腎移植術後使用Sunitinib導致腎病症候群合併急性腎衰竭-罕見病例報告

柯旭承1、周詠欽1,2、沈正煌1、林昌德1、鄭明進1

1戴德森醫療財團法人嘉義基督教醫院 外科部 泌尿科

2亞洲大學 食品營養與保健生技學系

Sunitinib related nephrotic syndrome with acute renal failure in patient with renal transplantation – a rare case report

Hsu-Cheng Ko1, Yeong-Chin Jou1,2, Cheng-Huang Shen1, Chang-Te Lin1,Ming-Chin Cheng1

1Department of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan

2Department of Health and Nutrition Biotechnology, Asian University, Taichung

Introduction:

Sunitinib-induced nephrotic syndrome and irreversible renal allograft dysfunction is a rare condition. Herein, we report a case of recipient of renal transplantation, who developed clear-cell metastatic renal cell carcinoma later, taking sunitinib. Nephrotic syndrome and renal allograft dysfunction occurred five months after prescription of sunitinib.

Case presentation:

This 58-year-old male was a case of end stage renal disease with regular hemodialysis through arteriovenous fistula for 17 years and received cadaver kidney transplantation 5 years ago. Unfortunately, he developed clear-cell metastatic renal cell carcinoma with origin from left native kidney, diagnosed by clinical symptoms, image studies and pathological results 1 year ago. Sunitinib was prescribed. The follow-up urinary analysis showed proteinuria (500 mg/dL) half month after the prescriptions of sunitinib. Five months later, he was hospitalized due to deteriorating body weight gain, decreasing urine output, pitting edema at bilateral lower extremities and shortness of breath. The serum creatinine increased to 4.26 mg/dL and the urine protein-creatinine ratio raised to 1176 mg/g. The biopsy of renal allograft showed focal segmental glomerulosclerosis, acute interstitial nephritis and acute tubular injury. After reviewing the time sequence of clinical symptoms and signs, rise of serum creatinine, elevation of urine protein and drug consumption, sunitinib-induced renal allograft dysfunction and nephrotic syndrome went into the final diagnosis. Although we had adjusted medication from sunitinib to everolimus, renal allograft function was totally dysfunctional in the end. He then went back to receive hemodialysis through arteriovenous fistula three times per week. One month later, this patient passed away due to metastatic complications.

Discussion:

Renal transplantation recipients have a higher risk of developing renal cell carcinoma compared with the general population. Among renal transplantation recipients, the estimated incidence of de novo RCC in the native kidney and the renal allograft were 0.7% and 0.2%, respectively. Moreover, metastasis of renal cell carcinoma is known to occur in approximately 30% of cases. The first-line systemic treatment for clear-cell metastatic renal cell carcinoma included bevacizumab (combined with interferon), sunitinib, and pazopanib.

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) of the vascular endothelial growth factor (VEGF) signaling pathway. Moreover, the common side effects of sunitinib included hypertension, skin toxicity, and gastrointestinal disturbance. In the licensing trial of sunitinib, the elevation of serum creatinine level was more common in patients receiving sunitinib than in those receiving placebo. Furthermore, a multicenter, randomized, phase-3 trial shared similar results regarding serum creatinine elevation. However, in both sunitinib licensing and phase-3 trials, no report of nephrotic syndrome or acute renal failure exists. Several patients receiving sunitinib experienced a preeclampsia-like syndrome characterized by reversible hypertension, proteinuria, and edema. The incidences of proteinuria and renal insufficiency related to sunitinib were 18.9% and 7.7%, respectively, in a retrospective study from Korea. Moreover, renal function was preserved without deterioration after sunitinib discontinuation.

The pathology of renal biopsy could offer clinicians some hints on renal damage associated with sunitinib aside from the clinical symptoms of sunitinib-induced renal dysfunction. In the French Reins sous traitement Anti-VEGF Registre study, the renal biopsy of patients who were previously treated with sunitinib and developed nephrotic syndrome showed focal segmental glomerulosclerosis, glomerular thrombotic microangiopathy, and acute tubular necrosis. In another study, the pathology of renal biopsy shares similar results. Moreover, acute interstitial nephritis is also a common finding. The current case revealed focal segmental glomerulosclerosis, acute interstitial nephritis, and acute tubular injury in the renal allograft biopsy.

To date, there is no consensus on the management of sunitinib intolerance in patients with clear-cell metastatic renal carcinoma. These symptoms often subsided or disappeared after stopping sunitinib prescription. Moreover, the clinical trial study from RECORD‐1 Study Group compared everolimus with placebo, together with the best supportive care, in patients with previously failed or anti-VEGFR-intolerant treatment. The median progression-free survival was significantly prolonged in patients receiving everolimus compared with those receiving placebo. Consequently, no adverse event (e.g., acute renal failure or nephrotic syndrome) was reported in the clinical trial. Various studies after the clinical trial from RECORD‐1 Study Group also confirmed the efficacy and safety when switching regimens from sunitinib to everolimus.

Conclusions:

This case is a reminder that renal allograft dysfunction and nephrotic syndrome can simultaneously happen after taking sunitinib. Hence, clinicians must regularly check renal function and urine analysis for renal transplantation recipients. Keeping an eye on drug prescription, especially sunitinib, is necessary if persistent proteinuria accompanied by nephrotic syndrome and deteriorating serum creatinine level occurs. Moreover, renal biopsy may be considered if more hint was required to make a differential diagnosis.