[Biochemical analysis of an uncommon monoclonal peak on urine protein electrophoresis: a case report]. / Analyse biochimique d'un pic insolite d'allure monoclonale en électrophorèse des protéines urinaires: à propos d'un cas.

Urine protein electrophoresis is often required for diagnosis and monitoring of urological or renal diseases and lymphoid hemopathies. We here report an uncommon urine protein electrophoresis result. The test was performed using agarose gel electrophoresis and capillary electrophoresis. It was a monoclonal peak of unknown significance migrating with gammaglobulins. Scientific literature and the tests performed demonstrated that it was myoglobin. In fact, myoglobin (17 kDa) is freely filtered by the glomerulus and normally reabsorbed by the tubules. If tubule capacity for reabsorption is exceeded, its presence results in overcharging proteinuria. Myoglobinuria helped diagnose rhabdomyolysis in our patient. Thus, the analysis of unknown peaks, can provide information on symptoms but also underlying pathologies, which may be of clinical interest.

Cilastatin Ameliorates Rhabdomyolysis-induced AKI in Mice.

BACKGROUND: Rhabdomyolysis, the destruction of skeletal muscle, is a significant cause of AKI and death in the context of natural disaster and armed conflict. Rhabdomyolysis may also initiate CKD. Development of specific pharmacologic therapy is desirable because supportive care is nearly impossible in austere environments. Myoglobin, the principal cause of rhabdomyolysis-related AKI, undergoes megalin-mediated endocytosis in proximal tubule cells, a process that specifically injures these cells. METHODS: To investigate whether megalin is protective in a mouse model of rhabdomyolysis-induced AKI, we used male C57BL/6 mice and mice (14-32 weeks old) with proximal tubule-specific deletion of megalin. We used a well-characterized rhabdomyolysis model, injection of 50% glycerol in normal saline preceded by water deprivation. RESULTS: Inducible proximal tubule-specific deletion of megalin was highly protective in this mouse model of rhabdomyolysis-induced AKI. The megalin knockout mice demonstrated preserved GFR, reduced proximal tubule injury (as indicated by kidney injury molecule-1), and reduced renal apoptosis 24 hours after injury. These effects were accompanied by increased urinary myoglobin clearance. Unlike littermate controls, the megalin-deficient mice also did not develop progressive GFR decline and persistent new proteinuria. Administration of the pharmacologic megalin inhibitor cilastatin to wild-type mice recapitulated the renoprotective effects of megalin deletion. This cilastatin-mediated renoprotective effect was dependent on megalin. Cilastatin administration caused selective proteinuria and inhibition of tubular myoglobin uptake similar to that caused by megalin deletion. CONCLUSIONS: We conclude that megalin plays a critical role in rhabdomyolysis-induced AKI, and megalin interference and inhibition ameliorate rhabdomyolysis-induced AKI. Further investigation of megalin inhibition may inform translational investigation of a novel potential therapy.

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.

Cluster of exertional rhabdomyolysis in three young women.

Three young women, aged 18-24 years, presented to general practice with signs and symptoms of exertional rhabdomyolysis in 2016. All attended the same gym and had undertaken an intensive physical workout. Presenting symptoms were severe muscle pain and swelling, significantly reduced range of motion in affected muscles and, in two cases, dark-coloured urine. One case had presented to the out-of-hours service 4 months previously with similar symptoms but rhabdomyolysis was not considered, although retrospective history taking suggests that was the likely diagnosis. All three women were admitted to hospital, treated with intravenous fluids and discharged between 1 and 6 days later. All made a full recovery with no renal sequelae. The cases were questioned about potential risk factors, and the only commonality was unaccustomed strenuous exercise.

[Brown urine : Myoglobin-induced renal failure after concomitant administration of simvastatin and amiodarone]. / Brauner Urin : Myoglobininduziertes Nierenversagen nach gleichzeitiger Gabe von Simvastatin und Amiodaron.

