Rhabdomyolysis as the Initial Presentation of SARS-CoV-2 in an Adolescent.

The novel coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2, has created a global pandemic, with many cases affecting the elderly. However, children have been affected as well, with ∼2.4% to 3.7% of cases reported. This case is the first published case of an adolescent presenting with rhabdomyolysis as the first sign of novel coronavirus disease 2019, with extremely elevated creatinine kinase levels, approaching almost 400 000 U/L. This case adds to the growing body of literature of a variety of life-threatening manifestations associated with severe acute respiratory syndrome coronavirus 2 infection and highlights the importance of how prompt recognition of these unique presentations of the disease is important to mitigate complications.

Kidney involvement and associated risk factors in children with Duchenne muscular dystrophy.

BACKGROUND: Kidney dysfunction is a common complication in adults with Duchenne muscular dystrophy (DMD); however, little attention has been paid to kidney function in pediatric patients. METHODS: Medical records of patients with DMD who were followed up for ≥ 12 months were retrospectively reviewed. Inclusion criteria were (i) aged 5-18 years, (ii) proven mutations in the dystrophin gene, and (iii) absence of structural anomalies of the kidney and urinary tract. Serum creatine kinase (CK) was used as an indirect marker of muscle destruction. RESULTS: Forty-four patients (mean age, 10.9 ± 3.3 years) were included. Blood pressure was evaluated by 24-h ambulatory blood pressure monitoring in 28 patients. Hypertension was found in 9 (32.1%), eight of whom were using steroids. Mild proteinuria, hypercalciuria, hypocalciuria, and hyperphosphaturia in 24-h urine collection (n = 36) were detected in 3 (8.3%), 5 (13.9%), 7 (19.7%), and 6 (16.7%) patients, respectively. Twenty-one (58.3%) demonstrated hyperuricosuria, associated with hyperuricemia in 4. Logarithmic cystatin C (CysC) had a positive correlation to creatinine (Cr) (p = 0.001, r = 0.54), CK (p = 0.048, r = 0.30), and parathormone (PTH) (p = 0.001, r = 0.49). Moreover, the patients were divided into two groups according to median CysC value: group 1 (n = 20, CysC ≤ 0.76 mg/l) and group 2 (n = 24, CysC > 0.76 mg/l). Mean CK, PTH, and Cr levels were significantly elevated in group 2 compared with group 1 (p = 0.010, 0.033, and 0.023, respectively). CONCLUSIONS: Long-term exposure to the excessive burden of intracellular components released from damaged muscles may be associated with an increased risk over time of chronic kidney impairment in pediatric DMD patients. Graphical abstract.

Acute Kidney Injury Secondary to Rhabdomyolysis: A Rare Presentation of Chikungunya Fever.

Chikungunya fever is an arthropod-borne viral illness characterised by high grade fever and incapacitating arthralgias. It is considered benign; however, in the recent outbreaks, several complications have been reported worldwide. We report a case of male patient with Chikungunya fever, possibly contracted from infected mosquitoes endemic in Karachi, Pakistan. The clinical presentation included fever, myalgias and anuria. Investigations revealed renal failure and significantly raised creatinine phosphokinase (CPK), suggesting rhabdomyolysis to be the cause of acute kidney injury (AKI). Rhabdomyolysisis likely occurred due to virus-induced myositis; a rare presentation of Chikungunya fever. The patient gradually recovered from renal failure following supportive care and renal replacement therapy.

Biomarker evaluation of skeletal muscle toxicity following clofibrate administration in rats.

The use of sensitive biomarkers to monitor skeletal muscle toxicity in preclinical toxicity studies is important for the risk assessment in humans during the development of a novel compound. Skeletal muscle toxicity in Sprague Dawley Rats was induced with clofibrate at different dose levels for 7 days to compare standard clinical pathology assays with novel skeletal muscle and cardiac muscle biomarkers, gene expression and histopathological changes. The standard clinical pathology assays aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatine kinase (CK) enzyme activity were compared to novel biomarkers fatty acid binding protein 3 (Fabp3), myosin light chain 3 (Myl3), muscular isoform of CK immunoreactivity (three isoforms CKBB, CKMM, CKMB), parvalbumin (Prv), skeletal troponin I (sTnI), cardiac troponin T (cTnT), cardiac troponin I (cTnI), CKMM, and myoglobin (Myo). The biomarker elevations were correlated to histopathological findings detected in several muscles and gene expression changes. Clofibrate predominantly induced skeletal muscle toxicity of type I fibers of low magnitude. Useful biomarkers for skeletal muscle toxicity were AST, Fabp3, Myl3, (CKMB) and sTnI. Measurements of CK enzyme activity by a standard clinical assay were not useful for monitoring clofibrate-induced skeletal muscle toxicity in the rat at the doses used in this study.

