Sonidegib induced rhabdomyolysis in kidney transplant patient: a case report

Kidney transplant recipients (KTR) have a higher risk of developing malignancies compared to the general population, due to the immunosuppressive regimens which can promote the oncogenesis process. The incidence of de novo non-melanoma skin cancer (NMSC) in KTR is greater than in the general population. Basal cell carcinoma (BCC) represents one of the most frequent malignancies in KTR. Sonidegib is a Hedgehog signaling pathway inhibitor approved for the treatment of locally advanced basal-cell carcinoma (LABCC) that following surgery or radiation therapy, or is given to those candidates who are not eligible to surgery or radiation therapy. This paper reports the case of a kidney transplant patient, who developed severe acute kidney injury (AKI) due to rhabdomyolysis (RML) induced by sonidegib therapy which required renal replacement therapy (RRT).


Introduction
The overall incidence of non-melanoma skin cancer (NMSC) in kidney transplant recipients (KTR) is nearly 65-100-fold greater compared to the general population (1). In this context, the risk of developing basal cell carcinoma (BCC) increases 10-12 times compared to the age-matched general population (2,3). The prevalence and the incidence of skin cancer is directly correlated with the long-term and the intensity of immunosuppression therapy, which can promote the oncogenesis process by leading to lower immune-mediated tumor surveillance and development of malignant tumors (4,5).
Skin cancers in KTR could be clinically more aggressive and in have worse cancer histopathology than the general population (5). BCCs are generally slow growing and rarely metastasize, and patients who receive appropriate therapy typically have a good prognosis. A minority of patients develop locally advanced basal-cell carcinoma (LABCC) or recurrent BCC, who treatment can be challenging or associated with poorer outcomes (6,7).
Treatment requires a multidisciplinary approach, including surgery and/or radiation therapy and/or topical therapy and/or photodynamic therapy (8).
Mammalian target of rapamycin inhibitors (mTORi), such as everolimus, has been shown to reduce the incidence of BCC in KTR (9).
In the case of LABCC, the standard care and the switch of immunosuppressive therapy to mTORi can be insufficient.
The introduction of sonidegib, targeted therapy for LABCC in the form of hedgehog signalling pathway inhibitors represents one of the greatest successes of translational medicine, and a therapeutic option in patients with LABCC and recurrent BCC including KTR. Sonidegib is used to treat patients affected by LABCC that are not amenable to curative surgery or radiotherapy, or those who are not candidates for surgery or radiation therapy (10,11).
We present a case of kidney transplant patient who developed severe acute kidney injury (AKI) due to rhabdomyolysis (RML) induced by sonidegib therapy.

Case Presentation
The case study is based on a 74-yeasrs-old woman who underwent to kidney transplantation on December 2005 from a deceased donor. Her starting immunosuppression therapy was based on the use of steroids, azathioprine, and tacrolimus. Her medical history included: statin intolerance (muscle spasms) and multiple BCCs, diagnosed in 2012 and 2014. Subsequently, immunosuppressive therapy DOI:10.34172/jpd.2023.11204

Implication for health policy/practice/research/ medical education
Kidney transplant recipients (KTR) have a higher risk of developing malignancies. One of the most frequent malignancies in KTR is represented by BCC. The treatment in certain cases could be challenge as like in cases of locally advanced BCC. Sonidegib represents one of the greatest successes of translational medicine and it represent and therapeutic option in cases of LABCC. The sonidegib use could be complicated by RML. This case report can help to pay more attention to the administration of sonidegib in delicate subject such as KTR.
was modified, azathioprine was switched to m-TORi (everolimus) associated with a low dose of tacrolimus. in addition, the patient was evaluated by a dermatologist and plastic surgeon, and subsequently underwent treatment for BCC (surgery, local chemotherapy, photodynamic therapy). In view of frequent and recurrent episodes of BCCs and LABCC (from 2021 to 2022 there have been nine episodes), the patient started the therapy with sonidegib 200mg once a day from the 14-th of June 2022. Thereafter, the patient undertook routine monitoring of creatinine kinase (CK) and the kidney function, resulting normal until the July 20th when the patient was admitted to the emergency room, after an episode of fever, generalized myalgia, weakness, dark urine and fatigue lasting all day long. The physical evaluation showed normal arterial blood pressure (130/85 mm Hg), normal heart rate (73 bpm) and O 2 saturation (99%), fever (38°C), mental confusion and dehydration; diuresis was preserved.
The urine test showed the presence of proteinuria at 200 mg/dl. Myocardial necrosis markers were negative and no serum electrolytes alterations were registered.
The suspicion of sonidegib-induced RML was strongly supported by the mean time of clinical symptoms onset and laboratory alterations after starting therapy, as well as the absence of any other reasons that could explain the elevated CK. Given the known adverse effects of Hedgehog signaling pathway inhibitor use, sonidegib was discontinued immediately (12). Despite the IV hydration at 150/mL/h for almost 48 hours. CK levels continued to rise reaching a level above 160 000 UI/L, on day 2 The serum myoglobin and LDH levels were elevated up to 72 000 mg/mL (normal range 0-76 mg/mL) and 1819 UI/L respectively, associated with the evidence of acute kidney graft injury (serum creatinine 3.1 mg/dL) and worsening of myalgias and muscles spasms (Table 1).
Taking into account the whole picture of the clinical and laboratory data course, we decided to start renal replacement therapy (RRT) in intermittent hemodialysis modality for a total of two sessions, using a high-flux membrane dialyzer in convective technique to remove myoglobin from circulation, with the intent to limit a kidney graft injury induced by myoglobin. We decided to treat with a convective technique and high-flux membrane considering the myoglobin molecule weight (17500 Da) (13).
Given the preserved diuresis and the good hemodynamic status, we continued with hydration, alkalinization and diuretic therapy, which induced a forced diuresis achieving a urine output out of 5L/24 h, guaranteeing a slow but

Discussion
Sonidegib is a Hedgehog signaling pathway inhibitor, approved for the treatment of adult patients with LABCC who are not eligible for surgery or radiation therapy (10,11). This drug represents an important treatment tool for the category of KTR, who are at high risk of developing malignancies. Sonidegib use was described in the BOLT trial and its use was associated with many adverse effects like muscle spasms, myalgia, fatigue, elevated serum CK and transaminase levels. The average time for the appearance of elevated CK values was 12.9 weeks (range 2 to 39 weeks) after initiation of sonidegib therapy and the meantime of resolution was 12 days (range 8 to 14 days) (12). Despite none of the RML cases reported in the BOLT trial were confirmed, it should be considered a severe complication of therapy with sonidegib. Our patient demonstrated a temporary relationship between the exposure to sonidegib and the onset of elevated CK levels, followed by improvement in CK levels after discontinuation of the medication. AKI is one of the most severe complications of RML. Myoglobin can cause renal tubular damage by different mechanisms (14). The prompt recognition and treatment of RML could be the key to preventing AKI. As in our case, medical therapy may not be sufficient to treat RML, and it became necessary to resort to invasive therapy, in our case RRT. The guidelines suggest against the routine use of RRT in RML-induced AKI. However, there are no recommendations favouring the continuous renal replacement therapy (CRRT) versus intermittent haemodialysis, convection versus diffusion, or medium versus high cut-off membranes for AKI prevention/ treatment (15,16).

Conclusion
Clinicians need to be aware and vigilant about sonidegibrelated RML, particularly during the early phase of treatment. The discontinuation of sonidegib therapy, on one hand, allowed the resolution of the RML, but on the other hand, it represents a future challenge regarding LABCC therapy in KTR category.