Rhabdomyolysis is a rare but well-known complication of statin therapy. The risk is considerably increased when concomitant drugs are administered that inhibit metabolism and breakdown via the cytochrome CYP3A4. We report a case of myoglobin-induced acute renal failure secondary to the concomitant use of simvastatin and amiodarone. The risk of rhabdomyolysis is mainly determined by the statin dose; in the case of the concomitant use of CYP3A4 inhibitors, a maximal daily dose of 20 mg is recommended to avoid harmful drug interactions.

Severe rhabdomyolysis secondary to adenovirus infection: case report and literature review.

A 38-year-old male presented with renal failure in the setting of a flu-like illness. Urinalysis showed myoglobinuria and granular casts. His serum creatine phosphokinase was markedly elevated. He was diagnosed with rhabdomyolysis and was volume resuscitated with normal saline and bicarbonate-containing fluid. Workup included a respiratory viral panel which was positive for adenovirus. Other causes such as trauma, seizure, and intoxicants were excluded. He developed progressive renal failure necessitating hemodialysis. After ~ 4 weeks he recovered renal function and dialysis was discontinued. Viral-induced myopathy should be suspected in patients who present with rhabdomyolysis.

Exercise-induced rhabdomyolysis.

Exercise-induced rhabdomyolysis, or exertional rhabdomyolysis (ER), is a clinical entity typically considered when someone presents with muscle stiffness, swelling, and pain out of proportion to the expected fatigue post exercise. The diagnosis is confirmed by myoglobinuria, and an elevated serum Creatinine Phosphokinase (CPK) level, usually 10 times the normal range. However, an elevation in CPK is seen in most forms of strenuous exercise, up to 20 times the upper normal range. Therefore, there is no definitive pathologic CPK cut-off. Fortunately the dreaded complication of acute renal failure is rare compared to other forms rhabdomyolysis. We review the risks, diagnosis, clinical course and treatment for exercise- induced rhabdomyolysis.

Acute haemolytic anaemia and myolysis due to G6PD deficiency.

A 2-year-old African-American male patient with sickle cell trait developed cough, red coloured urine, pallor and fatigue. The patient was hospitalised. Diagnostic workup showed that he was glucose 6 phosphate dehydrogenase (G6PD) deficient in erythrocytes. He also had chest X-ray findings of pneumonia. His urine examination showed the presence of haemoglobin and myoglobin. On repeated questioning it was found that he had a moth ball in his mouth a few days prior to this medical episode. This case illustrates a rarely described complication of myolysis in G6PD deficient persons on exposure to a strong oxidant. A review of the literature showed that most people with G6PD deficiency tolerate exercise well without untoward effect in muscles. However, assay of myoglobin in urine has not been routinely performed in these patients during acute haemolytic episode, and thus it is uncertain how frequent myoglobulinaemia occurs in a similar stress situation.

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.

Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease.

McArdle disease (glycogenosis type V), the most common muscle glycogenosis, is a recessive disorder caused by mutations in PYGM, the gene encoding myophosphorylase. Patients with McArdle disease typically experience exercise intolerance manifested as acute crises of early fatigue and contractures, sometimes with rhabdomyolysis and myoblobinuria, triggered by static muscle contractions or dynamic exercises. Currently, there are no therapies to restore myophosphorylase activity in patients. Although two spontaneous animal models for McArdle disease have been identified (cattle and sheep), they have rendered a limited amount of information on the pathophysiology of the disorder; therefore, there have been few opportunities for experimental research in the field. We have developed a knock-in mouse model by replacing the wild-type allele of Pygm with a modified allele carrying the common human mutation, p.R50X, which is the most frequent cause of McArdle disease. Histochemical, biochemical and molecular analyses of the phenotype, as well as exercise tests, were carried out in homozygotes, carriers and wild-type mice. p.R50X/p.R50X mice showed undetectable myophosphorylase protein and activity in skeletal muscle. Histochemical and biochemical analyses revealed massive muscle glycogen accumulation in homozygotes, in contrast to heterozygotes or wild-type mice, which did not show glycogen accumulation in this tissue. Additional characterization confirmed a McArdle disease-like phenotype in p.R50X/p.R50X mice, i.e. they had hyperCKaemia and very poor exercise performance, as assessed in the wire grip and treadmill tests (6% and 5% of the wild-type values, respectively). This model represents a powerful tool for in-depth studies of the pathophysiology of McArdle disease and other neuromuscular disorders, and for exploring new therapeutic approaches for genetic disorders caused by premature stop codon mutations.

