A case of recurrent ovarian cancer with renal dysfunction associated with the use of olaparib

A case of recurrent ovarian cancer with renal dysfunction associated with the use of olaparib | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A case of recurrent ovarian cancer with renal dysfunction associated with the use of olaparib Yukiko Yamano, Tomokazu Minakata, Takahiro Tsuji, Shiko Hayashi, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1680826/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2023 Read the published version in SN Comprehensive Clinical Medicine → Version 1 posted 5 You are reading this latest preprint version Abstract Many anticancer drugs have been reported to damage the kidneys. Olaparib (ORB) is known not to largely affect renal function due to its specific pharmacological mechanism, and there are no reports on renal dysfunction associated with the drug. The patient was found to have diagnosed with recurrent ovarian cancer. She started therapy with Bevacizumab (BEV). Unfortunately, BEV was discontinued due to development of progressive renal dysfunction with proteinuria. Therefore, she started administration of ORB. However, after switching to ORB, her renal dysfunction progressed. Renal histopathology revealed membranoproliferative glomerulonephritis (MPGN) and thrombotic microangiopathy (TMA). During the clinical course, her renal function deteriorated after administration of ORB and improved after the drug was discontinued because of bone marrow suppression. Moreover, sustained improvement of renal function was observed after complete discontinuation of the drug. This case is considered to be the first report of renal dysfunction due to ORB. Although ORB is not considered to cause renal damage when administered alone, it can be considered to further exacerbate the preceding BEV-induced renal dysfunction. Since switching of anticancer drugs is common, clinicians should be aware of the risk of developing renal dysfunction. Olaparib Bevacizumab membranoproliferative glomerulonephritis thrombotic microangiopathy poly ADP-ribose polymerase (PARP) inhibitor Figures Figure 1 Figure 2 Introduction In recent years, a wide variety of drugs have been used in chemotherapy for recurrent ovarian cancer. These include cytotoxic anticancer drugs and molecular targeted drugs. Bevacizumab (BEV), a molecular drug targeting vascular endothelial growth factor (VEGF), is widely used in clinical practice; however, proteinuria and hypertension are relatively frequently observed as adverse events[1.2]. The incidence of proteinuria increases in a dose-dependent manner, and there are several reported cases of nephrotic syndrome and renal dysfunction[ 3 , 4 ]. Although renal histopathology was not performed because of serious cancer in most of the cases, there were many reported cases of thrombotic microangiopathy (TMA) as an endothelial cell dysfunction[ 5 , 6 , 7 ] The suggested mechanism is that BEV inhibits the production of VEGF in podocytes and reduces the expression of nephrin, leading to failure of filtration function of the glomerular capillary wall, resulting in leakage of protein. It was also suggested that inhibition of VEGF that plays a role in maintaining the morphology and function of endothelial cells may cause cell damage[ 8 ]. We treated a patient with recurrent ovarian cancer who discontinued BEV due to development of proteinuria and renal dysfunction and was then treated with olaparib (ORB), a poly (ADP-ribose) polymerase (PARP) inhibitor. ORB exhibits an antitumor effect by inducing cell death by inhibiting PARP, an enzyme playing an important role in base excision repair of single-strand DNA breaks, and inducing DNA double-strand breaks. On the basis of the mechanism of action and clinical results, ORB is considered to have less renal toxicity, and there are no detailed reports on renal dysfunction associated with the drug. However, in the present case, the patient’s renal dysfunction progressed after switching to ORB. To our knowledge, this is the first reported case of renal dysfunction associated with ORB. It is inferred that BEV-induced renal dysfunction was exacerbated by ORB administration. Case Report Patient: Women in their 60s. Chief complaint: Renal dysfunction. Past history: Not remarkable. Family history: There was no family history of renal diseases. Life-style habits and other factors: There was no history of drinking alcohol, smoking, or allergy. History of present illness: In X-6 (year), the patient was found to have a right ovarian tumor. In the same year, she underwent radical surgery for ovarian cancer (abdominal total hysterectomy, bilateral adnexectomy, pelvic lymph node dissection, omentectomy, and resection of peritoneal dissemination) at the department of obstetrics of our hospital, and was diagnosed with stage IIIa serous ovarian adenocarcinoma. Postoperative chemotherapy with Paclitaxel Carboplatin (PC) therapy was administered for 6 cycles and the patient was followed up. In X-3 (Year), positron emission tomography-computed tomography (PET-CT) examination showed disseminated lesions in the vicinity of