Rhabdomyolysis-induced acute kidney injury in a patient with undifferentiated connective tissue disease: A case report and literature review rhabdomyolysis-induced AKI in a patient with UCTD.

RATIONALE: Acute kidney injury (AKI) accounts for 8% to 16% of hospital admissions and can quadruple hospital mortality, placing a serious burden on the health economy. Acute kidney injury (AKI) is mainly caused by dehydration, shock, infection, sepsis, heart disease, or as a side-effect of nephrotoxic drugs. About 10% to 60% of patients with rhabdomyolysis develop AKI, and 10% of AKI is attributable to rhabdomyolysis. However, rhabdomyolysis-induced AKI secondary to undifferentiated connective tissue disease (UCTD) has rarely been reported before. PATIENT CONCERNS: We report the case of a 50-year-old male of UCTD presented with dark brown urine, swelling and edema of the upper limbs, and decreased urine output. DIAGNOSIS: The patient was diagnosed with rhabdomyolysis-induced AKI secondary to UCTD.
INTERVENTIONS: The patient was successfully treated with intravenous methylprednisolone with other supportive treatment. OUTCOMES: After 3 days of initiating treatment of medicinal charcoal tablets, sodium bicarbonate and intravenous fluids upon admission, the patient's serum creatinine changed mildly from 145.0 μmol/L to 156.0 μmol/L, but the urinary output increased from 1000 mL/24 h to 2400 mL/24 h, with his creatine kinase (CK) and myoglobin rose from 474 IU/L to 962 IU/L and from 641.5ng/mL to 1599 ng/mL, respectively. We then tried to empirically initiate UCTD therapy by giving corticosteroids. After the administration of the 40 mg of methylprednisolone daily, the serum creatinine level dropped to 97 μmol/L the second day, CK decreased to 85 IU/L within 1 week and myoglobin decreased to 65.05 ng/mL within 10 days. When maintenance dose of 4 mg daily was given, the patient showed no abnormalities in creatinine or CK levels. LESSONS: There have been few reports on the association between rhabdomyolysis-induced AKI and UCTD and its mechanism remains unclear. Clinicians should be aware of UCTD as a possible cause to rhabdomyolysis-induced AKI.

Introduction

Acute kidney injury (AKI) is a life-threatening complication of rhabdomyolysis. A recent Chinese epidemiological survey found that the overall incidence of acute kidney injury (AKI) is 11.6%, with in-hospital mortality of AKI being 8.8%.[ Risk factors that can lead to rhabdomyolysis and future AKI include trauma, severe muscle strain, exposure to extreme temperatures, dehydration, infection, autoimmune diseases, and genetic disorders.[ Trauma and crush injury that result from natural disasters such as earthquakes can cause rhabdomyolysis and AKI.[ Rhabdomyolysis is characterized by acute and extensive destruction of rhabdomyocytes in lesion areas and muscle fiber necrosis accompanied by scattered muscle fiber regeneration. This is followed by the release of muscle cell contents, including intracellular metabolites (potassium, phosphate, and urate) and intracellular proteins (aldolase, myoglobin, creatine kinase [CK], lactate dehydrogenase, and aspartate transaminase), into the blood.[ Myoglobin is the major nephrotoxin in rhabdomyolysis and can cause renal tubule obstruction, oxidant damage, and vascular contraction, which can lead to AKI. Myoglobin is easily filtered by glomeruli in the kidney and precipitated in the renal tubules, especially in acidic environments where it is more likely to precipitate in the renal tubules by interacting with the Tamm-Horsfall protein. Oxidative stress injury is caused by the dissociation of iron in myoglobin, which results in free radical release and oxidative injury of the renal parenchyma. Other studies have shown that myoglobin induces lipid peroxidation, which produces isoprostanes, leading to renal arteriolar dysfunction and hypoperfusion. Of course, while myoglobin is a key factor in rhabdomyolysis onset, but other factors such as low blood volume, secondary injuries, metabolic abnormalities, and drug effects are also important causes.[ The clinical presentation of rhabdomyolysis varies,[ and while current diagnostic criteria are lacking, the rapid elevation of serum creatine kinase levels is widely recognized as an indicator of rhabdomyolysis.[ Treatment may include volume resuscitation, urine alkalization and diuresis, maintaining homeostasis, and renal replacement therapy when necessary.[ Early and active volume resuscitation can restore renal perfusion and increase urine flow to dilute nephrotoxin and promote the excretion of myoglobin and toxic products. Urine alkalization (pH >6.5) can hinder the formation of an acidic environment and reduce the precipitation of myoglobin in the renal tubules, however, there is insufficient clinical evidence for its efficacy in treating rhabdomyolysis. Diuresis is also a common therapy for rhabdomyolysis, as it can increase urine volume and reduce renal tubule obstruction.[ Although continuous renal replacement therapy (CRRT) has been reported to be beneficial for rhabdomyolysis, there is not enough evidence to support that CRRT for patients with rhabdomyolysis can effectively prevent secondary AKI.[ In order to prevent hyperkalemia, metabolic acidosis, metabolic alkalosis, and hypervolemia, it is important to monitor electrolyte balance and homeostasis during therapy for rhabdomyolysis. It has also been reported that rhabdomyolysis is associated with connective tissue diseases (CTD), such as polymyositis,[ dermatomyositis,[ systemic lupus erythematosus (SLE),[ adult still disease,[ and vasculitis.[ This report details the development and treatment of a case of rhabdomyolysis-induced AKI in the setting of an undifferentiated connective tissue disease (UCTD) relapse. We speculate that UCTD may be a potential cause of rhabdomyolysis. The patient has provided informed consent for publication of this case.

