past medical history of papillary thyroid cancer status post total thyroidectomy presented with lethargy, confusion, decreased oral intake and decreased urination. He recently ran out of levothyroxine. Notably, the patient had also been taking rosuvastatin. On examination, the patient was afebrile, with a pulse of 70 bpm and blood pressure of 111/70 mmHg. He was oriented to self and place but not to time. He demonstrated slow deep voice along with macroglossia and trace non-pitting lower extremity edema. There were no signs of proximal myopathy or neurological deficits. Workup was remarkable for TSH >90.00 mcU/mL, free T4 < 0.1 ng/dl, CPK 22,030 mcg/L, AST 233 U/L, ALT 205 U/L, creatinine 31.6 mg/dl, and BUN 124 mg/dl. The last known TSH was 4.5, free T4 was 1 ng/dL, and creatinine was 0.9 in January 2021. The urine specimen was positive for loaded red blood cells. Renal ultrasound showed no obstruction. Diagnosis of rhabdomyolysis with acute renal failure was made and he was promptly started on dialysis. Endocrinology was consulted and he was started on intravenous levothyroxine. A renal biopsy confirmed acute tubular necrosis due to rhabdomyolysis. After several days, his symptoms improved, and he was transitioned to oral levothyroxine however he remained on dialysis on discharge. Hypothyroid myopathy is most often limited to myalgia, cramps, and sometimes mildly elevated levels of muscle enzymes. Rhabdomyolysis can rarely develop due to severe hypothyroidism. Muscle breakdown in hypothyroidism is caused by poor contractility, low myosin ATPase activity, and low ATP turnover in the skeletal muscles. These metabolic abnormalities may sensitize patients with hypothyroidism to develop rhabdomyolysis. Acute renal failure, as a result of an accumulation of myoglobin in renal tubules, is the most life-threatening complication of rhabdomyolysis and can develop in up to 33% of patients. There have been very few case reports of hypothyroidism causing rhabdomyolysis, with a precipitating factor such as exercise, trauma, or drugs such as statin. Our patient presented with severe hypothyroidism complicated by rhabdomyolysis resulting in acute renal failure requiring dialysis. The patient was also on a statin which may cause statin-induced rhabdomyolysis due to hypothyroidism. This case emphasizes the importance of adherence to levothyroxine in hypothyroid patients as well as the importance of considering rhabdomyolysis in patients with severe hypothyroidism as a cause of acute renal failure. It also shows the importance of reviewing the patient's medication list and discontinuing all those medications which can escalate the process of rhabdomyolysis in a patient with hypothyroidism.

Myoglobin-driven ET-1 production and downstream activation of TRPC3- but not TRPC6-dependent vasoconstriction contributes to rhabdomyolysis-induced AKI

Acute kidney injury (AKI) is the most severe and life-threatening complication of rhabdomyolysis, with 10-40% of patients developing some form of kidney insufficiency within days. Experimental evidence indicates that renal vasoconstriction plays a significant role in the pathophysiology of rhabdomyolysis-induced AKI. Rodents subjected to glycerol-induced rhabdomyolysis exhibited increased plasma concentrations of endothelin-1 (ET-1). Treating glomerular mesangial cells with myoglobin has also been shown to increase the cellular production of ET-1. The downstream effectors of ET-1-induced vasoconstriction are smooth muscle Ca2+ permeable transient receptor potential canonical (TRPC) channels. There are seven members of the TRPC gene family (TRPC1-7). Whereas TRPC2 and 7 are absent, TRPC1, 3, 4, 5, and 6 are expressed in renal vessels, with TRPC3 predominant. TRPC3, TRPC6, and TRPC7 are highly homologous. Although the ET system is known to be associated with rhabdomyolysis-induced AKI, the function of renal vascular ion channels in the disease is unclear. Here, we investigated the involvement of TRPC3 and TRPC6 in glycerol-induced rhabdomyolysis in rats. ET-1 production is increased in myoglobin-treated epithelial cells, the primary source of renal ET. Rhabdomyolysis also increased renal ET-1 production, decreased renal blood flow (RBF), and increased renal vascular resistance, effects attenuated by ET receptor and TRPC channel blocker Pyr3. Furthermore, we used TRPC3 and TRPC6 knockout (KO) rats to support the pharmacological approaches. Basal day and night arterial pressure, heart rate, GFR, plasma creatinine, and BUN were unchanged in WT vs. KO rats. Twenty-four h rhabdomyolysis led to comparable increases in urinary ET-1 production in WT and KO rats. However, rhabdomyolysis-induced decreases in GFR, elevations in BUN, and plasma creatinine were all attenuated in the TRPC3 but not TRPC6 KO rats. Similarly, morphological kidney damage (tubular necrosis, casts, and dilatation) was mitigated in the TRPC3 KO with no protection offered by the KO of TRPC6 channels. Together, our data suggest that myoglobin-driven ET-1 production and downstream activation of TRPC3- but not TRPC6-dependent vasoconstriction contributes to rhabdomyolysis-induced AKI. American Heart Association Predoctoral Fellowship This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PARAPHENYLENEDIAMINE POISONING : A CASE REPORT AND REVIEW OF LITERATURE