Accuracy of urine dipstick in the detection of patients at risk for crush-induced rhabdomyolysis and acute kidney injury.

OBJECTIVES: To evaluate the utility of urine dipstick test (UDT) for detecting rhabdomyolysis and acute kidney injury (AKI) due to crush injury. METHODS: All the rescued victims of the Bam earthquake who had a documented urine analysis and serum creatine phosphokinase and creatinine levels during their hospitalization period were eligible to enter the study. The sensitivity and the specificity, along with the positive and negative likelihood ratios, of UDT in detecting at-risk patients for rhabdomyolysis and crush-related AKI were calculated. RESULTS: Urine red blood cell count of 5 or less in blood-positive UDT, as a surrogate marker for myoglobinuria, was reported in 210 (31.7%) of the total 1821 urine analyses. Blood-positive UDTs (without considering the urine red blood cell count) had a 92.5% (95% confidence interval: 79.6-98.4) sensitivity in creatine phosphokinase, with a cut-off of 15,000 (IU/l). Comparing the results of the serum creatinine level and the urine blood, analysis showed that UDT had a sensitivity and a specificity of as high as 83.3 and 56.6% in detecting high-risk patients for AKI, respectively. CONCLUSION: UDT can be considered as an early screening tool for the detection and triage of patients at risk of developing AKI because of traumatic rhabdomyolysis after mass disasters.

Episodes of exercise-induced dark urine and myalgia in LGMD 2I.

BACKGROUND: Mutations in the fukutin-related protein gene FKRP (MIM *606596) cause a form of congenital muscular dystrophy (MDC1C) and also limb girdle muscular dystrophy type 2I (LGMD2I). Exercise-induced myoglobinuria, frequently occurring in metabolic myopathies, has been described in Becker muscular dystrophy and in a few cases of LGMD. OBJECTIVES: To describe that episodes with myoglobinuria, often associated with exercise-induced myalgia, may be common and a presenting symptom in patients with LGMD2I. METHODS: Data on episodes of suspected myoglobinuria and myalgia were collected from the patient records on 14 patients with a diagnosis of LGMDI. RESULTS: Five LGMD2I patients reported recurrent episodes of dark urine and myalgia after exercise, and in three of them, this was the only symptom for several years. CONCLUSIONS: We conclude that episodes compatible with exercise-induced myoglobinuria may be frequent in LGMD2I.

Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies.

Loss of mobility influences the quality of life for patients with neuromuscular diseases. Common measures of mobility and chronic muscle damage are the six-minute walk test and serum creatine kinase. Despite extensive pre-clinical studies of therapeutic approaches, characterization of these measures is incomplete. To address this, a six-minute ambulation assay, serum creatine kinase, and myoglobinuria were investigated for the mdx mouse, a dystrophinopathy mouse model commonly used in pre-clinical studies. mdx mice ambulated shorter distances than normal controls, a disparity accentuated after mild exercise. An asymmetric pathophysiology in mdx mice was unmasked with exercise, and peak measurements of serum creatine kinase and myoglobinuria were identified. Our data highlights the necessity to consider asymmetric pathology and timing of biomarkers when testing potential therapies for muscular dystrophy.

MRI quantitative study and pathologic analysis of crush injury in rabbit hind limb muscles.

