A Liver Transplant Patient Experienced Deterioration of Renal Function and Rhabdomyolysis after Taking Sirolimus: A Case report

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Case Report

A Liver Transplant Patient Experienced Deterioration of Renal Function and Rhabdomyolysis after Taking Sirolimus: A Case report

https://doi.org/10.21203/rs.3.rs-3998402/v1

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The occurrence of renal impairment and rhabdomyolysis in transplant patients taking sirolimus was very rare. We report a case of a 54-year-old male who received liver transplantation and was initially treated with tacrolimus, mycophenolate mofetil and glucocorticoids for immunosuppression. After developing renal dysfunction, tacrolimus was replaced with sirolimus. However, one month after taking sirolimus, the patient's renal function continued to deteriorate, and rhabdomyolysis developed one and a half months later. Serum analysis indicated high sirolimus concentration, while renal histopathology revealed acute tubular injury and interstitial arteriopathy. After reducing the dosage of sirolimus, the patient's creatine kinase levels returned to normal and renal function improved compared to before. 2 years after hospital discharge, the patient's renal function further recovered. This case highlights the importance of monitoring sirolimus blood concentration in clinical practice, as elevated drug concentrations can lead to renal dysfunction and rhabdomyolysis as adverse reactions. Further investigation into the pathogenic mechanisms of sirolimus-induced renal dysfunction and rhabdomyolysis may contribute to clinical practice.

sirolimus

liver transplantation

rhabdomyolysis

renal dysfunction

Sirolimus is a macrolide immunosuppressant that works by inhibiting the proliferation of T lymphocytes under cytokine stimulation ^[2]. Its structure is similar to that of tacrolimus, and its immunosuppressive potency was reported to be not inferior to tacrolimus, but with lower renal toxicity ^[3]. Sirolimus was mainly used to prevent organ rejection after liver, kidney, and other organ transplantation, especially for patients with concurrent hypertension, renal insufficiency, and tremors. It is a new type of low-toxicity potent immunosuppressant discovered to date ^[4]. Previous literature had shown that sirolimus had lower renal toxicity and was less likely to cause renal impairment ^[5]. When using sirolimus, there were still some adverse reaction reported, such as dys-lipidemia, bone marrow suppression, delayed wound healing, peripheral edema, neutropenia, pneumonitis et al^[6]. However, the incidence of concurrent creatine kinase (CK) elevation and rhabdomyolysis was rare ^[11]. Previous literature had reported a few cases of rhabdomyolysis and renal injury in transplant patients when taking both sirolimus and statins or fibrate drugs ^[13–15]. Since rhabdomyolysis was a common adverse event of lipid lowering drugs, the effect of sirolimus on the rhabdomyolysis in these cases was unclear. Here, we report a case of a liver transplant patient who experienced worsening renal function and rhabdomyolysis after switching from tacrolimus to sirolimus without the use of statin drugs.

On April 25, 2021, a 54-year-old male (height: 160 cm, weight: 62 kg) was admitted to Nephrology department of West China Hospital of Sichuan University with elevated blood creatinine for seven months and depressed edema of both lower extremities for eight days. Eight months prior to admission, the patient underwent an allogeneic liver transplantation for alcoholic liver cirrhosis. The renal function was normal before the surgery. The serum creatinine was 62 µmol/L after the surgery, and the evaluated glomerular filtration rate (eGFR) was 109.87 ml/min/1.73m². Following the surgery, he was started on regular oral administration of tacrolimus 2 mg twice daily, mycophenolate mofetil 500 mg twice daily, and prednisone 20 mg once daily. Seven months before admission, His serum creatinine increased to 120 µmol/L. One and a half months before admission, His serum creatinine gradually rose to 498 µmol/L. The medication was adjusted to sirolimus 2 mg twice daily, mycophenolate mofetil 500 mg twice daily and prednisone 10 mg once daily. Additionally, the patient used roxaresta, polysaccharide-iron complex, folic acid tablets for anemia correction, calcium carbonate, complex alpha-keto acid tablets for protein supplementation. Half a month before admission, his serum creatinine gradually increased to 571 µmol/L. Eight days before admission, the patient developed bilateral lower extremity pitting edema accompanied by generalized weakness, and his serum creatinine increased to 677 µmol/L.

