Rhabdomyolysis and Acute Kidney Injury Associated With Terbinafine Use: A Case Report.

RATIONALE: Terbinafine is an antimicrobial agent commonly prescribed for fungal infections. Its side effect profile is generally benign, but there is limited evidence that it has the potential to cause rhabdomyolysis. Rhabdomyolysis is a potentially life-threatening condition caused by profound muscle injury. It has characteristic findings of muscle pain, weakness, and dark urine. When recognized early, patients with rhabdomyolysis can be managed conservatively with hydration and watchful monitoring. However, if treatments are delayed, or in severe cases of rhabdomyolysis, complications such as electrolyte abnormalities, acute kidney injury, and disseminated intravascular coagulation can develop. PRESENTING CONCERNS OF THE PATIENT: A previously healthy 22-year-old male presented with nausea, vomiting, and dark urine after taking terbinafine 250 mg daily for a tinea infection for 9 days. He developed severe rhabdomyolysis with a serum creatine kinase (CK) of >100 000 U/L as well as anuric acute kidney injury. DIAGNOSIS: The clinical history combined with the diagnostic findings suggest acute kidney injury and rhabdomyolysis associated with terbinafine use.
INTERVENTIONS: Terbinafine use was stopped immediately. The patient was started on intravenous fluids and bicarbonate drip. Hemodialysis was initiated to prevent further complications. After his CK level decreased and his clinical status stabilized, he was discharged home and continued to receive outpatient hemodialysis treatments. OUTCOME: The patient's kidney function returned to baseline after 1 month of outpatient hemodialysis treatments. NOVEL FINDING: In this report, we present a case of rhabdomyolysis associated with terbinafine use that progressed to acute kidney injury requiring dialysis. Our case highlights a less known and severe side effect of this medication and emphasizes the importance of early recognition and treatment of rhabdomyolysis.

Introduction

Terbinafine hydrochloride is an antifungal agent used to treat tinea infection and onychomycosis. It is a type of allylamine antifungal that interrupts ergosterol synthesis via its inhibition on squalene epoxidase, resulting in toxic accumulation of squalene that eventually kills the fungal cell.[1] It is highly selective for fungal enzymes.[2] It has been widely prescribed for decades due to its general safety. Post-marketing surveillance data show that common adverse effects of terbinafine are limited to headaches, gastrointestinal disturbances such as nausea and dyspepsia, taste disturbance, and rash.[1,3] Severe complications such as hepatotoxicity have been identified in rare cases, presenting as a mix of acute hepatitis and cholestasis.[1] In the literature, there are a few cases of self-limiting rhabdomyolysis associated with terbinafine use, but the link is not clearly established yet. Here, we report a case of terbinafine-induced rhabdomyolysis that resulted in acute kidney injury (AKI) requiring renal replacement therapy, the first case described in the literature. We also present a brief review of rhabdomyolysis and AKI.

Presenting Concerns

A previously healthy 22-year-old male presented to the emergency department with a 2-day history of nausea, vomiting, and dark urine.

Clinical Findings

Nine days prior to his presentation, the patient started taking terbinafine hydrochloride 250 mg daily for a cutaneous ringworm infection. Two days prior to his presentation, he developed bilateral thigh pain and swelling, which he attributed to a 15-minute work-out of low-to-moderate intensity. The patient took 1 dose of diclofenac (50 mg), and the pain resolved within 24 hours. He continued to take his terbinafine. The following day, he started experiencing nausea and repeated emesis. He also noticed that he was producing less urine and the urine color appeared dark, which eventually prompted his emergency visit.

The patient had no medical issue prior to his ringworm infection. Alanine aminotransferase (ALT) was checked before terbinafine start and was within normal range. Estimated glomerular filtration rate (eGFR) was greater than 120 mL/min at the time. He reported no other prescription medication, over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs), nor herbal supplements. He denied any alcohol or illicit drug use. There was no recent trauma, immobilization, or other infection. Family history was unremarkable. He did not exercise regularly but denied any prior concerns with strenuous exercise. He had no history of steroid use.