Paraphenylenediamine (PPD) intoxication is a medical emergency with a very poor prognosis in the absence of early and adequate treatment. Its pathophysiological mechanism is now known and results from the destruction of muscle cells by peroxidation phenomena leading to major rhabdomyolysis. The diagnosis is essentially clinical, guided by a rapid history. As there is no specific antidote, treatment is mainly symptomatic and aims at securing the VAS, reducing intestinal absorption of the toxicant, as well as managing cervico-facial oedema and complications of rhabdomyolysis. In hospital, treatment includes gastric lavage, activated charcoal, filling with alkalinisation, antioxidant treatments, corticosteroids, diuretics and even dialysis. In order to shed light on the danger of this practice, the authors have taken the liberty of reporting the clinical case of PPD intoxication in a young woman admitted to the maternity ward of the Harouchi Hospital in Casablanca.

Partial ceratohyoidectomy as surgical treatment for horses with temporohyoid osteoarthropathy: 10 cases (2010-2021).

To describe outcomes of horses with temporohyoid osteoarthropathy (THO) treated with partial ceratohyoidectomy. 10 client-owned horses. Medical records from 2 institutions were examined for records of horses with THO treated with partial ceratohyoidectomy between 2010 and 2021. History, signalment, clinical signs, diagnostics, medications, and surgery-related details were recorded. Horses with a minimum of 6 months follow-up were recruited for neurologic and imaging examinations in the hospital or field where radiography of the basihyoid-ceratohyoid articulation were performed along with CT, when available. 10 horses with THO were included (9 unilateral; 1 bilateral). Nine planned partial ceratohyoidectomies were performed in 8 horses, whereas 2 horses had preoperatively planned complete ceratohyoidectomies transitioned to partial ceratohyoidectomies during surgery due to intraoperative complications. Postoperative complications occurred mostly in transitioned surgeries (obstructed airway, tongue mobility issues, and incisional hemorrhage), whereas only 1 horse with a planned ceratohyoidectomy had postoperative complication of rhabdomyolysis. All complications resolved before hospital discharge. Neurologic signs improved in all 10 horses, with 2 showing complete resolution. Nine horses were available for radiographic follow-up, 6 of which also had head CT scans. A space between the ceratohyoid and basihyoid bones was measurable on radiography in all 9 horses, and was confirmed on CT. Three horses demonstrated proliferation of either ceratohyoid or basihyoid bones. The 9 horses with unilateral disease returned to previous work, and the horse with bilateral disease was retired. Partial ceratohyoidectomy is a surgical option for treatment of THO that provides similar clinical outcomes to published reports on ceratohyoidectomy.

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-1β, 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.

Rhabdomyolysis-associated Acute Kidney Injury.