Case presentation

A 50-year-old male was admitted to our department for oliguria, dark brown urine, and swelling and edema of the upper limbs for 1 day. The patient had a history of interphalangeal joint pain of the hands and a positive cytoplasmic type of anti-nuclear antibody (ANA) with high titer (1:10000) for the past 2 years. In this case, he had no exertional causes of over-exercise, status epilepticus, hyperkinetic syndrome, or severe dystonia, as well as no history of non-exertional causes of alcohol/drug abuse, medication, toxic agents, infection, temperature extremes, and muscle ischemia, or trauma leading to rhabdomyolysis.[ Laboratory tests clearly showed a rise in creatinine levels from 59 μmol/L, observed a few weeks ago, to 182.0 umol/L at admission. We also observed a rapid decrease in the amount of urine output over the course of 2 days, leading to the diagnosis of AKI. In addition, increased CK (962 IU/L) and myoglobin (1599 ng/mL) indicated possible rhabdomyolysis. An ultrasound showed that the direction of muscle fibers in the lesion area was disordered and the striated muscle texture was blurred, appearing cloudy.[ As an effective means of diagnosing rhabdomyolysis, further ultrasound examination revealed edema in subcutaneous tissue on upper and lower limbs, and the muscle layer of the limbs was disordered and appeared glassy. Electromyography revealed myogenic injury of the upper arms, which strengthened the evidence of rhabdomyolysis diagnosis. In addition, the patient developed a cough and fever at the time of admission. Computed tomography (CT) showed signs of pulmonary infection, and sputum culture confirmed a diagnosis of Klebsiella pneumoniae.

The patient was given medicinal carbon tablets, piperacillin-tazobatan, sodium bicarbonate, intravenous saline infusion, and furosemide diuretic treatment after admission. After 3 days of initial treatment, the serum creatinine levels decreased from 182.0 μmol/L to 156.0 μmol/L, while CK and myoglobin rose from 474 IU/L to a peak of 962 IU/L and from 641.50 ng/mL to a peak of 1599 ng/mL, respectively. In addition, serological examination was positive for a cytoplasmic type of ANA with high titer (1:10000), specific to SLE, but negative for other types of autoimmune antibodies such as rheumatoid factor, anti-SCL70, anti-Jo-1, anti-RNP, anti-SS-A, anti-SS-B, c-antineutrophil cytoplasmic antibodies (ANCA), and p-ANCA. These results suggested a diagnosis of UCTD, however, there is currently no generally accepted diagnostic criteria for UCTD. The clinical features of UCTD manifest like systemic autoimmune diseases such as arthralgias, arthritis, Raynaud's phenomenon, leukopenia, anemia, xerostomia, or xerophthalmia, but about 90% of UCTD patients are ANA positive. Positive expression of other autoimmune antibodies such as anti-SCL70 (skin sclerosis, pulmonary fibrosis, and tumors), anti-Jo-1 (dermatomyositis specific antibodies), anti-SS-A (Sjogren's syndrome, SLE, and rheumatoid arthritis), anti-SS-B (Sjogren's syndrome and SLE), c-ANCA, and p-ANCA (vasculitis) is rare, and is not up to current CTD diagnostic criteria. However, UCTD may evolve into CTD, where SLE is more common.[