On initial exam, his vital signs were normal. He appeared well. He was of average height and weight. On each of his thighs, there were 5 to 7 ring-like rashes with a papular center. There was no swelling or tenderness on palpation of his thighs. Both passive and active range of motion were normal in his lower limbs. Cardiovascular, neurological, abdominal, and respiratory exams were normal. There was no costovertebral angle tenderness on percussion. No hepatosplenomegaly was appreciated. Urine output was <50 mL/24 hours.

Diagnostic Focus and Assessment

Initial investigations showed a creatinine of 514 µmol/L (62-115 µmol/L) and creatine kinase (CK) of >100 000 U/L, concerning for severe rhabdomyolysis and AKI. Electrolytes showed a high phosphate level of 1.68 mmol/L (0.8-1.45 mmol/L), a normal magnesium level of 0.97 mmol/L (0.66-1.07 mmol/L), and a low ionized calcium level of 1.07 mmol/L (1.15-1.29 mmol/L). Potassium and sodium were both normal. Bicarbonate was low at 19 mmol/L (21-32 mmol/L). Serum pH on venous blood gas was normal at 7.35 (7.31-7.41). Complete blood count was normal.

AST was elevated at 2329 U/L (<37 U/L), ALT elevated at 499 U/L (11-61 U/L). Alkaline phosphate, gamma glutamyltransferase (GGT), and bilirubin were normal. Albumin was mildly depressed at 31 g/L (34-50 g/L).

An ultrasound of the kidneys did not show any evidence of obstruction or signs of chronic disease. Urine qualitative testing for myoglobin was positive. The urinalysis result (Table 1) did not show any evidence of a urinary tract infection. Surprisingly, it showed no casts either. Urine and serum drug screens were negative.

Table 1.

Initial Urinalysis.

Clarity	Cloudy
Color	Yellow
Glucose urine	5.5 mmol
Ketone urine	Trace mmol
Specific gravity	1.015
Blood	ca. 200 ery/µL
pH urine	7.0
Protein urine	≥3.0 g/L
Nitrite	Negative
Leukocytes	Negative
WBC urine microscopic	5-10
RBC urine microscopic	100+
Bacteria (urine)	2+
Squamous epithelial	Few
Mucous	2+
Casts, amorphous urates, amorphous phosphates, calcium oxalate, triple phosphate, uric acid crystals, miscellaneous crystals, other elements	none

Note. RBC = red blood cell; WBC = white blood cell.

Therapeutic Focus and Assessment

Patient was admitted under the internal medicine service. Terbinafine was stopped. He was treated conservatively for rhabdomyolysis with intravenous fluids (normal saline) at 250 mL/hr and bicarbonate drip. He was placed on telemetry. His electrolytes including potassium, sodium, phosphate, ionized calcium, and magnesium were monitored closely.

After 12 hours of fluid resuscitation, patient remained anuric and the serum creatinine continued to trend up. To prevent further complications of AKI and rhabdomyolysis, patient was started on intermittent hemodialysis. Intravenous fluids were stopped after 24 hours of resuscitation, as patient developed volume overload; instead, volume status was adjusted through hemodialysis.

Follow-up and Outcomes

The patient continued to improve during the following week. His creatinine kinase trended down to 3187 U/L. AST and ALT continued to normalize. Patient’s urine output remained less than 100 mL/24 hours, but he was medically well otherwise. After 1 week, patient was discharged home and continued on 3 dialysis treatments per week as an outpatient.

After discharge, patient’s urine output gradually improved. Over approximately 1 month, he was successfully weaned off dialysis. His creatinine had improved to approximately 100 µmol/L consistently over the ensuing several weeks. See Table 2 for a summary of events and timeline.

Table 2.

Timeline.