Monoclonal antibody against macrophage colony-stimulating factor suppresses circulating monocytes and tissue macrophage function but does not alter cell infiltration/activation in cutaneous lesions or clinical outcomes in patients with cutaneous lupus erythematosus.

This study's objective was to assess the effects of PD-0360324, a fully human immunoglobulin G2 monoclonal antibody against macrophage colony-stimulating factor in cutaneous lupus erythematosus (CLE). Patients with active subacute CLE or discoid lupus erythematosus were randomized to receive 100 or 150 mg PD-0360324 or placebo via intravenous infusion every 2 weeks for 3 months. Blood and urine samples were obtained pre- and post-treatment to analyse pharmacokinetics and pharmacodynamic changes in CD14(+) CD16(+) monocytes, urinary N-terminal telopeptide (uNTX), alanine/aspartate aminotransferases (ALT/AST) and creatine kinase (CK); tissue biopsy samples were taken to evaluate macrophage populations and T cells using immunohistochemistry. Clinical efficacy assessments included the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Among 28 randomized/analysed patients, peak/trough plasma concentrations increased in a greater-than-dose-proportional manner with dose increases from 100 to 150 mg. Statistically significant differences were observed between active treatment and placebo groups in changes from baseline in CD14(+) CD16(+) cells, uNTX, ALT, AST and CK levels at most time-points. The numbers, density and activation states of tissue macrophages and T cells did not change from baseline to treatment end. No between-group differences were seen in CLASI. Patients receiving PD-0360324 reported significantly more adverse events than those receiving placebo, but no serious adverse events. In patients with CLE, 100 and 150 mg PD-0360324 every 2 weeks for 3 months suppressed a subset of circulating monocytes and altered activity of some tissue macrophages without affecting cell populations in CLE skin lesions or improving clinical end-points.

Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease.

The aim of this study was to assess a 12-min self-paced walking test in patients with McArdle disease. Twenty patients (44.7 ± 11 years; 11 female) performed the walking test where walking speed, distance walked, heart rate (HR) and perceived muscle pain (Borg CR10 scale) were measured. Median (interquartile range) distance walked was 890 m (470-935). From 1 to 6 min, median walking speed decreased (from 75.0 to 71.4 m∙min(-1)) while muscle pain and %HR reserve increased (from 0.3 to 3.0 and 37% to 48%, respectively). From 7 to 12 min, walking speed increased to 74.2 m∙min(-1), muscle pain decreased to 1.6 and %HR reserve remained between 45% and 48%. To make relative comparisons, HR and muscle pain were divided by walking speed and expressed as ratios. These ratios rose significantly between 1 and 6 min (HR:walking speed P = .001 and pain:walking speed P < .001) and similarly decreased between 6 and 11 min (P = .002 and P = .001, respectively). Peak ratios of HR:walking speed and pain:walking speed were inversely correlated to distance walked: rs (HR) = -.82 (P < .0001) and rs (pain) = -.55 (P = .012). Largest peak ratios were found in patients who walked < 650 m. A 12-min walking test can be used to assess exercise capacity and detect the second wind in McArdle disease.

High-intensity exercise may compromise renal morphology in rats.

We investigated the renal effects of a high-intensity exercise (HIE) program based on strength training. 20 Wistar rats were randomly assigned to 2 experimental groups performing HIE or control over 12 weeks. Urinary volume, pH, citrate and calcium, and plasma urea, total proteins, creatinine, albumin, lactate dehydrogenase, creatine kinase (CK), calcium, magnesium, corticosterone and testosterone were measured. We also studied renal morphology with the Fibrosis HR(®) software. Plasma urea and CK concentrations were higher in the HIE compared to the control group (p < 0.05), whereas plasma creatinine was lower (p < 0.01). Plasma corticosterone was higher (p < 0.05) and testosterone lower (p < 0.01) in the HIE group. Except for the higher urinary volume found in the HIE group (p < 0.05), no differences between groups were observed in the rest of urinary parameters analyzed. Renal interstitial connective tissue was ~30% higher in the HIE group (p < 0.05). Glomerular tufts and mesangial areas were also higher in the HIE group (all, p < 0.05). No differences between groups were observed in the glomerular area. Overall, HIE promoted a worse morphological renal profile that might be associated with a higher risk for incidence of kidney disease in the long-term. The stress induced by the type of exercise performed could be on the basis of this worse morphological renal status.