the rectum, and she was diagnosed with recurrent ovarian cancer. PC therapy was continued for an additional 4 cycles, and doxorubicin therapy was performed for 20 cycles, but the disseminated lesions increased in size and a new liver metastasis was found. BEV was thus started in July X-1. In July X-1, BEV In September of the same year, proteinuria was detected for the first time. During the treatment, her qualitative tests for urinary proteins were (1+) and (2+), but hypertension developed for which an antihypertensive drug was administered. The proteinuria persisted, and her renal function deteriorated over time. Therefore, in March X, BEV was discontinued. In May of the same year, oral administration of the new drug ORB (600 mg/day) was started. However, her renal dysfunction progressed (serum creatinine 3.15 mg/dL), and thus a renal biopsy was performed in July. Physical findings on admission was as follows: Height 148 cm; weight 38.9 kg; blood pressure 118/61 mmHg; pulse rate 65 beats/minute (regular); body temperature 36.3°C; SpO 2 97% (room air); alert and conscious; anemia in the palpebral conjunctiva; there was no discoloration of the bulbar conjunctiva; no abnormal findings were observed in the oral cavity; superficial lymph nodes were not palpated; there were no abnormal respiratory sounds or heart sounds; no abnormal findings were observed in the abdomen; and mild edema was observed in bilateral lower thighs. Laboratory findings on admission are shown in Table. Serum chemistry showed severe anemia, leukocytopenia, and elevated urea nitrogen and creatinine. Urinary examination showed urinary protein (1+) and increases in urinary NAG and urinary β2-microglobulin. Regarding abdominal CT and renal echo, there were no particular abnormalities in the morphology of the kidney. The renal biopsy findings are shown in Fig. 1 . A total of 17 glomeruli were obtained. Most of the glomeruli showed lobulation, endocapillary hypercellularity, mesangiolysis, subendothelial edema, and glomerular capillary duplication. The tubulointerstitium was relatively preserved. Immunofluorescent staining showed diffuse deposition of fibrinogen in the glomeruli, but there was no deposition of immune complexes. Unfortunately, glomeruli were not included in the specimen for electron microscopic studies. The clinical course is shown in Fig. 2 . Thereafter, ORB was temporarily discontinued twice due to an adverse drug reaction of bone marrow suppression, and improvement in renal function was observed during the discontinuation periods. In addition, the tumor increased in size during the therapy with ORB. We concluded that ORB was ineffective in the maintenance therapy and completely discontinued the drug in September X. After that her renal dysfunction improved over time. In November, the creatinine level improved to 1.48 mg/dL. Since then, there has been no deterioration in her renal function. Discussion We treated a patient with recurrent ovarian cancer who discontinued BEV due to development of proteinuria and renal dysfunction and developed protracted renal dysfunction following treatment with ORB. In recent years, significant advances have been made in the development of molecular targeted therapies, and it has contributed to the improvement of prognosis. BEV is a monoclonal antibody targeting VEGF. The functions of VEGF include promoting proliferation of vascular endothelial cells, controlling their survival, enhancing the permeability, and inducing the production of active substances from the endothelial cells. BEV exerts antitumor effect by binding to and neutralizing VEGF and inhibiting angiogenesis, proliferation, and metastasis of tumor cells[ 9 , 10 , 11 ]. It also reduces stromal pressure in tumor tissue by normalizing vascular structure and reducing vascular permeability. Although BEV is widely applied to the treatment of advanced cancers, BEV inhibits not only cancerous tissue but also normal angiogenesis, and specific adverse events such as proteinuria (3–36%), hypertension (21–64%), bleeding, thromboembolism, and protracted wound healing have been reported[ 12 ]. The incidence of proteinuria increases in a dose-dependent manner, and there are several reported cases of nephrotic syndrome and renal dysfunction[ 13 ]. The suggested mechanism is that BEV inhibits the production of VEGF in podocytes and reduces the expression of nephrin required for maintenance of slit diaphragm structure between foot processes, leading to failure of filtration function of the glomerular capillary wall, thereby resulting in leakage of protein[ 8 ]. In addition, since VEGF plays a role in maintaining the morphology and function of vascular endothelial cells, the disruption of VEGF pathway may cause damage to glomerular endothelial cells[ 14 ]. Although renal histopathology was not performed because of serious cancer in most of the cases developing proteinuria or renal dysfunction, there were many reported cases of renal-limited TMA as an endothelial cell dysfunction[ 2 , 3 , 13 ]. The incidence and mechanism of TMA have not been elucidated[ 15 ]. Typical histopathological findings of TMA include: