Physical Therapy–Induced Rhabdomyolysis andAcute Kidney Injury Associated With ReducedActivity of Muscle Lactate Dehydrogenase ABENJAMIN J. LEE,1 LADAN ZAND,2 NISHA J. MANEK,2 LI-LI HSIAO,3

DUSICA BABOVIC-VUKSANOVIC,2 MARK E. WYLAM,2 AND QI QIAN2

CASE PRESENTATION

Chief SymptomsA 70-year-old woman was transferred to our institution inMarch 2010 for severe myalgia and lactic acidosis follow-ing a physical therapy session.

History of the Present IllnessOne week prior to the presentation, the patient underwenther first session of physical therapy for muscle weakness atthe recommendation of her primary care physician. Shehad exercised all extremities for approximately an hour,followed by whirlpool for 30 minutes. At the end of thesession, she began to experience whole-body pain andweakness. Her symptoms worsened over the ensuing sev-eral days. She took narcotics for the pain and developednausea, decreased appetite, and constipation. On day 5following physical therapy, she was admitted to a localhospital where evaluation revealed stable vital signs, butmarked creatine kinase (CK) elevation (22,000 IU/liter),leukocytosis (white blood cell [WBC] count of 18.3 � 109

cells/ml), and lactic acidosis (lactate of 3.49 mmoles/liter).Her serum creatinine level was 1.0 mg/dl, and a chestradiograph showed bibasilar atelectasis versus infiltrates.She was started on empiric antimicrobials for possible

pneumonia. Despite the treatment, her condition failed toimprove. Two days later, she was transferred to our insti-tution for further evaluation and management.

Medical HistoryHer medical history included well-controlled hyperten-sion and hyperlipidemia, and an episode of severe illnessfollowing a massage session in 1999 shortly after her 59thbirthday. Immediately following the massage (a birthdaygift), she developed proximal muscle weakness associatedwith severe pain. She was admitted to a local hospital,where evaluation revealed a serum CK level of 33,000IU/liter. This episode coincided with the initiation of ator-vastatin 2 weeks prior; the medication was promptly dis-continued. She was treated with intravenous fluids, andher symptoms gradually resolved in 2 weeks. The impres-sion was that the episode was related to atorvastatin andno further investigation was pursued. She had not beenreceiving statins since then and denied taking nonpre-scription remedies such as red yeast rice extract. Follow-ing that episode, she experienced muscle pain and weak-ness intermittently, especially after physical exertion. Sheoften required over-the-counter nonsteroidal antiinflam-matory drugs for pain. Approximately 5 months prior toadmission, her muscle weakness and pain worsened, lim-iting her daily activities. She sought treatment at 2 majoruniversity centers; no diagnosis was reached. For betterpain control, narcotics were initiated, and it was recom-mended that she should start physical therapy to improveher symptoms.

Family HistoryShe had no known family history of myopathy. Her fatherreportedly had exertional myalgia late in his life but nomedical attention was sought. She has 2 sisters and 3brothers, none reporting similar symptoms.

Social HistoryThe patient reported no alcohol, tobacco, or illicit druguse. She denied being on any special diet, apart from the

1Benjamin J. Lee, BA: Harvard Medical School, Boston,Massachusetts; 2Ladan Zand, MD, Nisha J. Manek, MD,MRCP, Dusica Babovic-Vuksanovic, MD, Mark E. Wylam,MD, Qi Qian, MD: Mayo Clinic College of Medicine,Rochester, Minnesota; 3Li-Li Hsiao, MD, PhD: Brigham andWomen’s Hospital, Boston, Massachusetts.

Dr. Hsiao has received consultant fees, speaking fees,and/or honoraria (less than $10,000) from Genzyme. Dr.Wylam receives royalties for providing serum from MayoClinic patients with alveolar proteinosis to a biostart com-pany to isolate B cells, which make GM-CSF autoantibodies.

Address correspondence to Qi Qian, MD, Department ofMedicine, Division of Nephrology and Hypertension, MayoClinic College of Medicine, 200 First Street SW, Rochester,MN 55905. E-mail: qian.qi@mayo.edu.

Submitted for publication May 18, 2011; accepted in re-vised form August 5, 2011.

Arthritis Care & ResearchVol. 63, No. 12, December 2011, pp 1782–1786DOI 10.1002/acr.20584© 2011, American College of Rheumatology

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recommended diet for patients with hypertension and hy-perlipidemia. She has never been athletically active andreported avoiding exertional sports to avoid “muscleache.” She denied producing dark urine after activity. Sheis married and has lived with her husband for more than40 years.