Creatine kinase levels during preseason camp in National Collegiate Athletic Association Division I football athletes.

OBJECTIVE: To investigate mean creatine kinase (CK) levels in National Collegiate Athletic Association (NCAA) Division I football athletes and the relationship between mean CK levels and demographic variables. DESIGN: Observational cohort. SETTING: NCAA Division I football program. PARTICIPANTS: NCAA Division I football athletes. INTERVENTIONS: Blood and urine samples were obtained from 32 athletes on the first (time 1), third (time 2), and seventh (time 3) days of football camp. MAIN OUTCOME MEASURES: Mean CK levels. The hypotheses were formulated before the data were collected. RESULTS: All urine samples tested negative for blood. Mean CK levels were 284.7 U/L at time 1, 1299.8 U/L at time 2, and 1562.4 U/L at time 3. The increases in means were statistically significant (P < 0.005 for all pairwise comparisons). Most demographic variables were not related to mean CK levels. The number of days in the precamp conditioning program was negatively associated with mean CK levels (P = 0.0284). CONCLUSIONS: Mean CK levels in NCAA Division I football athletes during camp were higher than the serological criteria for rhabdomyolysis commonly used in clinical practice. More data are needed to assess if the number of days of participation in precamp conditioning is related to lower CK levels in NCAA Division I football athletes during camp.

Acute kidney injury in scrub typhus.

BACKGROUND: We studied the urinary abnormalities and acute kidney injury (AKI) as per RIFLE criteria in scrub typhus. METHODS: A prospective case record-based study of scrub typhus was carried out from January 2009 to December 2010 in a tertiary hospital in South India. Patients were followed up until renal recovery or for at least 3 months after discharge. Univariate, chi-squared tests and multivariate logistic regression analyses were performed to identify the predictors of AKI. RESULTS: Scrub typhus was diagnosed in 259 patients. Urinary abnormalities were seen in 147 patients (56.7%) with 60 patients (23.2%) having AKI. All AKI patients had urinary abnormalities and 17 (28.3%) were oliguric. Applying RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria, R, I, F were present in 23 (38.33%), 13 (21.67%), and 24 patients (40%), respectively. Creatine phosphokinase (CPK) was raised in 33 patients (55%) and hemodialysis was required in 6 patients (10%). The case fatality rate in this study was 2 out of 259 (0.77%), both having AKI and others recovering clinically. Significant predictors of AKI were tachycardia [odds ratio (OR) 2.28], breathlessness (OR 2.281), intensive care requirement (OR 2.43), mechanical ventilation (OR 3.33), thrombocytopenia (OR 2.90) and CPK>80 U/L (OR 1.76) by univariate analysis and intensive care requirement (adjusted OR 2.89) and thrombocytopenia (AOR 2.28) by multivariable logistic regression. CONCLUSION: Scrub typhus should be part of the differential diagnosis of acute febrile illness with AKI. AKI in scrub typhus is usually mild, non-oliguric, and renal recovery occurs in most patients. Rhabdomyolysis may be contributory to AKI. Thrombocytopenia and intensive care requirement are significant predictors of AKI in scrub typhus.

An investigation of the antidepressant action of xiaoyaosan in rats using ultra performance liquid chromatography-mass spectrometry combined with metabonomics.