endothelial cell swelling and edematous expansion of the subendothelial space, platelet thrombosis, fibrin thrombosis, mesangiolysis, and fibrinoid necrosis in the acute stage; base membrane duplication, mesangial interposition, proliferative change, and segmental sclerosis in the chronic stage. Renal histopathology showed diffuse mesangial proliferation, lobulated appearance with endocapillary hypercellularity, mesangiolysis, and glomerular capillary duplication, showing membranoproliferative glomerulonephritis (MPGN)-like findings. Immunofluorescent staining showed no significant deposition of immune complexes, and this was considered to be the morphology of pauci-immune MPGN. It is known that chronic TMA presents with cell proliferation and lobulation, and sometimes forms glomerular lesions that are difficult to be differentiated from MPGN[ 3 , 16 ]. On the basis of renal histopathological findings, the lesion was considered to be TMA secondary to BEV therapy. It is reported that proteinuria caused by BEV improves after discontinuation of the drug in most cases[ 17 ]. However, there are reported cases of persistent proteinuria resulting in end-stage renal failure or death even after discontinuation of the drug[ 1 , 3 ]. Therefore, the criteria for discontinuation of BEV has been established in order to prevent irreversible renal dysfunction due to long-term leakage of protein in urine. The Clinical Practice Guidelines for the Management of Kidney Disease in Cancer Survivors in 2016 in Japan recommend as follows: When the level of proteinuria is 2 + or higher or 1.0 g/day or higher, BEV should be discontinued or reduced, and specialists should be consulted, as necessary. In the present case, hypertension and proteinuria developed after starting BEV, but the drug was not discontinued at that time because the qualitative tests for urinary proteins were 1 + and 2 + and the quantitative results were around 0.5 g/day. Then BEV was discontinued due to development and progression of renal dysfunction, and ORB was started. However, as exacerbation of renal function was noted, we suspected the involvement of ORB and performed a renal biopsy. ORB is a PARP inhibitor and it blocks the enzyme involved in repair of both single- and double-strand breaks in DNA[ 18 ]. PARP binds to DNA at sites of single-strand breaks. The activated PARP promotes DNA repair by inducing poly-ADP ribosylation of proteins involved in DNA repair by chain addition polymerization of ADP-ribose residues using oxidative nicotinamide adenine nucleotide (NAD + ) as a substrate. However, excessive activation of PARP can deplete NAD + and ATP and induces the release of apoptosis-inducing factors (AIF) from mitochondria. The AIF released to the cytoplasm together with endonuclease G from mitochondria translocate to the nucleus, resulting in segmentation of the nucleus and cell death. When DNA single-strand break repair is blocked by PARP inhibitors, cell death does not usually occur in normal cells because DNA breaks are usually repaired through homologous recombination repair. However, when cells with homologous recombination defects, such as BRCA mutations, are present, the defects in homologous recombination together with PARP inhibition leads to synthetic lethality. Thus, PARP inhibitors selectively act on cells with homologous recombination defects. Approximately 50% of patients with ovarian cancers have abnormalities in genes involved in homologous recombination repair, such as BRCA genes. In addition, platinum anticancer drugs exert their cytotoxic effect by increasing DNA double-strand breaks through generation of interstrand DNA crosslinks. It is therefore expected that patients with recurrent ovarian cancers who responded to postoperative chemotherapy with platinum drugs have a deficiency in homologous recombination repair, for whom PARP inhibitors can induce synthetic lethality and exert antitumor effects. Serious adverse reactions of ORB include bone marrow suppression, such as anemia, neutropenia, leukocytopenia, and thrombocytopenia, and interstitial lung disease. Other adverse reactions include skin symptoms and digestive symptoms; however, renal dysfunction has not been reported as an adverse reaction to ORB. According to clinical trial data, hypercreatinemia was observed in 2 patients and elevated blood creatinine was observed in 21 patients. It is recognized that ORB is less likely to cause renal dysfunction, In fact, an animal experiment showed that a PARP inhibitor was protective against acute kidney injury[ 19 , 20 , 21 ]. However, in the present case, the patient’s renal function deteriorated after treatment with ORB, and improved after discontinuation of the drug, and the same pattern was repeated. This clinical course strongly suggested that ORB was related to the renal dysfunction. What could be the underlying mechanism for ORB to cause exacerbation of renal dysfunction? The suggested mechanism is that BEV-induced secondary TMA decreased the glomerular blood flow, resulting in transient tubular damage. Then ORB inhibited the repair mechanism and prevented the recovery from