Upon admission, the patient had a temperature of 36.8°C, a respiratory rate of 20 breaths per minute, a heart rate of 91 beats per minute, and a blood pressure of 138/88 mmHg. The 24-hour urine output was approximately 1500 ml. Physical examination revealed no significant positive findings in the cardiovascular, respiratory, or abdominal regions, but bilateral lower limb pitting edema was observed. The results of peripheral blood routine examination showed hemoglobin level of 74 g/L, white blood cell count of 20.31 × 10⁹/L, and platelet count of 125 × 10⁹/L. Blood biochemistry analysis showed an albumin level of 31.2 g/L, alanine aminotransferase level of 51 IU/L, aspartate aminotransferase level of 137 IU/L, creatine kinase(CK) level of 25468 IU/L, serum creatinine level of 677 µmol/L, uric acid level of 75 µmol/L, calcium ion level of 1.29 mmol/L, potassium ion level of 2.56 mmol/L, anion gap of 20.9 mmol/L, myoglobin level of > 3000 ng/mL, troponin T level of 291.3 ng/L, creatine kinase-MB level of 1.92 ng/mL, pro-B-type natriuretic peptide level of 21695 ng/L, C-reactive protein level of 20.30 mg/L, procalcitonin level of 0.74 ng/mL, and sirolimus blood concentration of 21.1 ng/mL. Urine analysis revealed protein 3+, white blood cells of 7/HP, and red blood cells of 8/HP. The protein-creatinine ratio in urine was 0.268 g/mmol creatine. The 24-hour urine protein excretion was 1.51 g/24h. Clinical immunological examination showed no obvious abnormalities. 1,3-β-D-glucan (G) test, aspergillus galactomannan (GM) test, interferon-gamma release assay for tuberculosis infection, TB-IGRA, Epstein-Barr virus DNA real-time fluorescence quantification, BK-JC virus load analysis, cytomegalovirus nucleic acid quantification, mycoplasma pneumoniae antibody, and TORCH panel testing were all negative. The tests of sputum smear, sputum culture, and blood culture were also negative. Ultrasonography of the urinary system showed slightly enhanced renal parenchymal echogenicity, with the right kidney measuring 12 cm × 5.1 cm × 5.3 cm and the left kidney measuring 11.9 cm × 5.2 cm × 5.6 cm. Single-photon emission computed tomography (SPECT) renal imaging showed reduced blood perfusion and severe impairment of renal function (glomerular filtration rate of 11.3 ml/min in the left kidney and 19.2 ml/min in the right kidney). Chest computed tomography (CT) showed minimal signs of inflammation in both lungs and a small amount of pleural effusion.

The patient was diagnosed with chronic renal failure with acute exacerbation, rhabdomyolysis, pulmonary infection. Upon admission, they received treatment, including citric acid and potassium supplementation to correct electrolyte imbalances, intravenous piperacillin sodium and tazobactam sodium for infection control, water-soluble vitamins for antioxidation, and volume expansion. Due to elevated blood drug concentration of sirolimus, the sirolimus dose was reduced to 1 mg once daily. After two weeks of treatment, the patient's creatine kinase level dropped to normal level, but the level of serum creatinine was still high as 574umol/L. On the 16th day after admission, a renal biopsy was performed. Pathological findings showed: Optical Microscopy Findings: Glomeruli: A total of 22–23 glomeruli were observed, with 2 exhibiting global sclerosis and 1 demonstrating fibrous thickening. No significant alterations were noted in the mesangium, basement membrane, or capillary lumina. Tubules: Approximately 25% of the tubules displayed atrophy, accompanied by moderate to severe degeneration of tubular epithelial cells. Protein tubular casts were observed in some tubular lumens. Interstitium: Around 25% of the interstitium exhibited fibrosis, accompanied by infiltration of lymphocytes and monocytes. Vessels: Mild to moderate thickening of the small arterial walls was observed, and occasional foam-like changes were noted in the endothelial cells of some arteries (Fig. 1). Immunohistochemistry: IgG, IgM, IgA, C3, C4, C1q, µ, and λ are negative in all four glomeruli. (Fig. 1). The renal pathology indicated acute tubular injury, which could be explained by a consequence of rhabdomyolysis. This type of lesion is often self-limiting. However, the interstitial vascular changes were not typical pathologic manifestations of rhabdomyolysis. Based on the history, the vascular changes were considered to be highly associated with the nephrotoxicity of tacrolimus. Therefore, the sirolimus, instead of tacrolimus was continued and the blood concentration of sirolimus were rechecked. On the 14th day of hospitalization, the blood concentration of sirolimus was 10.8 ng/ml. Since the patient did not exhibit signs of liver dysfunction or rejection, the sirolimus dose was further reduced to 0.5 mg once daily. On the 20rd day of hospitalization, the sirolimus blood concentration was rechecked, revealing a level of 6.6 ng/ml.