Acute kidney injury represents one of the most severe complications of rhabdomyolysis. We performed a prospective observational study to analyze the etiology, clinical manifestations, laboratory profile, and outcome in patients with biopsy-proven pigment-induced nephropathy between January 2017 and September 2019. History, clinical examination findings, laboratory investigations, and outcomes were recorded. A total of 26 patients were included. Mean age was 34.81 ± 11.89 years. Mean peak serum creatinine was 6.79 ± 4.07 mg/dL. Median values of Creatine phosphokinase (CPK) and Lactate dehydrogenase (LDH) were 12500 U/L (3187, 17167.50) and 447 U/L (354.50, 908.75), respectively. Of the patients presenting with rhabdomyolysis, 12 patients (46%) had traumatic causes and 14 patients (54%) had nontraumatic causes. Nontraumatic etiology of rhabdomyolysis included seizures (1), wasp sting (1), paraphenylenediamine ingestion (2), rat killer ingestion (2), leptospirosis (2), dehydration (3), acute limb ischemia (1), Gloriosa superba ingestion (1), and prolonged immobilization (1). On renal biopsy, 16 patients had myoglobin cast nephropathy and one had immunoglobulin A deposits in addition to pigment nephropathy. Twenty (76.9%) were initiated on hemodialysis, and two patients (7.6%) were treated with peritoneal dialysis and four patients (15.5%) were treated with forced alkaline diuresis. A total of four patients died (15.4%) due to sepsis/disseminated intravascular coagulation and respiratory failure. At the mean follow-up of 6 months, two patients (7.7%) progressed to chronic kidney disease (CKD). Rhabdomyolysis-associated acute kidney injury is an important cause of renal failure requiring renal replacement therapy. In our study, it was more common in males. Traumatic and nontraumatic causes played an equal causative role. Most of the patients recovered from AKI. Forced alkaline diuresis was found useful in nontraumatic rhabdomyolysis AKI.

The effectiveness of various approaches to the use of renal replacement therapy in the treatment of toxic rhabdomyolysis complicated by acute kidney injury

BACKGROUND. 60 % of cases of acute poisoning are complicated by the occurrence of rhabdomyolysis . The most common and dangerous complication of rhabdomyolysis is acute kidney injury (AKI), which increases mortality by up to 10 %. One of the most promising directions of pathogenetic therapy of rhabdomyolysis complicated by AKI is extracorporeal removal of myoglobin and other factors of endogenous intoxication from the systemic bloodstream . THE AIM: to improve the results of treatment of patients with toxic rhabdomyolysis complicated by acute kidney injury by applying the most effective tactics of renal replacement therapy . PATIENTS AND METHODS. The prospective study included 81 patients with toxic rhabdomyolysis complicated by AKI. In the first group , standard basic intensive therapy was performed ; in the second group , hemodiafiltration was performed at an early stage of AKI, in the third group , early application of hemodiafiltration with selective hemosorption was performed . The analysis of laboratory parameters of rhabdomyolysis , renal damage , as well as the outcomes of treatment of patients in groups was carried out . RESULTS. Early use of renal replacement therapy (RRT) increased the severity of reduction of myoglobin concentrations in blood and KIM-1 in urine during the first week of treatment from 26.3 % to 73.4 % and from 76.1 % to 96.8 %, respectively . The inclusion of RRT with selective hemosorption in the intensive therapy at an early stage of AKI allowed to increase these indicators to 88.0 % and 99.0 %, respectively . The most effective method is the use of a combination of RRT with selective hemosorption , which allows to increase the rate of recovery of kidney function and reduce the duration of the necessary use of RRT from 15 to 6 days , as well as to reduce hospital mortality from 14.3 % to 6.9 %.

EGFR mediated the renal cell apoptosis in rhabdomyolysis-induced model via upregulation of autophagy

AimsRhabdomyolysis is a life-threatening condition. One of the most common complications of rhabdomyolysis is acute kidney injury (AKI), and 10 % of all AKI patients present with rhabdomyolysis. EGFR is associated with different types of AKI. However, the function and regulatory mechanism of EGFR in rhabdomyolysis-induced AKI model remain unknown. Here, we performed the experiments to explore the role of EGFR in this model. Main methodsWe used proximal tubule-specific Atg7 knockout mice and Wa-2 mice to establish animal models. Then, the samples were collected for pathology assay and IB detection. In vitro, the BUMPT cells treated with myoglobin were collected for the detection of apoptosis and autophagy. IB detection were processed for the analysis of protein expressions, FCM analysis for the cell apoptosis, GFP-LC3 transfection and immunofluorescent for autophagy. Key findingsEGFR promotes autophagy to mediate rhabdomyolysis-induced AKI via STAT3/Atg7 axis, and gefitinib is a potential therapeutic option for AKI. Here, we demonstrated that EGFR was activated by myoglobin and glycerol both in vitro and in vivo, respectively. Genetic or pharmacological inhibition of EGFR ameliorated myoglobin and glycerol-induced renal cell apoptosis. Mechanistically, EGFR mediated autophagy induction via STAT3/Atg7 axis, thereby resulting in kidney cell apoptosis. Furthermore, Wa-2 mice or gefitinib treatment prevented the progression of rhabdomyolysis-induced AKI as well as renal cell apoptosis and autophagy via inhibiting STAT3/Atg7 axis. SignificanceResearchers can use this finding to better study the function and regulatory mechanism of EGFR in RM-induced AKI model. And gefitinib represents a potential target for treatment of AKI.