A rapid, highly sensitive, and selective method was applied in a non-invasive way to investigate the antidepressant action of Xiaoyaosan (XYS) using ultra performance liquid chromatography-mass spectrometry (UPLC-MS) and chemometrics. Many significantly altered metabolites were used to explain the mechanism. Venlafaxine HCl and fluoxetine HCl were used as chemical positive control drugs with a relatively clear mechanism of action to evaluate the efficiency and to predict the mechanism of action of XYS. Urine obtained from rats subjected to chronic unpredictable mild stress (CUMS) was analyzed by UPLC-MS. Distinct changes in the pattern of metabolites in the rat urine after CUMS production and drug intervention were observed using partial least squares-discriminant analysis. The results of behavioral tests and multivariate analysis showed that CUMS was successfully reproduced, and a moderate-dose XYS produced significant therapeutic effects in the rodent model, equivalent to those of the positive control drugs, venlafaxine HCl and fluoxetine HCl. Metabolites with significant changes induced by CUMS were identified, and 17 biomarker candidates for stress and drug intervention were identified. The therapeutic effect of XYS on depression may involve regulation of the dysfunctions of energy metabolism, amino acid metabolism, and gut microflora changes. Metabonomic methods are valuable tools for measuring efficacy and mechanisms of action in the study of traditional Chinese medicines.

Urine dipstick analysis for identification of runners susceptible to acute kidney injury following an ultramarathon.

This study examined whether urine dipstick testing might be useful to predict the development of acute kidney injury after an ultramarathon. Participants in the 2011 161-km Western States Endurance Run underwent post-race blood and urine dipstick analyses. Of the 310 race finishers, post-race urine dipstick testing was completed on 152 (49%) and post-race blood also was obtained from 150 of those runners. Based on "injury" and "risk" criteria for acute kidney injury of blood creatinine 2.0 and 1.5 times estimated baseline, respectively, 4% met the criteria for injury and an additional 29-30% met the criteria for risk of injury. Those meeting the injury criteria had higher creatine kinase concentrations (P < 0.001) than those not meeting the criteria. Urine dipstick tests that read positive for at least 1+ protein, 3+ blood, and specific gravity ≥ 1.025 predicted those meeting the injury criteria with sensitivity of 1.00 (95% confidence interval [CI] 0.54-1.00), specificity of 0.76 (95% CI 0.69-0.83), positive predictive value of 0.15 (95% CI 0.06-0.30), negative predictive value of 1.00 (95% CI 0.97-1.00), and likelihood ratio for a positive test of 4.2. We conclude that urine dipstick testing was successfully able to identify those individuals meeting injury criteria for acute kidney injury with excellent sensitivity and specificity.

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.

Systemic administration of PRO051 in Duchenne's muscular dystrophy.

BACKGROUND: Local intramuscular administration of the antisense oligonucleotide PRO051 in patients with Duchenne's muscular dystrophy with relevant mutations was previously reported to induce the skipping of exon 51 during pre-messenger RNA splicing of the dystrophin gene and to facilitate new dystrophin expression in muscle-fiber membranes. The present phase 1-2a study aimed to assess the safety, pharmacokinetics, and molecular and clinical effects of systemically administered PRO051. METHODS: We administered weekly abdominal subcutaneous injections of PRO051 for 5 weeks in 12 patients, with each of four possible doses (0.5, 2.0, 4.0, and 6.0 mg per kilogram of body weight) given to 3 patients. Changes in RNA splicing and protein levels in the tibialis anterior muscle were assessed at two time points. All patients subsequently entered a 12-week open-label extension phase, during which they all received PRO051 at a dose of 6.0 mg per kilogram per week. Safety, pharmacokinetics, serum creatine kinase levels, and muscle strength and function were assessed. RESULTS: The most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary α(1)-microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (±SD) improvement of 35.2±28.7 m (from the baseline of 384±121 m) on the 6-minute walk test. CONCLUSIONS: Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment. (Funded by Prosensa Therapeutics; Netherlands National Trial Register number, NTR1241.).

Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency.