On the 23rd day of hospitalization, the creatinine decreased to 393umol/L. the hemoglobin increased to 89g/L. The level of creatine kinase (68IU/L), aspartate aminotransferase, alanine aminotransferase, blood potassium, and blood calcium remained normal. The patient was discharged on the 24th day. After discharge, the patient continued to take oral sirolimus 0.5mg once a day and mycophenolate mofetil 500mg twice a day. Regular monitoring of sirolimus blood drug concentration was conducted and the level fluctuated between 7 ng/ml and 15 ng/ml. Two months after discharge, the patient's serum creatinine decreased to 234 umol/L. At 6 months after discharge, the creatinine was 192 umol/L. At two years after discharge, the patient's renal function furtherly improved, with serum creatinine level of126µmol/L and evaluated glomerular filtration rate of54.96ml/min/1.73m2.(Fig. 2)

Tacrolimus is a type of calcineurin inhibitor (CNI) ^[1]. The reliable immunosuppressive effects of CNIs have been widely recognized, but the hepatorenal toxicity by long-term use of CNIs is common^[1]. Sirolimus is a large-ring lactone antibiotic immunosuppressant that works by inhibiting the proliferation of T lymphocytes under cytokine stimulation^[2]. As a lipophilic 35-membered lactone compound, its structure is similar to that of tacrolimus (a 23-membered lactone compound), but its immunosuppressive potency was reported to be higher than that of tacrolimus, and its renal toxicity is lower^[3]. Sirolimus is mainly used to prevent rejection reactions of organs such as liver and kidney transplantation, especially suitable for patients with concurrent hypertension, renal insufficiency, and tremors^[4]. It is a new type of potent immunosuppressive agent with low toxicity discovered so far^[4]. In patients with confirmed calcineurin inhibitor nephrotoxicity through biopsy, switching to sirolimus could improve renal function. The study by Xu et al. invested 44 renal transplant recipient with chronic transplant kidney disease (confirmed by transplant kidney biopsy pathology) who had their immunosuppressants switched from tacrolimus to sirolimus. After one to two months, the average blood creatinine level of patients decreased and the average glomerular filtration rate increased. By the sixth month, the difference in serum creatinine before and after conversion was statistically significant (P < 0.05), suggesting that sirolimus may have lower renal toxicity than tacrolimus ^[5].