Inhalation of 4% and 67% hydrogen ameliorates oxidative stress, inflammation, apoptosis, and necroptosis in a rat model of glycerol-induced acute kidney injury

Acute kidney injury (AKI) is the major complication of rhabdomyolysis (RM) clinically, which is usually mimicked by glycerol injection in basic research. Oxidative stress, inflammatory response and apoptosis are recognized to play important roles in development of this disease. Recently, numerous studies have reported the therapeutic effects of molecular hydrogen (H2) on oxidative stress and inflammation-related diseases. Here, the effects of H2 against glycerol-induced AKI and the underlying mechanisms were explored in rats. Low (4%) and high (67%) concentrations of H2 were prepared using a self-made device to investigate the dose-response. After 72 hours of glycerol injection (8 mL/kg), we found that glycerol triggered oxidative stress, inflammatory reactions, and apoptotic events. These caused subsequent renal damage, evidenced by a significant reduction of antioxidases and up-regulation of the relevant damaged biomarkers. H2 inhalation reversed the above alterations and exerted renoprotective effects. Interestingly, for RM/AKI-related factors, no consistent dose-response benefits of H2 were observed. However, higher concentration of H2 inhalation improved histological and morphological changes better. This study suggests that H2 is a potential alternative therapy to prevent or minimize RM induced AKI possibly via its antioxidant, anti-inflammatory, anti-apoptotic and anti-necroptotic properties.

Functional consequence of myeloid ferritin heavy chain on acute and chronic effects of rhabdomyolysis-induced kidney injury.

Acute kidney injury (AKI) is a serious complication of rhabdomyolysis that significantly impacts survival. Myoglobin released from the damaged muscle accumulates in the kidney, causing heme iron-mediated oxidative stress, tubular cell death, and inflammation. In response to injury, myeloid cells, specifically neutrophils and macrophages, infiltrate the kidneys, and mediate response to injury. Ferritin, comprised of ferritin light chain and ferritin heavy chain (FtH), is vital for intracellular iron handling. Given the dominant role of macrophages and heme-iron burden in the pathogenesis of rhabdomyolysis, we studied the functional role of myeloid FtH in rhabdomyolysis-induced AKI and subsequent fibrosis. Using two models of rhabdomyolysis induced AKI, we found that during the acute phase, myeloid FtH deletion did not impact rhabdomyolysis-induced kidney injury, cell death or cell proliferation, suggesting that tubular heme burden is the dominant injury mechanism. We also determined that, while the kidney architecture was markedly improved after 28 days, tubular casts persisted in the kidneys, suggesting sustained damage or incomplete recovery. We further showed that rhabdomyolysis resulted in an abundance of disparate intra-renal immune cell populations, such that myeloid populations dominated during the acute phase and lymphoid populations dominated in the chronic phase. Fibrotic remodeling was induced in both genotypes at 7 days post-injury but continued to progress only in wild-type mice. This was accompanied by an increase in expression of pro-fibrogenic and immunomodulatory proteins, such as transforming growth factor-β, S100A8, and tumor necrosis factor-α. Taken together, we found that while the initial injury response to heme burden was similar, myeloid FtH deficiency was associated with lesser interstitial fibrosis. Future studies are warranted to determine whether this differential fibrotic remodeling will render these animals more susceptible to a second AKI insult or progress to chronic kidney disease at an accelerated pace.

