標靶治療相關腎病症候群導致移植腎衰竭：病例分享
柯旭承¹、林益聖¹、歐宴泉¹、童敏哲¹ 

童綜合醫療社團法人童綜合醫院 外科部 泌尿科  

Target therapy-Associated Nephrotic-Range Proteinuria Leading to Renal Allograft Failure in a Kidney Transplant Recipient

Hsu-Cheng Ko¹、Yi-Sheng Lin ¹、Yen-Chuan Ou¹、Min-Che Tung ¹ 

¹ Division of Urology, Department of Surgery, Tungs'  Taichung MetroHarbor Hospital, Taichung City, Taiwan  

Background: 
Renal transplant recipients have a higher risk of developing renal cell carcinoma (RCC) than the general population. Targeted therapies inhibiting the vascular endothelial growth factor (VEGF) pathway, such as sunitinib, are widely used as first-line treatment for metastatic clear-cell RCC. Although effective, sunitinib has been associated with renal adverse effects, including hypertension, proteinuria, and renal insufficiency. These complications are usually mild and reversible after discontinuation. However, severe renal injury involving transplanted kidneys is rarely reported. We describe a renal transplant recipient who developed nephrotic syndrome and progressive renal allograft dysfunction after receiving sunitinib for metastatic RCC.

Case presentation: 
We report a 53-year-old man with end-stage renal disease who underwent deceased-donor kidney transplantation in 2012 after 19 years of hemodialysis. His graft function remained stable, with serum creatinine levels ranging from 1.3 to 2.3 mg/dL. In 2017, he was diagnosed with metastatic cc-mRCC originating from the native left kidney with lung and lymph node metastases. The patient declined nephrectomy and was treated with sunitinib.

Three weeks after treatment initiation, urinalysis revealed new-onset proteinuria. Six months later, he developed rapid weight gain, oliguria, peripheral edema, and dyspnea. Laboratory tests showed nephrotic-range proteinuria, hypoalbuminemia, and worsening renal function (serum creatinine 4.54 mg/dL). Renal allograft biopsy revealed focal segmental glomerulosclerosis, acute interstitial nephritis, and acute tubular injury without evidence of rejection.

Despite discontinuation of sunitinib and adjustment of immunosuppressive therapy, graft function progressively deteriorated, requiring hemodialysis.

Discussion:

Renal transplant recipients have a significantly higher risk of developing renal cell carcinoma (RCC) compared with the general population. Among these patients, the estimated incidence of de novo RCC is approximately 0.7% in native kidneys and 0.2% in renal allografts. Furthermore, metastasis occurs in nearly 30% of RCC cases. Systemic treatment options for metastatic clear-cell RCC include targeted therapies such as bevacizumab (in combination with interferon), sunitinib, and pazopanib.

Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that inhibits the vascular endothelial growth factor (VEGF) signaling pathway. Common adverse effects of sunitinib include hypertension, dermatologic toxicity, and gastrointestinal disturbances. In the licensing trial of sunitinib, elevation of serum creatinine was observed more frequently in patients receiving sunitinib compared with those receiving placebo, and similar findings were reported in subsequent multicenter randomized phase III trials. However, nephrotic syndrome and acute renal failure were not reported in these trials. Some patients treated with sunitinib have developed a preeclampsia-like syndrome characterized by reversible hypertension, proteinuria, and edema. A retrospective study from Korea reported incidences of proteinuria and renal insufficiency of 18.9% and 7.7%, respectively, among patients receiving sunitinib. In most cases, renal function improved or remained stable after discontinuation of the drug.

Renal biopsy may provide valuable insights into renal injury associated with sunitinib beyond the clinical manifestations of drug-induced renal dysfunction. In the French Reins sous traitement Anti-VEGF Registre study, renal biopsies from patients treated with sunitinib who developed nephrotic syndrome revealed focal segmental glomerulosclerosis, glomerular thrombotic microangiopathy, and acute tubular necrosis. Similar pathological findings have been reported in other studies, and acute interstitial nephritis has also been described. In the present case, renal allograft biopsy demonstrated focal segmental glomerulosclerosis, acute interstitial nephritis, and acute tubular injury.

Currently, there is no consensus regarding the optimal management of sunitinib intolerance in patients with metastatic clear-cell RCC. In many cases, symptoms improve or resolve after discontinuation of sunitinib. The RECORD-1 clinical trial compared everolimus with placebo in patients with previously failed or VEGFR-intolerant therapy, both administered with best supportive care. The study demonstrated significantly prolonged progression-free survival in patients receiving everolimus compared with placebo. Subsequent studies have further confirmed the efficacy and safety of switching treatment from sunitinib to everolimus.

Conclusion: 
This case highlights that renal allograft dysfunction and nephrotic syndrome may occur concurrently in patients receiving sunitinib. Therefore, clinicians should closely monitor renal function and perform regular urinalysis in renal transplant recipients undergoing treatment with this agent. Particular attention should be paid to medication exposure, especially sunitinib, when persistent proteinuria, nephrotic syndrome, and worsening serum creatinine levels are observed. In such situations, renal biopsy may be considered to provide additional diagnostic information and assist in establishing an accurate differential diagnosis.