Case report: Nephrotic syndrome induced by lenvatinib treatment in a patient with von Hippel-Lindau syndrome

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Tyrosine kinase inhibitor (TKI) is one of the targetd treatment for VHL syndrome. Lenvatinib (LEN), an oral small-molecule multiple TKI, and proteinuria is one of the most common adverse events associated with LEN. We reported a case of lenvatinib-induced nephrotic syndrome in a Chinese patient with VHL syndrome. The renal biopsy was proved with thrombotic microangiopathy (TMA) and focal segmental glomerulosclerosis (FSGS)-like pattern. Drug-induced kidney injury deserves further attention. Drug-Induced Kidney Injury Nephrotic syndrome von Hippel-Lindau syndrome Tyrosine kinase inhibitor Lenvatinib Figures Figure 1 Figure 2 Introduction Von Hippel-Lindau (VHL) syndrome is a rare genetic disease presented with mutiple organ tumors, including central nervous system haemangioblastomas (CHB), retinal hemangioblastomas (RB), pancreatic neuroendocrine tumors (pNETs), renal cell carcinoma (RCC) and pheochromocytoma [ 1 ] . It related closely to the mutation of tumour suppressor gene VHL located on chromosome 3p25-26, lead to the ubiquitin and degradation of hypoxia inducible factor (HIF-1α), then further result in the increased expression of vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1) and erythropoietin [ 2 ] . The treatment for VHL syndrome includes surgery, radiotherapy, targeted therapy, immunotherapy, and gene therapy. It was reported that belzutifan and tyrosine kinase inhibitor (TKI) had been approved in the targeted treatment of VHL syndrome [ 3 , 4 ] . Lenvatinib (LEN), an oral multiple TKI that could inhibit VEGF receptors, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptor, and rearranged during transfection (RET) [ 5 ] . Commonly reported adverse events of LEN include hypertension, gastrointestinal manifestations, hypothyroidism, fatigue, and proteinuria [ 6 ] . In this paper, we reported a case of LEN-induced nephrotic syndrome, presenting with secondary thrombotic microangiopathy (TMA) and focal segmental glomerulosclerosis (FSGS)-like lesion, in a VHL syndrome patient and emphasize the significance of monitoring urinalysis and individualized treatment in the management of rare disease patients. Case description A 50-year-old male was admitted due to the foaming in his urine and lower limbs edema since two months ago. Massive urine protein, hypoalbuminemia, and hypercholesterolemia were observed in Table 1 . The urinary Bence-Jones protein, serum tumor markers, ANCA, ANA, dsDNA antibodies, PLA2R antibodies and complement were negative. In 2008, he was diagnosed with VHL syndrome via genetic testing, presenting with spinal hemangioblastoma, cerebellar hemangioblastoma, and pheochromocytoma. The patient underwent three surgeries to remove the tumors. Three years ago, he was diagnosed with pNET and treated with octreotide 20mg every month for 6 times (the last dose was two years ago). In January 2022, the patient was treated with LEN at 12mg/day. The patient has a history of hypertension and hypothyroidism for 2 years and diabetes for 3 months. Three months ago, he was diagnosed with acute cerebral infarction with no symptoms of movement and sensation abnormality and treated with mannitol for dehydration. Three days ago, the patient had a fever, accompanied by cough and expectoration and took oral ibuprofen, then the symptoms relieved. The patient's father died at the age of 50 (cause unknown), and his son and daughter have been diagnosed with VHL syndrome. The vital signs were as follows: temperature, 37.1℃; heart rate, 97 bpm; respiratory rate, 18 breaths/min; and blood pressure 172/88mmHg. No special findings were noted on cardiac, pulmonary and abdominal physical examination. Table 1. Clinical data on admission. Blood Urine White blood cells (/μL) 6.49 pH 7.5 Hemoglobin (g/L) 128 Specific gravity 1.017 Platelete (*103/μL) 273 Protein 3+ Total protein (g/L) 52.1 Occult blood 1+ Albumin (g/L) 23.9 White blood cell (/μL) 3.5 AST (g/L) 16 RBC (/μL) 181.5 ALT (g/L) 7.1 24-hour protein urine (g) 7.5 Urea nitrogen (mmol/L) 3 Creatinine (μmol/L) 81 eGFR (mL/min/1.73m2) 97.1 Uric acid (μmol/L) 396 Ca (mmol/L) 2.12 Na (mmol/L) 138.2 K (mmol/L) 4.3 Cl (mmol/L) 105.9 CHOL (mmol/L) 8.86 TRIG (mmol/L) 2.38 CRP (mg/L) 78.42 HbA1c (%) 6.3 In view of the nephrotic syndrome presenting in a VHL syndrome patient, we excluded other possible causes, tumor-related nephropathy and drug-related nephrotoxicity were finally considered. Then a renal biopsy was performed. The light microscopy showed the proliferation of mesangial cells and mesangial matrix, segmental mesangial dissolution with microvascular aneurysmal dilation of the capillary loops, endothelial swelling, duplication of the glomerular basement membrane, endothelial swelling, mesangiolysis, and vacuolar degeneration of the podocytes, and 3 ischemic sclerotic glomerulus. In tubular epithelial cells, vacuolar and granular degeneration, focal loss of brush borders were observed. Focal lymphocytic and mononuclear cell infiltration with fibrosis in the interstitial area, and the thickening of the small artery walls with hyaline degeneration were presented. The electron microscopy showed marked electron-dense material in the mesangial and subendothelial space. Podocyte foot process effacement and vacuolar degeneration in tubular epithelial cells was observed ( Figure 1 ). Based on the above analysis and renal pathology, the etiology of nephrotic syndrome in the patient was due to LEN-induced kidney damage. With the multidisciplinary advice of oncology department and the pNET was stable, lenvatinib was discontinued. The other treatment included the control of blood pressure with RAAS