BACKGROUND: To explore the value of quantitative magnetic resonance imaging (i.e., T2 map technique) in the diagnosis of crush injury in rabbit hind limb muscles. MATERIALS AND METHODS: We established a rabbit hind limb crush injury model and performed examinations on magnetic resonance imaging (MRI) (T1WI, T2WI, and T2 map), muscle pathology, serum level of muscular troponin (sTnI), and urine myoglobin (Myo) at 1, 3, 7, 14, and 30 d after injury to investigate the correlation of MRI, library examination, and histopathology. RESULTS: T2WI of the injured muscle showed high signal intensity at 1, 3, and 7 d after crush injury and the T2 value continued to rise. The pathologic findings of the muscle included swollen and ruptured cells, expanded extra-cellular space, inflammatory reactions, and fine muscle fiber regeneration. The serum sTnI and urine Myo were high. At 14 d, these indices returned to normal gradually. The T2WI changes and T2 value were positively associated with the pathological changes of the muscles, serum sTnI and urine Myo. However, the signal intensity of T1WI did not vary significantly at different time points. CONCLUSION: T2WI and T2 value from T2 mapping are very useful methods of choice to evaluate the distribution and extension of the affected muscles. The high signal intensity on T2WI of the affected muscles after crush injury may be due to an increased extracellular space, local inflammation, and incomplete muscle fiber regeneration.

[Treatment for crush syndrome of extremities with antioxidants].

OBJECTIVE: To study the clinical therapeutic effect of antioxidants assistant treatment of extremities crush syndrome (CS)in order to find new therapy. METHODS: Twenty-one male patients (aged from 24 to 48 years, mean 36 years) were treated with the next antioxidants in early stage: (1) 20% Mannitol 250 ml intravenous drip in 30 minutes (one time per 6 to 8 h). (2) Sodium aescinate 20 mg, Salvia Miltiorrhiza 20 ml were dissolved respectively in isotonic saline or 5% glucose 200 ml and dripped by intravenous drip (50 to 60 drips per minute). The drugs were used for 5 to 7 days (one time per day). Basifying urine, keeping the nagative liquid banlance and electrolyte banlance, preventing infection and hold out treatment were done. When the pressure of muscular osteofascial compartment was more than 30 mmHg, deep fasia was cut to decompress timely and the above-mentioned drugs were continuously applied for patients. RESULTS: Myoglobin urine of 21 cases died out after 2 to 3 days, of them, 13 cases were performed to decompress. After open decompression, 2 cases suffered from amputation because of long time of ischemia, 2 cases took place slight dysfunction of lower limbs, one hand had ischemia muscular contracture in 1 case and one foot down-vertical in 1 case. After followed-up of 8 months to 1 year, according to the function standard, the result were excellent in 8 cases, good in 7 cases, fair in 2 cases, poor in 4 cases. The excellent and good rate was about 71.4% (15/21). CONCLUSION: After extremities crushed for long time, application of antioxidents as early as possible can decrease significantly the incidence and invalidity rate of CS.

Muscle cell injury, haemolysis and dark urine in children with falciparum malaria in Papua New Guinea.

During a prospective study of red cell variants and severe malaria in children, a surprising observation was the occurrence of dark urine. Children were grouped according to urine findings: 22 had dark urine that contained a haem protein (Group I), 93 had urine of normal colour that contained a haem protein (Group II) and 236 had normal urine (Group III). To investigate the cause of dark urine, haemolysis and muscle cell injury were assessed. Intravascular haemolysis was greater in Group I than in Groups II and III. However, anaemia was more severe in Group III and is likely to have resulted mainly from extravascular haemolysis. Median plasma myoglobin concentrations were greater in Groups I and II than Group III (P = 0.00060). Plasma myoglobin was greater in children with cerebral malaria, hyperlactataemia and those who died but was not associated with acidosis. Urine myoglobin was greater in Group I than Groups II and III (P = 0.00054). It is likely that both haemoglobin and myoglobin contributed to dark urine. The association between muscle cell injury and coma suggests sequestration of parasitized red cells as a common underlying pathology. In malaria, hyperlactataemia may result directly from breakdown of muscle protein as well as tissue hypoxia.

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.