This case suggests that UCTD might be a notable addition the list of causes of rhabdomyolysis and rhabdomyolysis-induced AKI. A causal association between UCTD and rhabdomyolysis was unclear because muscle biopsy was rejected by the patient, and so we empirically initiated UCTD therapy to achieve AKI and rhabdomyolysis remission after conventional therapies for AKI and rhabdomyolysis failed. An intravenous methylprednisolone infusion (40 mg, once a day) was administered on the fourth day of admission, along with the aforementioned conventional therapy. The patient's indicators of AKI and rhabdomyolysis decreased notably. His creatinine levels dropped to 97 μmol/L within 1 day, CK levels dropped to 85 IU/L within 1 week, and myoglobin levels dropped to 65.05 ng/mL within 10 days and showed no increasing trend thereafter (Figs. 1 and 2). After 12 days of methylprednisolone administration, the patient was discharged and followed regularly by department of Rheumatology. After 6 weeks of oral methylprednisolone therapy, the methylprednisolone dose was gradually reduced to 16 mg, once a day, to 12 mg 1 month later, and again to 10 mg the following month. The maintenance therapy of oral methylprednisolone (10 mg, once a day) was reduced to 8 mg after 5 months, and to 6 mg after 1 month. Currently, maintenance treatment of methylprednisolone (4 mg, once a day) is given after 2 months for the methylprednisolone of 6 mg. During methylprednisolone reduction, the patient was reviewed monthly and showed no abnormalities in creatinine or CK levels.

Figure 1

Trends in CK and Myo levels for the patient over time. CK = creatine kinase, Myo = myoglobin.

Figure 2

Trends in urine volume and serum CREA for the patient over time. CREA = creatinine.

Discussion

The presented case illustrated an unusual presentation of rhabdomyolysis-induced AKI secondary to UCTD. The patient featured rhabdomyolysis and AKI, and had a history of UCTD for two years. However, a definitive initial diagnosis was delayed because of the unclear cause of rhabdomyolysis. The concept of UCTD was developed from the basis of undifferentiated connective tissue syndrome and postulated mainly by LeRoy in 1980 when he put forward the question of whether certain patients experienced UCTD, rather than definite connective tissue disease.[ However, there is currently no generally accepted diagnostic classification and criteria for UCTD. The clinical features of UCTD share the same manifestations as systemic autoimmune diseases, but the autoimmune spectrum is mainly only positive for ANA, not up to any of the connective tissue disease diagnostic criteria.[ This case suggests that UCTD might be added to the list of causes of rhabdomyolysis and rhabdomyolysis-induced AKI.

Rhabdomyolysis was first reported in Germany in 1881 and was described in greater detail after the battle of London during the Second World War.[ Rhabdomyolysis is primarily caused by acute muscle injury and results in muscle pain, weakness, tightness, and edema from the release of muscular contents into the bloodstream.[ This may lead to a series of physiological pathologies, which are characterized by the increasing of serum creatine kinase, myoglobin, uric acid, potassium, and phosphorus, influencing the stability of internal environment, and leading to AKI.[ Many symptoms of rhabdomyolysis are non-specific, including myalgia, swelling, weakness, and so on. Severe cases have had diffuse intravascular coagulation, liver damage, respiratory distress syndrome, circulatory collapse, multiple organ dysfunction, coma, or even death. The most important complication is AKI, which is mainly caused by both obstruction and toxicity to the renal tubules by myoglobin. The occurrence rate of which varies from 14% to 46%.[ Despite there being many pathogenic factors of rhabdomyolysis, autoimmune diseases are an uncommon cause. Since symptoms of autoimmune diseases such as muscle pain, muscle weakness, and muscle enzyme elevation all resemble rhabdomyolysis, which is prone to misdiagnosis, it is necessary to screen autoantibodies series for CTD or UCTD in rhabdomyolysis patients presenting with significantly elevated serum creatinine, CK, and myoglobin, so as to undergo a timely, positive, and effective treatment.