inhibitor, management with blood glucose and lipid, correction of thyroid function, and palliative diuretics. The covid-19 of the patient was positive and active control of infection is also important. The patient was followed up in the outpatient clinic for six months. After discontinuation of LEN and continuous supportive therapy, proteinuria slowly decreased to 0.66 g/day with stable renal function ( Figure 2 ). An abdominal enhanced CT showed a slightly reduction in the pancreatic lesion. In conclusion, we presented a VHL syndrome patient who developed massive proteinuria, hypertension and hypothyroidism after lenvatinib treatment. In this case, discontinuation of LEN was effective. Discussion VHL syndrome is an autosomal dominant genetic disease, clinically manifested with hemangioblastoma (CHB and RB), renal cell carcinoma, pheochromocytoma, multiple pancreatic cysts, neuroendocrine tumors, and endolymphatic sac tumors. The diagnosis of VHL syndrome could be established when one of the following conditions is met: 1. There is an explicit family history, and one of the seven types of tumors mentioned above exists; 2. There is no family history, but at least 2 hemangioblastomas or 1 hemangioblastoma and one of the seven types of tumors mentioned above exist [ 1 ] . This paper reported a case of LEN-related TMA and FSGS-like renal damage in VHL syndrome patient during LEN treatment. The TKI treatment could achieve partial alleviation in VHL disease-related tumors, including gastroenteropancreatic neuroendocrine neoplasms [ 7 , 8 ] . Due to pNET, our patient was treated with LEN at a relatively large dose. This patient developed nephrotic syndrome in 2 years after LEN treatment. The clinical manifestation related with LEN adverse events in this patient also included hypertension and hypothyroidism. To date, there have been several reported cases of LEN-induced nephrotoxicity in cancer patients [ 9 – 15 ] , emphasizing the LEN’s effect for renal impairment and presented with different pathological forms (Table 2 ). Whether it was drug-related kidney damage, or primary glomerular disease was involved in, or other secondary factor such as metabolic factors and infection, the renal pathology contibuted to further clarify the etiology. The renal pathology showed secondary thrombotic microangiopathy kidney injury, mainly glomerular microangiopathy, and FSGS-like lesions, consisted with the vascular endothelial disorder and podocyte damage induced by LEN treatment in previous case reports. Table 2 The renal pathological patterns in case reports on lenvatinib-induced renal toxicity. FSGS, focal segmental glomerulosclerosis; TMA, thrombotic microangiopathy; RAI, radioactive iodine Case Gender/Age Race Cancer LEN duration (months) initiated LEN dose (mg) 24-hour protein urine(g) Creatinine (µmmol/L) Renal pathology Treatment Renal outcome 2018 [ 9 ] F/36 Caucasian medullary thyroid cancer 19 24 3.1 Normal FSGS Discontinued LEN Negative proteinuria in 1 year 2018 [ 10 ] F/79 Japanese papillary thyroid carcinoma 3 10 11.8 103.4 FSGS Discontinued LEN complete remission 2018 [ 11 ] M/44 Caucasian papillary thyroid carcinoma 48 24 3.5 168.0 FSGS, tubulointerstitial vascular necrosis, TMA-like pattern Discontinued LEN partial remission in 1 month 2018 [ 12 ] F/70 Japan RAI-refractory papillary thyroid carcinoma 26 24 3.5 99.0 TMA Discontinued LEN partial remission in 2 months 2022 [ 13 ] M/37 Filipino papillary thyroid cancer 41 24 2.7 97.2 TMA Discontinued LEN partial remission with preserved renal function 2022 [ 13 ] M/66 Caucasian metastatic follicular thyroid carcinoma 18 20 4.8 88.4 TMA Discontinued LEN complete remission 2022 [ 13 ] F/56 Caucasian hurthle cell thyroid carcinoma 8 20 1.8 70.7 TMA LEN reduction to 10 mg/d proteinuria decrease renal function stable 2022 [ 14 ] F/77 Japanese hepatocellular carcinoma 2 8 15.84 150.3 FSGS, TMA Discontinued LEN complete remission 2022 [ 15 ] F/68 Filipino metastatic follicular thyroid carcinoma 22 20 nephrotic range proteinuria NA FSGS, TMA, interstitial nephritis Discontinued LEN Worsening renal function improved and returned to her baseline our case, 2024 50/M Chinese VHL 28 12 7.5 81 TMA, FSGS-like pattern Discontinued LEN complete remission LEN-induced nephrotoxicity, such as massive proteinuria and nephrotic syndrome, could be caused by VEGFR and PDGFR inhibitors, which play important roles in the PI3K/AKT and RAS/RAF/MEK signaling pathway [ 16 ] . The VEGFR inhibitor could lead to the breakdown of endothelial fenestration and finally result in the damage of the glomerular basement membrane [ 17 ] . The proximal tubule regeneration also could be inhibited by PDGFR [18] . Side effects of LEN could be observed at any time after lenvatinib initiation [ 19 ] , nephrotic syndrome developed after 2 years following initiation of LEN treatment for pNET in our patient, and these side effects are mainly caused by the inhibition of VEGF. TMA due to VEGF inhibitors is often reversible, the early discontinuation of LEN could lead to partial remission, even complete remission [ 20 ] . There was no association between LEN-induced proteinuria and renal dysfunction in cancer patients [ 21 ] , our patient maintained stable kidney function. As for the therapeutic strategies in LEN-induced renal damage, dosage adjustment and adapt to sorafenib treatment had been reported [ 9 – 15 , 22 ] . In this case report, the patient was initially treated with LEN at 12 mg/day. According to the clinical management of adverse events from LEN-induced proteinuria according to the Common Terminology Criteria for Adverse Events (CTCAE) [ 23 , 24 ] , we discontinued LEN treatment permanently. The relievation of symptoms began soon after LEN discontinuation. There was a growing awareness of its renal adverse events as