Exercise Induced Myoglobinuria is Determined by Haptoglobin Polymorphism.

BACKGROUND: In professional soccer players (n = 27), confounders of quantitative myoglobinuria following physical training were assessed in order to improve interpretation of post-exercise myoglobinuria. METHODS: Urine samples were collected in the morning before training sessions, 48 to 72 hours following a game. Urine myoglobin was assayed using immunoturbidimetry. Blood was drawn 48 hours following training session. Creatinine was assayed using a Jaffe method. Creatine kinase (CK) activity was assayed according to the IFCC reference method. Serum myoglobin was assayed using the same assay as the one used for urine. Hp polymorphism was assessed on hemoglobin supplemented serum. Serum Hp concentration was assayed nephelometrically. Training intensity was assessed using a wearable GPS tracking system. Physical load monitoring included the covered total distance, the distance at different speed zones, and the number of sprints/accelerations/decelerations/jumps. Multiple regression analysis was used to detect the determinants of post-exercise myoglobinuria. RESULTS: Myoglobinuria negatively correlated with serum haptoglobin (Hp) concentration. Athletes presented with Hp values, which were lower than the Hp phenotype reference ranges, which can be explained by depletion of circulating Hp stores. Myoglobinuria was most pronounced in players carrying a Hp 2-2 phenotype, which is associated with the lowest Hp reference range. Myoglobin clearance was inversely correlated with Hp 2-2 concentration. Correlation between myoglobinuria and biomarkers of muscle damage was weak. Neither age nor glomerular filtration rate were found to be confounders of myoglobinuria. When comparing myoglobinuria with training intensity, the number of sprints, average acceleration speed, and maximal speed were determining factors for predicting exercise-induced myoglobinuria. CONCLUSIONS: In athletes, plasma myoglobin binding capacity is depleted. Moderate myoglobinuria not only should be regarded as a muscle damage marker, but also should be interpreted as an indicator for Hp depletion. Apart from its significance as a biomarker for muscle damage and rhabdomyolysis, myoglobinuria in athletes should be a warning that the heme binding capacity of plasma Hp is depleted, indicating an exhausted defense against Fenton chemistry induced free radicals. Fenton chemistry is associated with free radical formation, which is to be avoided because of the causative relationship with inflammatory processes and tissue damage.

Histopathological kidney changes and myoglobinuria in neotropical non-human primates attacked by dogs, Brazil.

BACKGROUND: Non-human primates (NHPs) are susceptible to dogs' attacks, events that may cause muscle damage along with stress, and could be in some extent compatible with capture myopathy, a syndrome that results in myoglobinuria and renal damage. METHODS: We aimed to evaluate by histopathology pre-existing lesions and subsequent sequelae related to dogs' attacks, acute tubular necrosis (ATN) and myoglobinuria, as well as the usefulness of Pearls Stain and IHC to diagnose it. Histopathology was performed in available organs, and sections of kidney submitted to Prussian blue stain and myoglobin immunohistochemistry. RESULTS: During January 2014-June 2016, 16/145 (11%) of NHPs received by Adolfo Lutz Institute, Brazil were reported as attacked by dogs. A high frequency of young and debilitated animals was found. Myoglobinuria was observed in more than half animals (9/16; 56.2%), from which (5/9; 55.5%) presented ATN. CONCLUSIONS: Kidney lesions are plausible findings in NHPs attacked by dogs.

The effect of hyperbaric oxygen therapy on rhabdomyolysis-induced myoglobinuric acute renal failure in rats.