Medication on AdmissionShe was receiving intravenous piperacillin/tazobactam3.37 gm every 6 hours (initiated at the outside hospital)and oral gabapentin 300 mg 3 times daily, aspirin 81 mgdaily, trazodone 200 mg daily, morphine sulfate (con-trolled release) 30 mg every 4 hours, ondansetron 4 mg asneeded, metoprolol tartrate 75 mg twice daily, omeprazole20 mg daily, bisacodyl, and omega-3 fatty acids/fish oil.

Physical ExaminationUpon arrival at our hospital, the patient was alert andoriented, but appeared weak and deconditioned. Herblood pressure was 130–150/60–80 mm Hg, her pulse was100–110 beats/minute, and her oxygen saturation on roomair was 99–100%. Her jugular venous pressure was nor-mal, lung fields clear, heart rhythm regular, abdomen be-nign, and extremities without dependent edema. Her skinand joint examination was normal. Musculoskeletal exam-ination revealed diffuse tenderness in the abdominal wall,back, and thigh muscles. Neurologic examination revealedintact cranial nerve function, normal muscle tone, andreduced muscle bulk without fasciculation. She had prox-imal muscle weakness; on a scale of 0–5 (5 being normalmuscle strength), her muscle strength was 3, and worse inthe iliopsoas bilaterally. Sensory and reflexes were intact.

Diagnostic TestingHer laboratory studies showed red blood cells of 14.0gm/dl (reference range 12–15.5), WBCs of 15.4 � 109/liter(reference range 3.5–10.5), serum sodium of 125 mmoles/liter (reference range 135–145), potassium of 5.4 mmoles/liter (reference range 3.6–5.2), bicarbonate of 16 mmoles/liter (reference range 22–29), creatinine of 1.0 mg/dl(baseline 0.4–0.5), aspartate aminotransferase of 2,720 IU/liter (reference range 8–43), alanine aminotransferase of1,679 IU/liter (reference range 7–45), total bilirubin of 1.2mmoles/liter (reference range 0.1–1.2), erythrocyte sedi-mentation rate of 0 mm/hour (reference range 0–29), lac-tate of 3.9 mmoles/liter (reference range 0.6–2.3), and CKof 33,700 IU/liter (reference range 38–176). Her urinalysisshowed myoglobin of 62.3 �g/ml (reference value �0.025),and microscopy was positive for granular casts and renaltubular epithelial cells (reference range 0/high-powerfield).

INITIAL DIAGNOSIS

The patient was diagnosed with rhabdomyolysis and acuterenal injury associated with metabolic derangements, in-cluding hyponatremia and lactic acidosis.

Her rhabdomyolysis appeared to be related to the phys-ical therapy session. However, the degree of muscle injury

seemed out of proportion to the degree of muscle exertion,concerning for underlying myopathy. Her acute serum cre-atinine elevation and abnormalities on urinalysis indi-cated myoglobin (pigment)–associated renal tubular in-jury. The lactic acidosis, which was persistent, occurred inthe absence of systemic hypotension, raising concerns forabnormalities in the glycolysis and mitochondrial oxida-tive process. The hyponatremia was thought to be multi-factorial in etiology, possibly related to antidiuretic hor-mone stimulation by pain and nausea, plus an element ofabnormal serum dilution in the context of acute kidneyinjury.

HOSPITAL AND CLINICAL COURSE

Shortly after admission, electromyography was obtained,which showed a proximally predominant myopathy withfibrillation potentials reflecting a degree of muscle necro-sis and fiber splitting, consistent with a myopathic pro-cess. Because of the atypical presentation and persistentlactic acidosis, further investigation including muscle bi-opsy and screening for abnormalities in glycolysis andmitochondrial function was planned. She was managedwith supportive care and pain control. Her muscle symp-toms and acid-base/electrolyte alterations gradually re-solved. Her serum creatinine concentration was reduced to0.5 mg/dl. Figure 1 shows the evolution of her circulatingCK, lactic acid, and pyruvate levels. She gradually re-gained sufficient strength to ambulate and was dischargedand followed as an outpatient.