the wide utilization of LEN in cancer patients. In these cases, a kidney biopsy was performed, most of the histological results showed features of microangiopathic lesion or podocytopathy [ 9 – 15 ] . To our knowledge, this is the first report about LEN-induced TMA and FSGS-like lesion in a VHL syndrome patient. Clinicians should individually evaluate the advantages and disadvantages of TKI treatment for patients who develop proteinuria in VHL syndrome patients and put forward practical treatment options for drug reduction or withdrawal. The limitation of this case lies in that we need a longer period of follow-up. On the other hand, it deserves further evaluation about adapting to belzutifan, which might has low-grade side effects and has shown effect in VHL disease patients with pNET, renal cell carcinoma, and hemangioblastomas. VHL syndrome is a complex and challenging rare disease and needs a multidisciplinary cooperation to improve the outcome. Conclusion This case report was the first to describe LEN-induced renal damage in a Chinese patient with VHL syndrome. His proteinuria achieved complete remission after LEN discontinuation. This case emphasized the importace of careful monitoring of urinalysis and timely renal biopsy in patients undergoing LEN treatment. Abbreviations VHL Von Hippel-Lindau TKI Tyrosine kinase inhibitor LEN Lenvatinib TMA thrombotic microangiopathy FSGS focal segmental glomerulosclerosis CHB central nervous system haemangioblastomas RB retinal hemangioblastomas pNETs pancreatic neuroendocrine tumors RCC Renal cell carcinoma HIF-1α hypoxia inducible factor VEGF vascular endothelial growth factor GLUT1 glucose transporter 1 PDGF platelet-derived growth factor FGF fibroblast growth factor RET rearranged during transfection Declarations Data availability he clinical data used in this case report is available from the corresponding author on reasonable request. Funding This work was supported by Beijing Hospitals Authority Clinical medicine Development of special funding (No. YGLX202332) and the Youth Fund of Beijing Tsinghua Changgung Hospital (No. 12023C01002). Authors ’ Contributions Shuyu Zhang and Yuehong Li collected the data, drafted and revised the manuscript. Wen Wen was involved in the patient case. All authors contributed to the article and approved the submitted version. Acknowledgement We appreciate the patient for his cooperation in the diagnostic procedure and follow-up. Ethics Approval and Informed Consent All procedures were ethically approved by the ethics committee in Tsinghua Changgung Hospital. Consent for publication Written informed consent was obtained from all participants/patient in this study. Competing Interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. References Wang Y, Song J, Zheng S, et al. Advancements in understanding the molecular mechanisms and clinical implications of Von Hippel-Lindau syndrome: A comprehensive review. Transl Oncol. 2025, 51:102193. Kaelin WG Jr. Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer. J Clin Invest. 2022. 132(18):e162480. Jonasch E, Donskov F, Iliopoulos O, et al; MK-6482-004 Investigators. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021. 385(22):2036-2046. Jonasch E, McCutcheon IE, Gombos DS, et al. Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol. 2018. 19(10):1351-1359. Zhao Y, Zhang YN, Wang KT, et al. Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy. Biochim Biophys Acta Rev Cancer. 2020. 1874(1):188391. Capozzi M, De Divitiis C, Ottaiano A, et al. Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment. Cancer Manag Res. 2019. 11:3847-3860. Lauricella E, Mandriani B, Cavallo F, et al. Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications. Front Oncol. 2022. 17;12:957068. Ma K, Hong B, Zhou J, et al. The efficacy and safety of tyrosine kinase inhibitors for von Hippel–Lindau disease: a retrospective study of 32 patients. Front Oncol. 2019. 9:1122. Fleming K, McGuinness J, Kipgen D, et al. A Case of Lenvatinib-Induced Focal Segmental Glomerulosclerosis (FSGS) in Metastatic Medullary Thyroid Cancer. Case Rep Oncol Med. 2018. 2018:6927639. Furuto Y, Hashimoto H, Namikawa A, et al. Focal segmental glomerulosclerosis lesion associated with inhibition of tyrosine kinases by lenvatinib: a case report. BMC Nephrol. 2018. 19(1):273. Cavalieri S, Cosmai L, Genderini A, et al. Lenvatinib-induced renal failure: two first-time case reports and review of literature. Expert Opin Drug Metab Toxicol. 2018. 14(4):379-385. Hyogo Y, Kiyota N, Otsuki N, et al. Thrombotic Microangiopathy with Severe Proteinuria Induced by Lenvatinib for Radioactive Iodine-Refractory Papillary Thyroid Carcinoma. Case Rep Oncol. 2018. 11(3):735-741. Delsante M, Monroy-Trujillo JM, Carter-Monroe N, et al. Lenvatinib-related renal microangiopathy: a case series. Virchows Arch. 2022. 480(2):467-473. Nakashima S, Sekine A, Sawa N, et al. Thrombotic Microangiopathy, Podocytopathy, and Damage to the Renal Tubules with Severe Proteinuria and Acute Renal Dysfunction Induced by Lenvatinib. Intern Med. 2022, 61(20):3083-3088. Pham B, Kwon SM, Castillo DR, et al. Late renal toxicity in patient with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib: A case report and literature review. J Oncol Pharm Pract. 2022. 28(8):1930-1935. Deng Q, Huang Y, Zeng J, et al. Recent advancements in the small-molecule drugs for hepatocellular carcinoma (HCC): Structure-activity relationships, pharmacological activities, and the clinical trials. Biomed Pharmacother. 2024. 179:117343. Estrada CC, Maldonado A, Mallipattu SK. Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities. J Am Soc Nephrol. 2019. 30(2):187-200. Schiessl IM, Grill A, Fremter K, et al. Renal Interstitial Platelet-Derived Growth Factor Receptor-β Cells Support Proximal Tubular Regeneration. J Am Soc Nephrol. 