Although a few cases of rhabdomyolysis-induced AKI with autoimmune diseases have been reported (Table 1), the mechanism is still largely unknown. To the best of our knowledge, only a few of cases of rhabdomyolysis secondary to CTD have been described in literature. In 2005, Kim et al[ reported the case of a 57-year-old female with polymyositis presenting with rhabdomyolysis, myoglobinuria, and AKI. She was stabilized with intravenous prednisone, volume resuscitation, and other supportive treatment. In 2018, Daniel et al[ described the case of a 36-year-old female with an SLE exacerbation, as well as concurrent rhabdomyolysis-induced AKI with massively elevated creatine phosphokinase (CPK) (304,700U/L) and massive myoglobin stain in the tubular casts on renal biopsy specimen. Her laboratory and clinical picture improved after hemodialysis and corticosteroid treatment. In this case, after the diagnosis of UCTD, AKI and rhabdomyolysis were equally relieved with methylprednisolone treatment.

Table 1

Patients with CTD combined with rhabdomyolysis.

Our current patient was diagnosed, not only with rhabdomyolysis-induced AKI and UCTD, but also a severe pulmonary infection caused by K pneumoniae. Two previous studies have indicated that infectious rhabdomyolysis accounts for 5% to 31% of all cases.[ We postulate that such infection may be a trigger for rhabdomyolysis. In a case report and literature review on a rhabdomyolysis patient with K pneumoniae, the authors reviewed 77 reported cases of bacterial rhabdomyolysis and found that the most common organismal causes were Legionella spp., Streptococcus spp., and Salmonella spp.[ Rhabdomyolysis caused by primary infection occurs mainly in the respiratory system. Compared to noninfectious rhabdomyolysis, cases of infectious rhabdomyolysis typically have lower CK levels.[ While there is no proven mechanism for the association between rhabdomyolysis and infection, some hypotheses have been proposed. It is often the case that muscle biopsies show inflammation or lymphocytic infiltration to severe muscle necrosis. Muscle virulence factors, especially tumor necrosis factor (TNF) in respond to virus infection, may be a cause of muscle damage.[ In the present case, rhabdomyolysis and AKI both occurred before the onset of pneumonia, which was thus unlikely to be the cause. Early diagnosis and treatment are necessary to minimize kidney damage and protect renal function, but in the event of acute renal failure or hyperkalemia, hemodialysis should be given if indicated.[ This case we report provides a possible cause and effective treatment for rhabdomyolysis-induced AKI. Further studies are warranted to shed light on the pathophysiology of rhabdomyolysis-induced AKI in the setting of a UCTD relapse.

Conclusions

Our case suggests that there might be an association between rhabdomyolysis-induced AKI and UCTD, which is rarely reported. Treatment mainly consists of volume resuscitation, urine alkalization and diuresis, and hemodialysis when necessary for rhabdomyolysis-induced AKI and corticosteroid treatment for UCTD.[ Early and accurate diagnosis and management of the primary disease, UCTD, is of vital importance for halting AKI progression. Clinicians should be aware of possible underlying connective tissue disease when treating patients with rhabdomyolysis-induced AKI. We believe this warrants screening of the autoimmune antibody spectrum as a clinical routine for such patients.

Acknowledgments

We thank Dr Jay L. Koyner (Section of Nephrology, University of Chicago Medicine and Biological Sciences Division, Chicago, IL) for providing many insightful comments and suggestions.

Author contributions

Conceptualization: Ping Fu.

Investigation: Hongxia Mai, Yuliang Zhao.

Methodology: Hongxia Mai, Yuliang Zhao.

Writing – original draft: Hongxia Mai, Yuliang Zhao, Stephen Salerno, Yi Li, Letian Yang.

Writing – review & editing: Ping Fu, Yuliang Zhao, Stephen Salerno, Yi Li.