Time	Event	Creatinine	eGFR	Creatine kinase	ALT	AST
Day 9	Started on terbinafine. Lab tests were completed.	75	>120		22
Day 2	Completed a 15-min workout routine. Developed myalgia.
Day 1	Developed significant nausea and dark urine, and decreased urine production. Myalgia resolved
Day 0	Presented to the emergency department. Started on fluid resuscitation. Hemodialysis was initiated.	514	<14	>100 000	499	2329
Day 3	Continued intermittent hemodialysis treatments inpatient			3187	178	249
Day 6	Discharged home. Continued on 3 hemodialysis treatments per week
Day 20	Off dialysis	141	61		31	20
One month later	Back to baseline health	93

Note. ALT = alanine aminotransferase; AST = aspartate aminotransferase; eGFR = estimated glomerular filtration rate.

Discussion

Rhabdomyolysis is a potentially life-threatening clinical and biochemical syndrome caused by extensive skeletal muscle injury. Its classic presentation includes a triad of myalgia, weakness, and tea-colored urine due to pigmenturia. Only 10% of cases, however, exhibit all 3 symptoms; a change in urine color is often the initial clue.[4] A diagnosis of rhabdomyolysis is made based on clinical presentation and biochemical markers. Serum creatine kinase is the most sensitive lab test for identifying muscle injury; usually an elevation of more than 5 to 10 times the upper limit of normal level, or >5000 U/L is concerning for rhabdomyolysis.[3,4] Urine dipstick, despite its high sensitivity for detecting heme, cannot differentiate between myoglobin or hemoglobin.[3] The utility of serum myoglobin for diagnosing rhabdomyolysis is also limited due to its early peak time in the serum and rapid metabolism.[5,6]

Any form of extensive muscle damage can trigger rhabdomyolysis. In adults, trauma, drugs, and infections are the most common culprits.[3] Regardless of etiology, rhabdomyolysis is initiated by skeletal cell damage, either through a direct insult to the myocytes or depleted energy supply. Intracellular calcium level increases, followed by protease activation, free radical production, and eventually apoptosis. Large quantities of intracellular content including electrolytes, uric acid, myoglobin, and proteins are released systemically.[3] Complications include electrolyte imbalance, cardiac arrhythmia, acute hepatic injury, AKI, and disseminated intravascular coagulopathy.[5,7,8] In addition, injury to local capillaries causes extensive third spacing and hypovolemia.[3] Our patient developed multiple electrolyte abnormalities such as hypocalcemia and hyperphosphatemia, but notably no hyperkalemia, a frequent and potentially lethal finding. He had elevated liver enzymes, which could be attributed to rhabdomyolysis-induced hepatic injury, or the extensive release of AST and ALT from damaged muscle cells.[9-11] A concurrent terbinafine-induced hepatotoxicity cannot be ruled out, but less likely.

In the English literature, there are only a few case reports of terbinafine-induced rhabdomyolysis.[11-13] Ly et al reported a case of rhabdomyolysis due to terbinafine use and concurrent exercise; CK was elevated at 14 400 U/L. Bui et al described a similar case in the context of increased exercise intensity, and the CK was <5000 U/L. Both patients were older, took the same dose of terbinafine, but it took much longer before they received medical attention. Their symptoms were milder, limited to generalized weakness and myalgia. The mechanism of rhabdomyolysis in these cases is unclear, but proposed to be a drug-facilitated reaction.[11]

Our patient similarly underwent an exercise regimen before presenting with rhabdomyolysis, but the level of CK (>100 000 U/L) was dramatically higher than in other cases. It was also disproportionate to the degree of exercise performed by our patient, especially considering patients in the other cases had much more rigorous exercises but lower peak CK measurements. An underlying metabolic dysfunction is unlikely, as the patient had no previous episode of rhabdomyolysis with intensive exercises. His history and lab results did not suggest any other causes for his presentation. We therefore conclude that terbinafine is the main cause of rhabdomyolysis in this case. We hypothesize that the level of CK elevation developed because the patient continued to use terbinafine despite having symptoms of rhabdomyolysis.