2018. 29(5):1383-1396. Izzedine H, Mangier M, Ory V, et al. Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy. Kidney Int. 2014. 85(2):457-70. Usui J, Glezerman IG, Salvatore SP, et al. Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature. Hum Pathol. 2014. 45(9):1918-27. Shibutani Y, Suzuki S, Sagara A, et al. Impact of lenvatinib-induced proteinuria and renal dysfunction in patients with thyroid cancer. Front Oncol. 2023. 13:1154771. Yang CH, Chen KT, Lin YS, et al. Improvement of lenvatinib-induced nephrotic syndrome after adaptation to sorafenib in thyroid cancer: A case report. World J Clin Cases. 2020. 8(20):4883-4894. Kim BH, Yu SJ, Kang W, et al. Expert consensus on the management of adverse events in patients receiving lenvatinib for hepatocellular carcinoma. J Gastroenterol Hepatol. 2022. 37(3):428-439. Santos MLC, de Brito BB, da Silva FAF, et al. Nephrotoxicity in cancer treatment: An overview. World J Clin Oncol. 2020. 11(4):190-204. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 09 Jul, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 21 May, 2025 Reviews received at journal 20 May, 2025 Reviews received at journal 15 May, 2025 Reviewers agreed at journal 08 May, 2025 Reviewers agreed at journal 07 May, 2025 Reviewers invited by journal 05 May, 2025 Editor assigned by journal 05 May, 2025 Editor invited by journal 05 May, 2025 Submission checks completed at journal 03 May, 2025 First submitted to journal 03 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6431528","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":453672491,"identity":"a8124b89-418a-4355-b18f-e7a94be7cd54","order_by":0,"name":"Shuyu Zhang","email":"","orcid":"","institution":"Beijing Tsinghua Chang Gung Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuyu","middleName":"","lastName":"Zhang","suffix":""},{"id":453672492,"identity":"0da07d4f-3571-49aa-84a2-9b4127122282","order_by":1,"name":"Yuehong Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIie3SsQrCMBCA4QtCXEJ1TAnUV0gpiEMf5orQqRbBB1AR4qJ7fQtHx4qDS9076q5QcBIdrMXFJe3okH9LwsfBEQCT6Q+zgAGg5FPaXgGQWXmV1hD6IcXYR4tlZNaYkKQI0eFRU8JH+zuTh5jat+P5sQPHypHcx1oSD0VJJlTEwXydgWfn2BKJlkTyQ4gSkbsgCoJtjrTF9MR7VsTOKjJtQvp2IsNAcVYRlLWEXfuDQvoeZXGwWSvubrLLQuhIpx15Ob6401ue0uKh/J51HJY71BDo4s+Rw/cP6Mak+neTyWQywRuo/0kbWARLUAAAAABJRU5ErkJggg==","orcid":"","institution":"Beijing Tsinghua Chang Gung Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yuehong","middleName":"","lastName":"Li","suffix":""},{"id":453672493,"identity":"4f8fce0c-4be5-440e-b7a7-6271c1ed7676","order_by":2,"name":"Wen Wen","email":"","orcid":"","institution":"Beijing Tsinghua Chang Gung Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Wen","suffix":""}],"badges":[],"createdAt":"2025-04-12 01:23:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6431528/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6431528/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04303-z","type":"published","date":"2025-07-09T15:57:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82560004,"identity":"d6eeb800-52c9-456c-a398-3bc3e36ac1ba","added_by":"auto","created_at":"2025-05-13 01:30:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3542940,"visible":true,"origin":"","legend":"\u003cp\u003eHistology Images for Renal biopsy. A, Masson trichrome stain; B, Periodic acid Schiff stain; C-E, periodic acid-Methenamine-silver stain; F, Electron microscopy. Pathological diagnosis: TMA, mainly glomerular microangiopathy and FSGS-like lesions.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6431528/v1/a525f69bb78b38022da38b8f.jpg"},{"id":82560001,"identity":"0243369e-4be3-430e-b05f-b8f754c96a1b","added_by":"auto","created_at":"2025-05-13 01:30:37","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":210469,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of change in 24-hour protein urine.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6431528/v1/f47af048d435f83f0f2808e1.jpg"},{"id":86700100,"identity":"524771f3-f64b-45ee-b60a-45f3d8a27e97","added_by":"auto","created_at":"2025-07-14 16:11:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4929103,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6431528/v1/add0f6ec-c525-469e-ab83-d1c96b9f1c1e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Case report: Nephrotic syndrome induced by lenvatinib treatment in a patient with von Hippel-Lindau syndrome","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVon Hippel-Lindau (VHL) syndrome is a rare genetic disease presented with mutiple organ tumors, including central nervous system haemangioblastomas (CHB), retinal hemangioblastomas (RB), pancreatic neuroendocrine tumors (pNETs), renal\u003c/p\u003e \u003cp\u003ecell carcinoma (RCC) and pheochromocytoma\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. It related closely to the mutation of tumour suppressor gene VHL located on chromosome 3p25-26, lead to the ubiquitin and degradation of hypoxia inducible factor (HIF-1α), then further result in the increased expression of vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT1) and erythropoietin\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The treatment for VHL syndrome includes surgery, radiotherapy, targeted therapy, immunotherapy, and gene therapy. It was reported that belzutifan and tyrosine kinase inhibitor (TKI) had been approved in the targeted treatment of VHL syndrome\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Lenvatinib (LEN), an oral multiple TKI that could inhibit VEGF receptors, platelet-derived growth factor (PDGF) receptors, fibroblast growth factor (FGF) receptor, and rearranged during transfection (RET)\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Commonly reported adverse events of LEN include hypertension, gastrointestinal manifestations, hypothyroidism, fatigue, and proteinuria\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. In this paper, we reported a case of LEN-induced nephrotic syndrome, presenting with secondary thrombotic microangiopathy (TMA) and focal segmental glomerulosclerosis (FSGS)-like lesion, in a VHL syndrome patient and emphasize the significance of monitoring urinalysis and individualized treatment in the management of rare disease patients.