Myoglobinuric acute renal failure (MARF) may develop after severe muscle injury. Heme oxygenase-1 (HO-1), a stress-response protein, has been implicated as a protective agent against MARF. We hypothesized that hyperbaric oxygen therapy (HBOT) may alleviate MARF by inducing renal HO-1 expression. Wistar-Albino rats were randomly assigned into three groups: Control (n = 4), MARF (n = 8), MARF + HBO (n = 8). MARF was induced by intramuscular glycerol (50%, 8 mL/kg) injection. Saline (8 mL/kg) was injected into the hind limb of the animals in the control group. Animals in the MARF + HBO group received two sessions of HBO therapy (90 min at 2.5 atm) 2 and 18 h after glycerol injection. Serum and tissue samples were taken at 24 h. Serum urea and creatinine levels increased in the MARF and MARF + HBO groups confirming the development of MARF. But, serum urea and creatinine levels were similar in MARF and MARF + HBO groups. Oxidative stress parameters were similar among all groups. Histological renal injury score was similar in MARF and MARF + HBO groups. HO-1 level, determined by immunohistochemistry, was significantly higher in MARF and MARF + HBO groups, compared to the control group. Although HO-1 level in MARF + HBO group was higher than MARF group, it was not statistically significant. We found that HBOT did not reduce renal injury in experimental MARF model. HBOT is used to reduce the muscle damage after crush injury, which may be accompanied by MARF. Therefore, more studies are needed to understand the effects of HBO treatment on renal functions after MARF.

Myoglobinuria as first clinical sign of a primary alpha-sarcoglycanopathy.

UNLABELLED: Myoglobinuria is a frequent complication of metabolic myopathies and may also occur in Duchenne and Becker dystrophies but is not a typical sign of limb-girdle muscular dystrophy. We describe an unusual presentation of alpha-sarcoglycanopathy with myoglobinuria at the onset of the disease. The boy presented an episode of dark urine, identified as presence of blood by a urine dipstick, occurred 10 days after an episode of fever and sore throat treated with antibiotics. He was admitted to the hospital and investigated for post-infectious nephritis, but further analysis revealed the presence of myoglobinuria. Immunohistochemistry on muscle tissue revealed absent expression of α-sarcoglycan confirmed by detection of a homozygous mutation in the alpha-sarcoglycan gene. Myoglobinuria has been previously reported four times in sarcoglycanopathies but only once in alpha-sarcoglycanopathy. CONCLUSION: The present observation reinforces the idea that the myoglobinuria should be considered a manifestation of a primary sarcoglycanopathy even as the only recognizable sign at the debut of the disease.

Myoglobinuria masquerading as acute rejection in a renal allograft recipient with recurrent post transplant diabetic nephropathy.

Rhabdomyolysis contributes to 7-10% of total AKI cases. Myoglobinuria as a cause of acute renal allograft dysfunction is extremely uncommon. Renal allograft recipient on cyclosporine or tacrolimus can develop myoglobinuria in presence of other precipitating factors. Present case describes an interesting report of myoglobinuria in a patient with post transplant diabetic nephropathy mimicking acute graft rejection. Clinically myoglobinuria presenting as renal allograft dysfunction is diagnosis of exclusion and renal biopsy is extremely important in making a correct diagnosis and planning optimal management in such cases.

Hyperthermia and postmortem biochemical investigations.

The postmortem diagnosis of heat-related deaths presents certain difficulties. Firstly, preterminal or terminal body temperatures are often not available. Additionally, macroscopic and microscopic findings are nonspecific or inconclusive and depend on survival duration after exposure. The diagnosis of hyperthermia is therefore essentially based on scene investigation, the circumstances of death, and the reasonable exclusion of other causes of death. Immunohistochemistry and postmortem biochemical investigations have been performed by several authors in order to better circumstantiate the physiopathology of hyperthermia and provide further information to confirm or exclude a heat-related cause of death. Biochemical markers, such as electrolytes, hormones, blood proteins, enzymes, and neurotransmitters, have been analyzed in blood and other biological fluids to improve the diagnostic potential of autopsy, histology, and immunohistochemistry. The aim of this article is to present a review of the medicolegal literature pertaining to the postmortem biochemical investigations that are associated with heat-related deaths.

Severe falciparum malaria with dengue coinfection complicated by rhabdomyolysis and acute kidney injury: an unusual case with myoglobinemia, myoglobinuria but normal serum creatine kinase.