Two months after the discharge, a biopsy of the patient’sright vastus lateralis was performed, and pathologyshowed occasional necrotic and degenerating fibers, con-sistent with the previous episode of rhabdomyolysis. Rareregenerating fibers and small clusters of macrophages thatlikely replaced necrotic fibers were present. There were noovert inflammatory infiltrates, nor connective tissue abnor-malities. The muscle fiber glycogens and lipid contentswere normal, as was the mitochondrial myopathy profile.Myoglobinuria profile, however, revealed a reduction inenzymatic activity of lactate dehydrogenase A (LDH-A).The estimated activity was 18.4 �moles/minute/gm ofthe muscle specimen (reference range 57.3–469.3). As re-duced LDH-A activity can be associated with exerciseintolerance, rhabdomyolysis, myoglobinuria, and increasedblood pyruvate and lactate, further targeted gene studieswere carried out. The currently available genetic testingfor LDH-A, limited to the gene deletion analysis, did notdetect a deletion in our patient. Further LDH-A gene mu-tation analysis is needed to determine a pathologic change,but such analysis is not commercially available.

DISCUSSION

Physical therapy is frequently prescribed and generallyconsidered safe for weakness, deconditioning, and non-specific muscle aches. As such, it is often recommendedas a first-line option for elderly patients with these pre-sentations (1,2). Rhabdomyolysis and acute kidney injury,although occasionally seen among military, law enforce-

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ment, and fire department trainees undergoing extraordi-narily strenuous physical exercise (incidence �0.2–3%)(3,4), have not been described previously in any elderlyindividual without a known history of myopathy follow-ing a regular physical therapy session. We report an un-usual case of rhabdomyolysis, pigment-associated acutekidney injury, and persistent lactic acidosis in an elderlywoman following a single session of physical therapy. Hermuscle biopsy sample revealed reduced LDH-A activity,which likely contributed to her acute illness.

During exercise, energy in the form of ATP is extractedfrom glucose by enzymatic splitting of glucose to pyruvateand oxidization of pyruvate in the mitochondria through

the tricarboxylic acid cycle (also known as the Krebs cycle)in an oxygen-dependent manner (Figure 2). ATP is gener-ated through this process, ensuring sufficient energy pro-vision for muscle metabolism. In the setting of extremelystrenuous exercise when the rate of glucose metabolismexceeds the oxidative capacity of the mitochondria, pyru-vate accumulates and is shunted to anaerobic lactate fer-mentation, leading to tissue lactic acid buildup and circu-lating lactic acidosis. Normally, lactic acidosis in such acondition is transient; lactate quickly converts to pyruvatethrough the action of LDH-A.

Exertional myalgia and myoglobinuria can be related toa number of metabolic myopathies (Table 1). LDH-A defi-

Figure 1. Evolution of our patient’s circulating creatine kinase (CK; reference range38–176 units/liter), lactic acid (reference range 0.6–2.0 mmoles/liter), and pyruvate(reference range 0.08–0.16 mmoles/liter) levels. Day 0 denotes the day of physicaltherapy.

Figure 2. Schematic presentation of alterations in glycolysis due to lactate dehydrogenaseA (LDH-A) deficiency. A diminished level of LDH-A in our patient’s skeletal muscle impairedthe reoxidation of NADH and conversion of glyceraldehyde-3-phosphate to glycerate 1,3-bisphosphate. Increase in NADH and dihydroxyacetone phosphate stimulated GAPDH ac-tivity. Consequently, triosephosphates derived from glucose were trapped in glycerol-3-phosphate and glycerol, away from the energy-producing tricarboxylic acid (TCA) cycle.

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ciency is one such myopathy, a rare condition. To date, atotal of 7 families have been reported (5–8). It is caused bymutations in the LDH-A gene, 1 of the 2 major LDH genes(LDH-A and LDH-B) in humans. LDH-A encodes LDH-A,also known as the M (muscle) subunit, and LDH-B encodesLDH-B, also known as the H (heart) subunit (11). (There isa third LDH-C gene, expressed restrictively in mature testisand sperm [9].) LDH-A and LDH-B combine to form 5enzymatically active tetramers: A4, A1B3, A2B2, A3B1,and B4. These tetramers catalyze the interconversion be-tween pyruvate and lactate. A4 is located primarily inskeletal muscle and B4 is located primarily in the myocar-dium. Exertional myoglobinuria related to LDH-A muta-tions follows an autosomal recessive inheritance with con-siderable genetic heterogeneity (5,7,8,10) and an estimatedcarrier frequency of �0.185% in 1 study (11).