\u003c/p\u003e"},{"header":"Case description","content":"\u003cp\u003eA 50-year-old male was admitted due to the foaming in his urine and lower limbs edema since two months ago. Massive urine protein, hypoalbuminemia, and hypercholesterolemia were observed in \u003cstrong\u003eTable 1\u003c/strong\u003e. The urinary Bence-Jones protein, serum tumor markers, ANCA, ANA, dsDNA antibodies, PLA2R antibodies and complement were negative. In 2008, he was diagnosed with VHL syndrome via genetic testing, presenting with spinal hemangioblastoma, cerebellar hemangioblastoma, and pheochromocytoma. The patient underwent three surgeries to remove the tumors. Three years ago, he was diagnosed with pNET and treated with octreotide 20mg every month for 6 times (the last dose was two years ago). In January 2022, the patient was treated with LEN at 12mg/day. The patient has a history of hypertension and hypothyroidism for 2 years and diabetes for 3 months. Three months ago, he was diagnosed with acute cerebral infarction with no symptoms of movement and sensation abnormality and treated with mannitol for dehydration. Three days ago, the patient had a fever, accompanied by cough and expectoration and took oral ibuprofen, then the symptoms relieved. The patient\u0026apos;s father died at the age of 50 (cause unknown), and his son and daughter have been diagnosed with VHL syndrome. The vital signs were as follows: temperature, 37.1℃; heart rate, 97 bpm; respiratory rate, 18 breaths/min; and blood pressure 172/88mmHg. No special findings were noted on cardiac, pulmonary and abdominal physical examination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eClinical data on admission.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"457\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 229px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlood\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 228px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUrine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eWhite blood cells (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003epH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHemoglobin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSpecific gravity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePlatelete (*103/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e273\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eProtein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal protein (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e52.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eOccult blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAlbumin (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e23.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eWhite blood cell (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAST (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eRBC (/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e181.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eALT (g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e24-hour protein urine (g)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUrea nitrogen (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCreatinine (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eeGFR (mL/min/1.73m2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e97.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eUric acid (\u0026mu;mol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCa (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNa (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e138.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eK (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCl (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e105.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCHOL (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e8.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTRIG (mmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCRP (mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e78.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eHbA1c (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn view of the nephrotic syndrome presenting in a VHL syndrome patient, we excluded other possible causes, tumor-related nephropathy and drug-related nephrotoxicity were finally considered. Then a renal biopsy was performed.\u0026nbsp;The light microscopy showed the proliferation of mesangial cells and mesangial matrix, segmental mesangial dissolution with microvascular aneurysmal dilation of the capillary loops, endothelial swelling, duplication of the glomerular basement membrane, endothelial swelling, mesangiolysis, and vacuolar degeneration of the podocytes, and 3 ischemic sclerotic glomerulus. In tubular epithelial cells, vacuolar and granular degeneration, focal loss of brush borders were observed. Focal lymphocytic and mononuclear cell infiltration with fibrosis in the interstitial area, and the thickening of the small artery walls with hyaline degeneration were presented. The electron microscopy showed marked electron-dense material in the mesangial and subendothelial space. Podocyte foot process effacement and vacuolar degeneration in tubular epithelial cells was observed\u0026nbsp;(\u003cstrong\u003eFigure\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eBased on the above analysis and renal pathology, the etiology of nephrotic syndrome in the patient was due to LEN-induced kidney damage. With the multidisciplinary advice of oncology department and the pNET was stable, lenvatinib was discontinued. The other treatment included the control of blood pressure with RAAS inhibitor, management with blood glucose and lipid, correction of thyroid function, and palliative diuretics. The covid-19 of the patient was positive and active control of infection is also important.