In this case, the patient developed chronic renal failure after taking tacrolimus, so tacrolimus was switched to sirolimus. However, one month after switching from tacrolimus to sirolimus, the patient's creatinine continued to increase, and the glomerular filtration rate continued to decline. The renal pathology revealed acute tubular injury, tubular epithelial cell shedding, mild to moderate thickening of the interstitial arterial walls, accompanied by endometrial fibrosis and individual arterial endothelial cell foam-like changes. Previous literature had shown that the adverse reactions of tacrolimus include acute and chronic renal injury^[6]. Acute renal injury is usually associated with afferent arteriolar vasoconstriction and is generally reversible^[6]. Chronic nephrotoxicity is often accompanied by characteristic histological changes, including arterial vascular lesions, striped interstitial fibrosis, and focal segmental glomerulosclerosis-like changes, with arterial lesions being the most common, characterized by island-like deposition of hyaline in the small arterial walls ^[6]. Immunofluorescence of renal biopsies in glomerular lesions often reveals the deposition of immune complexes such as IgG, IgM, C3, and others ^[6]. In this case, the patient experienced an increase in creatinine after taking tacrolimus for seven months, and the pathological biopsy indicated arterial vascular wall lesions, consistent with the pathological features of tacrolimus-induced renal injury. However, after switching from tacrolimus to sirolimus for one month, the patient's creatinine continued to rise, and considering the patient's high blood concentration of sirolimus (21.1 ng/ml), it is speculated that the elevated sirolimus concentration might contributed to the deterioration of kidney function. Foreign scholars believed that the appropriate blood concentration range of sirolimus is 5–15 µg/L, which can achieve higher efficacy while maintaining a lower incidence of adverse reactions. Some studies have indicated that in rat model, although sirolimus had no impact on renal function at doses sufficient to prevent heart and kidney transplant rejection (0.01–0.08 mg/kg/day intravenously), it did accelerate histological changes of necrotizing vasculopathy and tubular atrophy in the model. At higher doses (0.8 mg/kg), it indeed led to a decline in kidney function^[7]. In two multicenter, randomized, double-blind trials, 719 patients and 576 patients were randomly treated with sirolimus 2mg/d, sirolimus 5mg/d, or placebo. The results showed a negative correlation (P < 0.001) between the concentration of sirolimus and eGFR^[8]. Boratyn et al. reported five cases of renal transplant patients who received immunosuppression with cyclosporine and switched to sirolimus after experiencing renal function injury. The median serum creatinine before treatment was 167.96 µmol/L, and during the treatment, the blood concentration of sirolimus ranged from 9.0 to 18 ng/mL (average 12.5 ng/mL). Three months after using sirolimus, all five patients developed nephrotic syndrome, with a median serum creatinine increase to 309.4 µmol/L, primarily manifesting as glomerulosclerosis and arteriolar hyalinosis in renal pathology^[7]. Dittrich and colleagues also reported two kidney transplant patients who developed proteinuria and elevated serum creatinine (increased to 283 µmol/L and 354 µmol/L, respectively) two to nine months after switching from calcineurin inhibitors to sirolimus. Renal biopsy findings included mesangial proliferative glomerulonephritis and IgA nephropathy^[9]. Butani observed proteinuria in 12 out of 13 children treated with sirolimus, which resolved upon switching to a different medication. The author suggested that proteinuria may be due to sirolimus toxicity to the glomeruli, although this has not been supported by experimental models ^[10]. In this case, the patient's renal pathology did not indicate glomerular lesions, which was inconsistent with the previously reported sirolimus-induced kidney injury pathology. This suggests that the worsening of renal function after switching to sirolimus in this patient may be related to rhabdomyolysis occurring after the transition to sirolimus. It is advisable to monitor sirolimus blood concentrations during its usage and remain vigilant for the occurrence of rhabdomyolysis and renal function impairment.

Based on the patient's clinical presentation, elevated levels of serum creatine kinase and serum creatinine, as well as the pathological findings of acute renal tubular injury, it was determined that this case involved rhabdomyolysis and acute kidney injury (AKI) following the administration of sirolimus.

Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of muscle cell contents into the circulation, often presenting with significantly elevated levels of serum creatine kinase and may be accompanied by muscle pain, weakness, and myoglobinuria^[11]. In previous literature, reports of rhabdomyolysis in solid organ transplant recipients were rare, particularly in liver transplant patients ^[11]. In this case, the laboratory tests showed that serum CK levels were 10 times higher than the upper limit of normal, confirming the diagnosis of rhabdomyolysis^[12]. Based on the patient's sirolimus medication history, significantly elevated sirolimus blood concentration upon admission (21.1 ng/mL), and gradual normalization of CK levels after sirolimus reduction, the correlation between high sirolimus concentrations and rhabdomyolysis was suggested.