BACKGROUND: Primary coenzyme Q(10) (CoQ(10)) deficiency is rare. The encephalomyopathic form, described in few families, is characterized by exercise intolerance, recurrent myoglobinuria, developmental delay, ataxia, and seizures. OBJECTIVE: To report a rare manifestation of CoQ(10) deficiency with isolated mitochondrial myopathy without central nervous system involvement. METHODS: The patient was evaluated for progressive muscle weakness. Comprehensive clinical evaluation and muscle biopsy were performed for histopathologic analysis and mitochondrial DNA and respiratory chain enzyme studies. The patient began taking 150 mg/d of a CoQ(10) supplement. RESULTS: The elevated creatine kinase and lactate levels with abnormal urine organic acid and acylcarnitine profiles in this patient suggested a mitochondrial disorder. Skeletal muscle histochemical evaluation revealed ragged red fibers, and respiratory chain enzyme analyses showed partial reductions in complex I, I + III, and II + III activities with greater than 200% of normal citrate synthase activity. The CoQ(10) concentration in skeletal muscle was 46% of the normal reference mean. The in vitro addition of 50 micromol/L of coenzyme Q(1) to the succinate cytochrome-c reductase assay of the patient's skeletal muscle whole homogenate increased the succinate cytochrome-c reductase activity 8-fold compared with 2.8-fold in the normal control homogenates. Follow-up of the patient in 6 months demonstrated significant clinical improvement with normalization of creatine kinase and lactate levels. CONCLUSIONS: The absence of central nervous system involvement and recurrent myoglobinuria expands the clinical phenotype of this treatable mitochondrial disorder. The complete recovery of myopathy with exogenous CoQ(10) supplementation observed in this patient highlights the importance of early identification and treatment of this genetic disorder.

Lack of clinical utility of urine myoglobin detection by microconcentrator ultrafiltration in the diagnosis of rhabdomyolysis.

BACKGROUND: In the diagnosis of rhabdomyolysis, the microconcentrator qualitative assay for urine myoglobin (uMb) is often used as a screening tool. The accuracy and clinical utility of this assay in screening patients with rhabdomyolysis have not been examined. METHODS: We conducted a retrospective analysis of the relationship between creatine kinase (CK), serum myoglobin (sMb), the urine qualitative assay for myoglobin and the semi-quantitative assay for urine haem pigments (uH) in patients evaluated for rhabdomyolysis. RESULTS: There were 673 patients with CK and uMb recorded on the same day. The uMb assay had a sensitivity of only 26.4% [95% confidence interval (CI): 23.1-29.7%] and specificity of 96.8% (95% CI: 95.5-98.1%) for the detection of severe rhabdomyolysis, defined as a CK >10 000 U/l. SMb and CK measured simultaneously in 83 patients were highly correlated (R(2) = 0.72 for log-transformed values), suggesting that the negative uMb test was not a result of the absence of sMb. In 241 patients who had CK, uMb and uH measured on the same day, the presence of 'moderate' or 'large' uH in the absence of haematuria, indicating presence of myoglobinuria, had a sensitivity of 81% (95% CI: 76-86%) for the detection of CK >10 000 U/l vs a sensitivity of 22% (95% CI: 17-27%) for the uMb assay. CONCLUSIONS: The microconcentrator-based uMb assay has a poor and clinically inadequate sensitivity in the detection and diagnosis of rhabdomyolysis.

The use of clonidine in the management of autonomic overactivity in neuroleptic malignant syndrome.

The aim of this study was to identify the effectiveness of clonidine in the recovery of patients with neuroleptic malignant syndrome and autonomic dysfunction, including blood pressure lability. Nine patients with neuroleptic malignant syndrome and autonomic dysfunction were treated with clonidine in the intensive care unit, according to a protocol, and the results were compared with those of seven patients with the same syndrome who were not treated with clonidine. Clonidine was administered until blood pressure stability was fully restored, and thereafter the dose was gradually reduced. There was a significant reduction in the duration of ventilation and stay in the intensive care unit in the clonidine group. Three patients from the nonclonidine group died. The data suggest that in the clonidine group, patients with neuroleptic malignant syndrome and autonomic dysfunction appear to have better and faster recovery, especially in blood pressure control, after intravenous clonidine treatment.

Exercise-induced rhabdomyolysis.

We describe the case of a previously well 55-year-old man who presented to the accident and emergency department with marked swelling of both forearms 6 days after being pulled at speed on a 'fun ride' by a speedboat whilst holding on to a rubber dinghy. Immediately after the event he had marked weakness of both arms lasting 2 days and this was followed by swelling of his forearms. The patient had also noticed a darkening of his urine during this period. On examination there was marked pitting oedema of both forearms. Neurovascular examination of both arms was normal. Laboratory investigations revealed a grossly elevated serum creatinine kinase at 4969 IU/l, with normal urea and electrolyte levels. Urine dipstick testing was also normal at the time of presentation. The patient was discharged home and made an uneventful recovery. We describe the pathophysiology of exercise-induced rhabdomyolysis and discuss its clinical presentation and management.