\u003c/p\u003e\n\u003cp\u003eThe patient was followed up in the outpatient clinic for six months. After discontinuation of LEN and continuous supportive therapy, proteinuria slowly decreased to 0.66 g/day with stable renal function (\u003cstrong\u003eFigure\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e). An abdominal enhanced CT showed a slightly reduction in the pancreatic lesion. In conclusion, we presented a VHL syndrome patient who developed massive proteinuria, hypertension and hypothyroidism after lenvatinib treatment. In this case, discontinuation of LEN was effective.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVHL syndrome is an autosomal dominant genetic disease, clinically manifested with hemangioblastoma (CHB and RB), renal cell carcinoma, pheochromocytoma, multiple pancreatic cysts, neuroendocrine tumors, and endolymphatic sac tumors. The diagnosis of VHL syndrome could be established when one of the following conditions is met: 1. There is an explicit family history, and one of the seven types of tumors mentioned above exists; 2. There is no family history, but at least 2 hemangioblastomas or 1 hemangioblastoma and one of the seven types of tumors mentioned above exist\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. This paper reported a case of LEN-related TMA and FSGS-like renal damage in VHL syndrome patient during LEN treatment. The TKI treatment could achieve partial alleviation in VHL disease-related tumors, including gastroenteropancreatic neuroendocrine neoplasms\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Due to pNET, our patient was treated with LEN at a relatively large dose. This patient developed nephrotic syndrome in 2 years after LEN treatment. The clinical manifestation related with LEN adverse events in this patient also included hypertension and hypothyroidism. To date, there have been several reported cases of LEN-induced nephrotoxicity in cancer patients\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e, emphasizing the LEN\u0026rsquo;s effect for renal impairment and presented with different pathological forms (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWhether it was drug-related kidney damage, or primary glomerular disease was involved in, or other secondary factor such as metabolic factors and infection, the renal pathology contibuted to further clarify the etiology. The renal pathology showed secondary thrombotic microangiopathy kidney injury, mainly glomerular microangiopathy, and FSGS-like lesions, consisted with the vascular endothelial disorder and podocyte damage induced by LEN treatment in previous case reports.\u003c/p\u003e\n\u003cp\u003e\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe renal pathological patterns in case reports on lenvatinib-induced renal toxicity. FSGS, focal segmental glomerulosclerosis; TMA, thrombotic microangiopathy; RAI, radioactive iodine\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCase\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGender/Age\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRace\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCancer\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eLEN duration (months)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003einitiated LEN dose (mg)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e24-hour protein urine(g)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCreatinine (\u0026micro;mmol/L)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRenal pathology\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRenal outcome\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2018\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emedullary thyroid cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFSGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNegative proteinuria in 1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2018\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJapanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epapillary thyroid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e103.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFSGS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecomplete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2018\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epapillary thyroid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e168.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFSGS, tubulointerstitial vascular necrosis, TMA-like pattern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epartial remission in 1 month\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2018\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRAI-refractory papillary thyroid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epartial remission in 2 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2022\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFilipino\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epapillary thyroid cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epartial remission with preserved renal function\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2022\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emetastatic follicular thyroid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e88.