There had been a few reported cases of rhabdomyolysis and renal injury in transplant patients who were taking sirolimus ^[13–15]. However, the reported cases of transplant patients who developed rhabdomyolysis after using sirolimus often received concomitant treatment with statin drugs. Rhabdomyolysis was a common adverse effect of Statin use, and the interaction between sirolimus and statin drugs might furtherly increase the risk of rhabdomyolysis ^[13]. Yu Ah Hong et al. reported a 64-year-old female kidney transplant recipient who had been on long-term cyclosporine immunosuppression, concomitantly taking simvastatin for lipid control. After the diagnosis of lung adenocarcinoma, immunosuppression was switched from cyclosporine to sirolimus. Rhabdomyolysis developed 20 days after the change in immunosuppression ^[13]. The authors suggested that both sirolimus and statin drugs were major substrates of cytochrome P450 3A4 enzyme (CYP 3A4) in the liver. The competition for metabolic processing in the liver may lead to increased levels of statin drugs, enhancing their toxicity and causing rhabdomyolysis ^[13]. Basic and Dopazo also reported cases of rhabdomyolysis and acute kidney failure in two transplant patients following concurrent use of statin drugs and sirolimus ^[14]. However, in this case, the patient received oral tacrolimus, mycophenolate, corticosteroid immunosuppression after liver transplantation, and switched from tacrolimus to sirolimus after experiencing renal function impairment. Without the use of statin drugs or other potential causes of rhabdomyolysis, the patient developed rhabdomyolysis one month after switching to sirolimus. Rhabdomyolysis resolved after reducing the dose of sirolimus. Previous literature did not report cases of rhabdomyolysis with elevated blood levels of sirolimus. This case provides a possibility of a connection between the two, although the specific pathogenic mechanism remains unclear. It also indicated the importance of monitoring blood drug concentrations of sirolimus in patients with liver transplant patients.

Following a reduction in the oral dose of sirolimus, the rhabdomyolysis improved. After 2 years, the patient's renal function further recovered, with creatinine decreasing to 126 umol/L. This suggest that both sirolimus and tacrolimus can cause renal damage through various mechanisms. In addition, the gradually improved kidney function of the case indicated a reversible characteristic of renal injury induced by tacrolimus, although the recovery might take several months.

We reported a case of a liver transplant patient who developed deterioration of renal function and rhabdomyolysis after switching to sirolimus from tacrolimus. This case highlighted the importance of monitoring sirolimus blood concentration in patients with liver transplant. .

Competing Interests

The authors declared no conflict of interest.

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Relationship of living donor to the recipient

Related.

Ethics approval and consent to participate

The study received biomedical ethics approval from West China Hospital of Sichuan University and informed consent from the patients.

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All authors agreed to publish the pape.

Data Source Statement

All data utilized in this study were sourced exclusively from the hospital's medical record system. This dataset was carefully curated to ensure the complete anonymity and confidentiality of all patients involved. No information or images that could potentially identify any individual patient were included. Furthermore, prior to the commencement of this study, informed consent was meticulously obtained from each and every patient included in the dataset, in accordance with established ethical guidelines and regulations.

I hereby declare that the data used comply with the ethical principles of medical research and legal regulations, and strictly adhere to the requirements of personal privacy and data protection. The design and implementation of this study comply with internationally recognized ethical standards and have been approved by the hospital's research ethics review committee.

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The patient and his legally authorized guardians have carefully read the contents of this paper and consent to the use of the information and images therein for academic research or publication purposes. The patient and his legally authorized guardians agree to the confidential handling of their personal identity information in this paper and consent to the partial disclosure of relevant treatment information for academic research purposes. Hereby, we confirm that, in compliance with relevant laws and regulations, informed consent has been obtained for the use of patient information and images in this paper.

Funding

This study is supported by a grant of the Sichuan Provincial Science and Technology Department-Science and Technology Innovation Talent Project, No. 2020JDRC0022. The grant played a role in data collection of the case and follow-up of the patient, as well as the interpretation of data and the manuscript writing.

Author Contribution

C.G. wrote the main manuscript text and prepared Figures 1-2Z.Y.C. participated in data collection.S.J.G. and L.M. presented ideas and planned the writing purpose and methodologyAll authors reviewed the manuscript.

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A Liver Transplant Patient Experienced Deterioration of Renal Function and Rhabdomyolysis after Taking Sirolimus: A Case report

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