BACKGROUND: Acute kidney injury (AKI) is a complication of severe malaria, and rhabdomyolysis with myoglobinuria is an uncommon cause. We report an unusual case of severe falciparum malaria with dengue coinfection complicated by AKI due to myoglobinemia and myoglobinuria while maintaining a normal creatine kinase (CK). CASE PRESENTATION: A 49-year old Indonesian man presented with fever, chills, and rigors with generalized myalgia and was diagnosed with falciparum malaria based on a positive blood smear. This was complicated by rhabdomyolysis with raised serum and urine myoglobin but normal CK. Despite rapid clearance of the parasitemia with intravenous artesunate and aggressive hydration maintaining good urine output, his myoglobinuria and acidosis worsened, progressing to uremia requiring renal replacement therapy. High-flux hemodiafiltration effectively cleared his serum and urine myoglobin with recovery of renal function. Further evaluation revealed evidence of dengue coinfection and past infection with murine typhus. CONCLUSION: In patients with severe falciparum malaria, the absence of raised CK alone does not exclude a diagnosis of rhabdomyolysis. Raised serum and urine myoglobin levels could lead to AKI and should be monitored. In the event of myoglobin-induced AKI requiring dialysis, clinicians may consider using high-flux hemodiafiltration instead of conventional hemodialysis for more effective myoglobin removal. In Southeast Asia, potential endemic coinfections that can also cause or worsen rhabdomyolysis, such as dengue, rickettsiosis and leptospirosis, should be considered.

High cut-off renal replacement therapy for removal of myoglobin in severe rhabdomyolysis and acute kidney injury: a case series.

BACKGROUND/AIM: Rhabdomyolysis is associated with the release of myoglobin into the circulation, promoting acute kidney injury (AKI). In severe rhabdomyolysis, dialysis-dependent AKI doubles mortality. Standard blood purification techniques have limited efficacy in removing myoglobin. We describe high cut-off (HCO) renal replacement therapy (RRT) as a novel approach for extracorporeal elimination of myoglobin in rhabdomyolysis-associated AKI. METHODS: With an in vivo molecular cut-off at 45 kDa, HCO filters are effective in removing myoglobin (17.8 kDa). Clearances across standard and HCO filters using continuous or intermittent RRT are reviewed in a case series of 11 patients with severe rhabdomyolysis and dialysis-dependent AKI. RESULTS: Median myoglobin clearance across standard high-flux filters was 3.3 (interquartile range 2.3-3.9) ml/min for sustained low-efficiency daily dialysis (SLEDD) batch hemodialysis (HD) and 3.7 (2.9-6.7) ml/min for conventional HD. Respective clearances using HCO filters (membrane surface area: 1.1 m(2)) were 21.7 (20.3-26.1) ml/min (SLEDD) and 44.2 (41.3-47.0) ml/min (HD). Corrected for filter size, up to 20-fold higher clearances were obtained using HCO filters, resulting in profound and sustained reduction of plasma myoglobin concentration. CONCLUSIONS: As a novel approach, HCO RRT allows for rapid and effective removal of myoglobin from the circulation. In light of the pathogenic role in AKI, reducing exposure of the kidney to myoglobin may improve renal recovery and patient outcome. Our data pave the way for prospective trials, addressing this issue.

Acute kidney injury associated with rhabdomyolysis in a patient with COVID-19.

Rhabdomyolysis is defined as the breakdown of skeletal muscle leading to the release of muscle contents into the extracellular fluid. Patients with rhabdomyolysis can be asymptomatic or have myalgia symptoms, weakness, myoglobinuria with dark urine, significant electrolyte imbalance, and acute kidney injury. Here we describe a case on acute kidney injury associated to rhabdomyolysis in a patient with COVID-19.

Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.