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecomplete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2022\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaucasian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehurthle cell\u003c/p\u003e\n \u003cp\u003ethyroid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLEN reduction to 10 mg/d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eproteinuria decrease\u003c/p\u003e\n \u003cp\u003erenal function stable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2022\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eJapanese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehepatocellular carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e150.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFSGS, TMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecomplete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2022\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFilipino\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emetastatic follicular thyroid carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enephrotic range proteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFSGS, TMA, interstitial\u003c/p\u003e\n \u003cp\u003enephritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorsening renal function improved and\u003c/p\u003e\n \u003cp\u003ereturned to her baseline\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eour case,\u003c/p\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChinese\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVHL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMA, FSGS-like pattern\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiscontinued LEN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecomplete remission\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eLEN-induced nephrotoxicity, such as massive proteinuria and nephrotic syndrome, could be caused by VEGFR and PDGFR inhibitors, which play important roles in the PI3K/AKT and RAS/RAF/MEK signaling pathway\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. The VEGFR inhibitor could lead to the breakdown of endothelial fenestration and finally result in the damage of the glomerular basement membrane\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. The proximal tubule regeneration also could be inhibited by PDGFR\u003csup\u003e[18]\u003c/sup\u003e. Side effects of LEN could be observed at any time after lenvatinib initiation\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, nephrotic syndrome developed after 2 years following initiation of LEN treatment for pNET in our patient, and these side effects are mainly caused by the inhibition of VEGF. TMA due to VEGF inhibitors is often reversible, the early discontinuation of LEN could lead to partial remission, even complete remission\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. There was no association between LEN-induced proteinuria and renal dysfunction in cancer patients\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e, our patient maintained stable kidney function.\u003c/p\u003e\n\u003cp\u003eAs for the therapeutic strategies in LEN-induced renal damage, dosage adjustment and adapt to sorafenib treatment had been reported\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In this case report, the patient was initially treated with LEN at 12 mg/day. According to the clinical management of adverse events from LEN-induced proteinuria according to the Common Terminology Criteria for Adverse Events (CTCAE)\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, we discontinued LEN treatment permanently. The relievation of symptoms began soon after LEN discontinuation.\u003c/p\u003e\n\u003cp\u003eThere was a growing awareness of its renal adverse events as the wide utilization of LEN in cancer patients. In these cases, a kidney biopsy was performed, most of the histological results showed features of microangiopathic lesion or podocytopathy\u003csup\u003e[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. To our knowledge, this is the first report about LEN-induced TMA and FSGS-like lesion in a VHL syndrome patient. Clinicians should individually evaluate the advantages and disadvantages of TKI treatment for patients who develop proteinuria in VHL syndrome patients and put forward practical treatment options for drug reduction or withdrawal. The limitation of this case lies in that we need a longer period of follow-up. On the other hand, it deserves further evaluation about adapting to belzutifan, which might has low-grade side effects and has shown effect in VHL disease patients with pNET, renal cell carcinoma, and hemangioblastomas. VHL syndrome is a complex and challenging rare disease and needs a multidisciplinary cooperation to improve the outcome.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case report was the first to describe LEN-induced renal damage in a Chinese patient with VHL syndrome. His proteinuria achieved complete remission after LEN discontinuation. This case emphasized the importace of careful monitoring of urinalysis and timely renal biopsy in patients undergoing LEN treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eVHL Von Hippel-Lindau\u003c/p\u003e\n\u003cp\u003eTKI Tyrosine kinase inhibitor\u003c/p\u003e\n\u003cp\u003eLEN Lenvatinib\u003c/p\u003e\n\u003cp\u003eTMA thrombotic microangiopathy\u003c/p\u003e\n\u003cp\u003eFSGS focal segmental glomerulosclerosis\u003c/p\u003e\n\u003cp\u003eCHB central nervous system haemangioblastomas\u003c/p\u003e\n\u003cp\u003eRB retinal hemangioblastomas\u003c/p\u003e\n\u003cp\u003epNETs pancreatic neuroendocrine tumors \u003c/p\u003e\n\u003cp\u003eRCC Renal cell carcinoma\u003c/p\u003e\n\u003cp\u003eHIF-1\u0026alpha; hypoxia inducible factor\u003c/p\u003e\n\u003cp\u003eVEGF vascular endothelial growth factor\u003c/p\u003e\n\u003cp\u003eGLUT1 glucose transporter 1\u003c/p\u003e\n\u003cp\u003ePDGF platelet-derived growth factor\u003c/p\u003e\n\u003cp\u003eFGF fibroblast growth factor \u003c/p\u003e\n\u003cp\u003eRET rearranged during transfection\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ehe clinical data used in this case report is available from the corresponding author on reasonable request.