Acalculous cholecystitis and ascites in a patient with rhabdomyolysis: A case report

Introduction: Rhabdomyolysis is a muscle breakdown caused by a variety of factors. Based on a review of the literature, we are unaware of any case reports that discuss these complications of rhabdomyolysis with acalculous cholecystitis and ascites. Case Report: This patient is a 24-year-old man who had never had a chronic illness before. He was a nonsmoker and did not consume alcoholic beverages. He went to the emergency room (ER) because he was having upper abdominal pain and aches throughout his body. He was just started a rigorous physical activity-based training regimen. A total creatine kinase (CK) level more than 5 times higher than the upper normal value confirmed the diagnosis. For the upper abdominal pain, an ultrasound was performed. It reveals ascites and a thick-walled gallbladder. With a decrease in repeated total CK and clinical improvements, the patient was discharged home after aggressive hydration. The patient was asymptomatic at the follow-up appointment, and the ultrasound showed no ascites or gallbladder wall thickness. Conclusion: These are a rare complication of rhabdomyolysis. It implies that acalculous cholecystitis and ascites should be interpreted in light of the clinical scenario and presentation. The workup for ascites and acalculous differential diagnosis was uneventful. In a young patient with rhabdomyolysis, acalculous cholecystitis and ascites is an unusual occurrence.

Rhabdomyolysis-Induced AKI (RIAKI) Including the Role of COVID-19

Rhabdomyolysis is a compound disease that may be induced by many factors, both congenital and acquired. Statin therapy is considered one of the most common acquired factors. However, recent scientific reports suggest that serious complications such as rhabdomyolysis are rarely observed. Researchers suggest that, in many cases, side effects that occur with statin therapy, including muscle pain, can be avoided with lower-dose statin therapy or in combination therapy with other drugs. One of the most recent agents discovered to contribute to rhabdomyolysis is COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Rhabdomyolysis is defined as a damage to striated muscle cells with escape of intracellular substances into the bloodstream. These substances, including myoglobin, creatine kinase (CK), potassium, and uridine acid, are markers of muscle damage and early complications of rhabdomyolysis. Symptoms may be helpful in establishing the diagnosis. However, in almost 50% of patients, they do not occur. Therefore, the diagnosis is confirmed by serum CK levels five times higher than the upper limit of normal. One of the late complications of this condition is acute kidney injury (AKI), which is immediately life-threatening and has a high mortality rate among patients. Therefore, the prompt detection and treatment of rhabdomyolysis is important. Markers of muscle damage, such as CK, lactate dehydrogenase (LDH), myoglobin, troponins, and aspartate aminotransferase (AST), are important in diagnosis. Treatment of rhabdomyolysis is mainly based on early, aggressive fluid resuscitation. However, therapeutic interventions, such as urinary alkalinization with sodium bicarbonate or the administration of mannitol or furosemide, have not proven to be beneficial. In some patients who develop AKI in the course of rhabdomyolysis, renal replacement therapy (RRT) is required.

Ulinastatin Alleviates Rhabdomyolysis-Induced Acute Kidney Injury by Suppressing Inflammation and Apoptosis via Inhibiting TLR4/NF-κB Signaling Pathway.

Acute kidney injury (AKI) is an important complication of rhabdomyolysis (RM), but there is lack of effective treatments. Ulinastatin (UTI) is a broad-spectrum serine protease inhibitor isolated and purified from human urine with strong anti-inflammatory and cytoprotective actions. The aim of this research was to investigate the effect and potential mechanism of UTI on RM-induced AKI (RM-AKI). We established RM-induced AKI model and myoglobin (Mb)-stimulated NRK-52E cell model. In vivo, twenty-four rats were randomly divided into three groups (n = 8): control, RM-AKI, and RM-AKI + UTI. In vitro, the NRK-52E cells were divided into six groups according to the different treatment method. Mb-stimulated NRK-52E cells were treated with UTI or si-TLR4 transfection to characterize the mechanisms of UTI in RM-AKI. Indicators of the kidney injury, cell viability, cell cycle, oxidative stress, inflammation, apoptosis, and TLR4/NF-κB signaling pathway were assessed. In vivo and in vitro, UTI significantly decreased the expression of TLR4 and p65. In vivo, UTI significantly improved renal function and reduced inflammatory reaction and kidney injury. In vitro, UTI protected NRK-52E cells from Mb stimulation by suppressing cell cytotoxicity, cell cycle inhibition, overproduction of ROS, inflammation, and apoptosis. Additionally, UTI played a protective role by downregulating the TLR4 expression. The results indicate that UTI alleviates RM-AKI by suppressing the inflammatory response and apoptosis via inhibiting TLR4/NF-κB signaling pathway. Our study provides a new mechanism for the protective effect of UTI on RM-AKI.