Recurrent episodes of life-threatening myoglobinuria in childhood are caused by inborn errors of glycogenolysis, mitochondrial fatty acid beta-oxidation, and oxidative phosphorylation. Nonetheless, approximately half of the patients do not suffer from a defect in any of these pathways. Using homozygosity mapping, we identified six deleterious mutations in the LPIN1 gene in patients who presented at 2-7 years of age with recurrent, massive rhabdomyolysis. The LPIN1 gene encodes the muscle-specific phosphatidic acid phosphatase, a key enzyme in triglyceride and membrane phospholipid biosynthesis. Of six individuals who developed statin-induced myopathy, one was a carrier for Glu769Gly, a pathogenic mutation in the LPIN1 gene. Analysis of phospholipid content disclosed accumulation of phosphatidic acid and lysophospholipids in muscle tissue of the more severe genotype. Mutations in the LPIN1 gene cause recurrent rhabdomyolysis in childhood, and a carrier state may predispose for statin-induced myopathy.

Necrotizing vacuolar myopathy presenting with recurrent myoglobinuria.

Myoglobinuria occurs in a variety of systemic and neurological disorders and can pose diagnostic challenges. We report on a 23-year-old man in whom recurrent myoglobinuria was observed due to necrotizing vacuolar myopathy confirmed on muscle biopsy. Histopathologically the intramuscular vacuoles lacked the typical findings reported in vacuolar myopathy due to disorders of glycogen and lipid metabolism. We discuss the management approach to recurrent myoglobinuria. Recurrent myoglobinuria in the absence of toxin or drug exposure and seizure is more often due to primary muscle disease. Recognizing the presence of myoglobinuria and the proximate cause is essential in preventing the development of renal dysfunction and the future recurrence of symptoms.

Value and Use of Urinalysis for Myoglobinuria.

CONTEXT.­: Urine myoglobin testing is primarily indicated for diagnosis and risk assessment of kidney injury in patients with rhabdomyolysis. However, its utility is limited by a lack of rapid and reliable results. Myoglobin reacts positively for blood by urine dipstick, which can serve as an indicator of myoglobinuria. OBJECTIVE.­: To evaluate the performance and value of blood and red cell measurements by urinalysis as a surrogate test for myoglobinuria in routine clinical practice. DESIGN.­: This study is a retrospective observational study involving analysis of hemoglobin and red blood cell results by urinalysis in patients tested for urine myoglobin. RESULTS.­: A total of 13 139 urine myoglobin results from 88 Veterans Affairs facilities during a 15-year period ending in October 2014 were evaluated. Among methods used by each laboratory, qualitative urine myoglobin tests declined from 25 of 53 (47.1%) in 2000 to 5 of 77 (6.4%) in 2013. Of 7311 tests (55.6%) performed by quantitative methods with concomitant urinalysis, 3915 (53.5%) showed negative to trace blood results, of which myoglobin was 1000 µg/L or greater in 17 (0.4%). Among 1875 (25.5%) with 3+ (large) blood results, urine myoglobin was ≥1000 µg/L in 273 of 1533 (17.8%) with hematuria (≥5 red blood cells per microliter) and 109 of 342 (31.9%) without hematuria. CONCLUSIONS.­: Urinalysis results reliably predicted the absence of myoglobinuria and could be used to avert overtesting for urine myoglobin while also providing useful diagnostic information when urine myoglobin test results are not immediately available.

Rhabdomyolysis and acute myoglobinuric renal failure in a patient with bilateral pheochromocytoma following open pyelolithotomy.

Rhabdomyolysis is an unusual manifestation of pheochromocytoma. Early diagnosis and prompt management are crucial, as it may have life-threatening consequences. This is the case of a 19-year-old man with bilateral pheochromocytoma complicated with rhabdomyolysis and acute myoglobinuric renal failure after surgery for nephrolithiasis. A massive catecholamine release during the procedure manifested itself as a hypertensive crisis, producing severe vasoconstriction and thereby provoking ischemia of the patient's muscle tissue. This insult resulted in rhabdomyolysis and acute myoglobinuric renal failure. After making sure that all necessary medical precautions were performed, including blood pressure stabilization with alpha receptor blockade and adequate fluid replacement, the patient successfully underwent a bilateral cortex-sparing medullar adrenalectomy. The operation specimen was reported as pheochromocytoma.

Recurrent episodic myoglobinuric acute kidney injury as presenting manifestation of idiopathic polymyositis.