In patients with LDH-A deficiency, insufficient intercon-version between pyruvate and lactate following exercisecauses pyruvate and NADH accumulation (Figure 2). Theexcess NADH promotes conversion of glycerate 1,3-bis-phosphate to glyceraldehyde-3-phosphate via G3PDH. TheNADH is also reoxidized by cytosolic GAPDH throughconversion of dihydroxyacetone phosphate to glycerol-3-phosphate. Collectively, these reactions cause shunting oftriosephosphates toward glycerol (5), away from mito-chondrial ATP generation. Affected patients typically de-velop exercise intolerance at younger ages (between ages10 and 38 years), marked elevation in circulating pyruvateand other glycolysis intermediates, and less robust rise inlactic acid levels immediately following exercise. A sharpreduction in oxygen consumption in affected muscles fol-lowing exercise was independently demonstrated (6), con-firming diminished mitochondrial oxidative energy pro-duction. Energy deficiency during exertion causes musclecells to disintegrate (rhabdomyolysis), leaking cellular CK

and myoglobin into the circulation. The circulating myo-globin filters through glomeruli, causing pigment-associ-ated renal tubular injury.

In our patient, LDH-A activity in muscle was reduced toapproximately one-third of the lower limit of normal. Adiagnosis of possible exertional myoglobinuria related toLDH-A deficiency was entertained on the basis of hercharacteristic clinical, biologic, and histopathologic fea-tures. However, her muscle symptoms began at a laterstage of life than that in the reported cases (5–8), whichmight reflect the heterogeneity in clinical presentationsassociated with this condition. Some patients with con-firmed homozygous LDH-A mutations display minimummuscle symptoms (12–14). Alternatively, without gene se-quence information, we cannot rule out the possibilities ofa heterozygous state or acquired condition. HeterozygousLDH mutations in erythrocytes in a group of newbornsfrom Japan were linked to reduced LDH enzymatic activity(15). (We will pursue LDH-A gene sequence for the patientas soon as the testing is available.) Notwithstanding herunknown genetic status, her clinical course bears similar-ities to those seen in exertional myoglobinuria. The per-sistent elevation in pyruvate and development of rhabdo-myolysis in our patient following physical therapy canbest be explained by an insufficient conversion of pyruvateto lactate due to muscle LDH-A deficiency. Her persistentlactic acidemia is likely related to the elevated tissue py-ruvate load, leading to a low-grade lactate generation, ashas been observed in most cases of exertional myoglobin-uria related to LDH-A deficiency.

This case has important clinical implications, as rhab-domyolysis and acute kidney injury can cause permanentorgan damage if left untreated or if treatment is delayed.Recognizing these potential dangers cautions us to avoidindiscriminately prescribing physical therapy, especiallyfor those with a history of exercise intolerance. Physiciansshould carefully monitor patients at the beginning of phys-ical therapy. Severe exertional myalgia should promptthorough investigation to rule out underlying myopathy.

In summary, we describe an elderly patient with phys-ical therapy–induced rhabdomyolysis complicated byacute kidney injury. Evaluation revealed a reduction inmuscle LDH-A activity likely underlying her musclesymptoms. For patients intolerant of less than strenuousphysical exertion, it is prudent to consider further inves-tigation for myopathy and to reduce or personalize theintensity of physical therapy.

FINAL DIAGNOSIS

Exertional myoglobinuria associated with reduction inmuscle LDH-A.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors ap-proved the final version to be published. Dr. Qian had full accessto all of the data in the study and takes responsibility for theintegrity of the data and the accuracy of the data analysis.Study conception and design. Lee, Hsiao, Wylam, Qian.Acquisition of data. Lee, Zand, Qian.

Table 1. Differential diagnosis of metabolic myopathies

Disorders of glycogenolysisMyophosphorylase deficiency (McArdle’s disease)Phosphorylase kinase deficiencyMyophosphorylase B kinase*Disorders of glycolysis

Phosphofructokinase deficiency (Tarui type VII)*Phosphoglycerate kinase deficiency (type IX,

isoform A)*Phosphoglycerate mutase deficiency (type X) M

subunit*Lactate dehydrogenase (LDH) A and B deficiency†

Disorders of lipid metabolismCarnitine palmitoyltransferase deficiency*Carnitine deficiencyShort-chain acyl–coenzyme A dehydrogenase

deficiencyLong-chain acyl–coenzyme A dehydrogenase

deficiencyVery long-chain acyl–coenzyme A dehydrogenase

deficiencyDisorders of purine metabolism

Myoadenylate deaminase deficiency*

* Tested and not found to be abnormal in the patient.† LDH-A deficiency noted in the patient.

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Analysis and interpretation of data. Lee, Zand, Manek, Hsiao,Babovic-Vuksanovic, Qian.

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14. Nazzari G, Crovato F. Annually recurring acroerythema andhereditary lactate dehydrogenase M-subunit deficiency [let-ter]. J Am Acad Dermatol 1992;27:262–3.

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