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Beijing Hospitals Authority Clinical medicine Development of special funding (No. YGLX202332) and the Youth Fund of Beijing Tsinghua Changgung Hospital (No. 12023C01002).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e\u0026rsquo;\u003c/strong\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eShuyu Zhang and Yuehong Li collected the data, drafted and revised the manuscript. Wen Wen was involved in the patient case. All authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe appreciate the patient for his cooperation in the diagnostic procedure and follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Informed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures were ethically approved by the ethics committee in Tsinghua Changgung Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all participants/patient in this study.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWang Y, Song J, Zheng S, et al. 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Case Rep Oncol Med. 2018. 2018:6927639.\u003c/li\u003e\n\u003cli\u003eFuruto Y, Hashimoto H, Namikawa A, et al. Focal segmental glomerulosclerosis lesion associated with inhibition of tyrosine kinases by lenvatinib: a case report. BMC Nephrol. 2018. 19(1):273.\u003c/li\u003e\n\u003cli\u003eCavalieri S, Cosmai L, Genderini A, et al. Lenvatinib-induced renal failure: two first-time case reports and review of literature. Expert Opin Drug Metab Toxicol. 2018. 14(4):379-385.\u003c/li\u003e\n\u003cli\u003eHyogo Y, Kiyota N, Otsuki N, et al. Thrombotic Microangiopathy with Severe Proteinuria Induced by Lenvatinib for Radioactive Iodine-Refractory Papillary Thyroid Carcinoma. Case Rep Oncol. 2018. 11(3):735-741.\u003c/li\u003e\n\u003cli\u003eDelsante M, Monroy-Trujillo JM, Carter-Monroe N, et al. Lenvatinib-related renal microangiopathy: a case series. Virchows Arch. 2022. 480(2):467-473.\u003c/li\u003e\n\u003cli\u003eNakashima S, Sekine A, Sawa N, et al. 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Improvement of lenvatinib-induced nephrotic syndrome after adaptation to sorafenib in thyroid cancer: A case report. World J Clin Cases. 2020. 8(20):4883-4894.\u003c/li\u003e\n\u003cli\u003eKim BH, Yu SJ, Kang W, et al. Expert consensus on the management of adverse events in patients receiving lenvatinib for hepatocellular carcinoma. J Gastroenterol Hepatol. 2022. 37(3):428-439. \u003c/li\u003e\n\u003cli\u003eSantos MLC, de Brito BB, da Silva FAF, et al. Nephrotoxicity in cancer treatment: An overview. World J Clin Oncol. 2020. 11(4):190-204.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Drug-Induced Kidney Injury, Nephrotic syndrome, von Hippel-Lindau syndrome, Tyrosine kinase inhibitor, Lenvatinib ","lastPublishedDoi":"10.21203/rs.3.rs-6431528/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6431528/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVon Hippel-Lindau (VHL) syndrome is an autosomal dominant hereditary disease characterized with mutiple organ tumors. Tyrosine kinase inhibitor (TKI) is one of the targetd treatment for VHL syndrome. Lenvatinib (LEN), an oral small-molecule multiple TKI, and proteinuria is one of the most common adverse events associated with LEN. We reported a case of lenvatinib-induced nephrotic syndrome in a Chinese patient with VHL syndrome. The renal biopsy was proved with thrombotic microangiopathy (TMA) and focal segmental glomerulosclerosis (FSGS)-like pattern. Drug-induced kidney injury deserves further attention.\u003c/p\u003e","manuscriptTitle":"Case report: Nephrotic syndrome induced by lenvatinib treatment in a patient with von Hippel-Lindau syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 01:30:32","doi":"10.21203/rs.3.rs-6431528/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-21T07:19:55+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-20T06:23:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-15T22:57:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85446531363479078521975332822823729","date":"2025-05-08T08:34:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4697593108028473027106179250317731394","date":"2025-05-08T02:59:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-05T18:30:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-05T10:36:31+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-05T10:24:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-03T07:41:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-05-03T07:40:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1209d375-f35e-4448-8735-51fb10fcacc6","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-07-14T16:09:17+00:00","versionOfRecord":{"articleIdentity":"rs-6431528","link":"https://doi.org/10.1186/s12882-025-04303-z","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-07-09 15:57:40","publishedOnDateReadable":"July 9th, 2025"},"versionCreatedAt":"2025-05-13 01:30:32","video":"","vorDoi":"10.1186/s12882-025-04303-z","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04303-z","workflowStages":[]},"version":"v1","identity":"rs-6431528","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6431528","identity":"rs-6431528","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}