Polymyositis (PM) is a rare heterogeneous group of disorders with frequent multisystem involvement including uncommon renal manifestations. Acute kidney injury (AKI) as the primary manifestation of PM is extremely rare. Herein, we report a case of recurrent episodic AKI in an adult female who was subsequently diagnosed to have PM.

History and clinical features of atypical myopathy in horses in Belgium (2000-2005).

BACKGROUND: The emergent nature of atypical myopathy or atypical myoglobinuria (AM) necessitates precise description of its clinical and epidemiologic features. PURPOSE: To define key features of AM to help practitioners recognize the disease and to advise owners to take preventive measures. ANIMALS: Belgian cases of AM confirmed by histology (CC horses; n = 57) from autumn 2000 to spring 2005 were included in the study. Co-grazing horses (Co-G horses; n = 77) that remained free of any abnormal clinical signs constituted a control group. METHODS: History, environmental characteristics, clinical signs, and laboratory results associated with AM were determined by a retrospective case series study. RESULTS: Young horses in poor or normal body condition were found to be at risk for AM. Pastures were characterized by poor natural drainage and vegetation of low nutritional value. Features of AM were seasonal occurrence, apparent link with weather conditions (ie, lack of solar radiation with no heavy frost and an excess of precipitation or relative humidity), sudden onset of clinical signs, and rapid death. Evaluation of serum creatine kinase activity indicated severe muscle destruction in CC horses and subclinical disease in a few Co-G horses. CONCLUSIONS: The association of AM with specific environmental conditions and individual animals suggests that young horses should not be pastured on bare premises subject to humidity when the weather has been very wet and cold for several days. Management of AM outbreaks should include control of Co-G horses who are apparently healthy.

Case Report: Red Urine After Day Care Strabismus Surgery.

In the absence of surgery on the urinary tract, the emission of red urine after anesthesia should be considered as a diagnostic emergency because it can be a sign of hematuria, hemoglobinuria, blood transfusion reaction, significant myoglobinuria, or porphyria.This case describes the management of a 12-year-old boy who presented red urine at the day care unit after strabismus surgery.

Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects.

Muscle carnitine palmitoyltransferase (CPT) II deficiency is an autosomal recessive disorder of fatty acid oxidation characterized by attacks of myalgia and myoglobinuria. This review summarizes the clinical features of this disease, analyzing data of 28 patients with biochemically and genetically confirmed CPT II deficiency. The review shows that exercise-induced myalgia is the most frequent symptom, whereas myoglobinuria, known as the clinical hallmark, is missing in 21% of the patients. Typically, myalgia starts in childhood, whereas attacks with myoglobinuria mostly emerge in adolescence or early adulthood. However, there are also patients with only myalgia, patients with attacks triggered by factors other than exercise, and patients with late-onset disease. Molecular or biochemical analysis is necessary for diagnosis, since no myopathologic hallmark exists. For screening patients, analysis of not only the common S113L mutation but also the P50H and Q413fs-F448L mutations is recommended. The phenotype of muscle CPT II deficiency might be influenced by the underlying mutation, and patients with a truncating mutation on 1 allele might be affected more severely.

Factors affecting urinary myoglobin stability in vitro.

Urine myoglobin concentrations are measured clinically to assess rhabdomyolysis and the related risk of renal damage. We studied urine myoglobin concentrations in vitro to explore the factors affecting stability. Myoglobin was very unstable in urine specimens, especially below pH 6.5, and its immunoreactivity deteriorated rapidly with increasing temperatures. The deterioration rate was influenced greatly by urine myoglobin concentration, suggesting rate-limiting kinetics. Myoglobin in acidic phosphate-buffered saline was significantly more stable than in acidic urine, indicating that urinary factors in addition to pH are involved in myoglobin instability. These unidentified urinary factors had a molecular weight of less than 10 kd. Our results provide additional insight into the mechanism involved in the instability of the urine myoglobin concentration. Understanding the stability of myoglobin in the preanalytic in vitro phase and its potential in vivo instability is essential in assuring the reliability and clinical usefulness of urine myoglobin measurements.