Our patient also developed AKI requiring dialysis. A common and serious complication, AKI occurs in 10% to 55% of patients with rhabdomyolysis.[3,10] The development of AKI is multifactorial; main players include myoglobinuria, metabolic acidosis, and hypovolemia. Myoglobin from damaged muscle cells precipitates with Tamm-Horsfall protein in the renal tubule. Free radicals are also produced from breakdown products of myoglobin and further contribute to tubule damage. These processes are enhanced in acidic urine, a common finding in rhabdomyolysis. Furthermore, hypovolemia from significant tissue edema leads to renal hypoperfusion.[3] Patients with AKI due to rhabdomyolysis commonly have oliguria, and occasionally anuria. The serum creatinine tends to rise more rapidly in rhabdomyolysis-induced AKI than in other causes.[5] These findings were observed in our patient.

Currently, there is no consensus on which lab parameter strongly predicts the likelihood of AKI in rhabdomyolysis.[5,10] Peak serum myoglobin level >15 000 µg/L has been found to correlate with the risk of AKI and the need for hemodialysis.[14] Given the short peak time of serum myoglobin, however, it may not be a practical indicator. Serum CK predicts the severity of rhabdomyolysis well, but not the risk of AKI.[5] The risk of kidney injury is thought to be low when CK is less than 15 000 to 20 000 U/L, although the presence of other comorbidities can lower the threshold.[5] This is consistent with the current and previously reported cases. Our patient, with a CK more than 100 000 U/L developed severe kidney injury, while none of the other cases did with CK levels less than 15 000 U/L. Our case serves as a reminder that a significantly high level of CK should raise concern of rhabdomyolysis-induced severe AKI.

The prognosis of rhabdomyolysis depends on the underlying etiology. When treated early and without evidence of renal injury, rhabdomyolysis has an excellent prognosis. Treatment of rhabdomyolysis is 3-pronged: removal of offending agent, stabilization and resuscitation of the patient, and preservation of renal function. Aggressive fluid replacement with crystalloids is important in treating and preventing AKI, although there is no clear evidence on which type of crystalloid is preferred.[3] The use of bicarbonate drip to alkalize urine and of mannitol for osmotic diuresis to prevent intrarenal heme pigment deposition is also common practice, albeit with weak clinical evidence.[8,15] When severe kidney injury develops, mortality rates vary significantly based on the setting.[5] In cases of refractory hyperkalemia, acidosis, volume overload, oliguria, or anuria, renal replacement therapy—either intermittent or continuous—should be considered.[5,16] For our patient, hemodialysis was initiated early during his illness course and he recovered well.

Limitations of our case include the lack of kidney biopsy, which could clarify the mechanism and extent of the injury. Serum quantitative myoglobin level was not tested due to lack of access, although its impact on diagnosis and treatment would be limited.

Based on the lack of reports, terbinafine-induced rhabdomyolysis is rare but can have serious consequences. Diagnosis of rhabdomyolysis can be difficult, especially in patients with active lifestyles who may attribute symptoms of muscle toxicity to exercise alone and delay medical care. When prescribing terbinafine, clinicians should be aware of the possibility of rhabdomyolysis and have a low threshold for CK testing if patients develop symptoms of myotoxicity. In addition, while hepatic toxicity is a more likely adverse event, caution should be taken to rule out any underlying rhabdomyolysis that may be contributing to elevated liver enzymes.

In summary, rhabdomyolysis is a potentially lethal condition with highly variable clinical presentation. Early detection is instrumental in preventing AKI. Most importantly, we are reminded that commonly prescribed and well-tolerated medications such as terbinafine can lead to rhabdomyolysis, and we are obliged to screen for this potentially lethal condition.