tubular damage, resulting in protracted renal dysfunction. To our knowledge, this is the first report of renal dysfunction associated with ORB. The use of ORB after developing BEV-induced TMA was considered to be the cause of the drug-induced renal dysfunction. Given that ORB can be used in the treatment of intractable cancers, clinicians should be aware of the risk of developing renal dysfunction. Conclusion We described a patient with recurrent ovarian cancer who developed protracted renal dysfunction after discontinuation of BEV and administration of ORB. The ORB is known as a drug with almost no renal impairment, but physicians should be careful that renal impairment may occur due to the relationship with other drugs such as BEV. Postscript: The abstract of this paper was presented at the 50th Annual Meeting of the Japanese Society of Nephrology (Western Meeting). At that time, this paper was awarded the Excellent Presentation Award. Declarations Acknowledgements We would like to acknowledge the patient and the patient’s family for allowing the case to be published. Compliance with Ethical Standards Funding : Not applicable. (No funding) Conflict of interest ： The authors have declared no competing interest. Ethics approval/ Ethical standards: This article does not contain any studies with human participants or animals performed by any of the authors. Consent to participate: Not applicable Consent for publication/ Informed consent: Informed consent was obtained from the patients mentioned in this study. Informed consent is given in writing. Also, although this patient is dead, her husband has given her consent even after her death. Availability of data and material: The data used to support the findings of this study are available from the corresponding author upon request. We will disclose all information except personally identifiable information. Code availability: Not applicable Authors' contributions: all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. YY is the chief editor of this paper. YY, TM, SH and SH are the doctors who actually treated. TT performed a pathological analysis. SH is the corresponding author of this paper. References Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevasizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186–93. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE. VEGF Inhibition and Renal Thrombotic Microangiopathy. N Engl J Med. 2008;358:1129–36. Stokes MB, Erazo MC, D’Agati VD. Glomerular disease related to anti-VEGF therapy. Kidney Int. 2008;74:1487–91. Stylianou K, Lioudaki E, Papadimitraki E, Kokologiannakis G, Kroustalakis N, Liotsi C, Giannakakis K, Georgoulias V, Daphnis E. Crescentic glomerulonephritis associated with vascular endothelial growth factor(VEGF) inhibitor and bisphosphonate administration. Nephrol Dial Transplant. 2011;26:1742–45. Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE. VEGF inhibition and renal thrombotic micro- angiopathy. N Engl J Med. 2008;358:1129–36. Advani A. Vascular endothelial growth factor and the kidney: something of the marvellous. Curr Opin Nephrol Hy-pertens. 2014;23:87–92. Ollero M, Sahali D. Inhibition of the VEGF signalling pathway and glomerular disorders. Nephrol Dial Transplant. 2015;30:1449–55. Ostendorf T, Vriese ASD, Floege J. Renal side effects of anti-VEGF therapy in man: a new test system. Nephrol Dial Transplant. 2007;22:2778–80. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011–27. Gerber HP, Ferrara N. Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies. Cancer Res. 2005;65:671–80. Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6:465–77. Wu S, Kim C, Baer L, Zhu X. Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol. 2010;21:1381–89. Shimamura Y, Maeda T, Takizawa H. Bevacizumab-induced thrombotic microangiopathy and nephrotic syndrome. Clin Exp Nephrol. 2019;23:142–43. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788–95. Brocklebank V, Wood KM, Kavanagh D. Thrombotic Microangiopathy and the Kidney. Clin J Am Soc Nephrol. 2018;13:300–17. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol. 2011;31:341–48. Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents. Clin J Am Soc Nephrol. 2012;7:1713–21. Hou WH, Chen SH, Yu X. Poly-ADP ribosylation in DNA damage response and cancer therapy. Mutat Res. 2019;780:82–91. Kapoor K, Singla E, Sahu B, Naura AS. PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice. Mol Cell Biochem. 2015;400(1–2):153–62. Kalmar-Nagy K, Degrell P, Szabo A, Sumegi K, Wittmann I, Gallyas F Jr, Sumegi B. PARP inhibition attenuates acute kidney allograft rejection by suppressing cell death pathways and activating PI-3K-Akt cascade. PLoS One. 2013; 3; 8(12). Liu S, Liu J, Liu D, Wang XT, Yang RL. Inhibition of Poly-(ADP-Ribose) Polymerase Protects the Kidney in a Canine Model of Endotoxic Shock. Nephron. 2015;130:281–92. Tables Table 1 is available in the Supplementary Files section. Supplementary Files Table.pdf Table Laboratory examinations on admission Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2023 Read the published version in SN Comprehensive Clinical Medicine → Version 1 posted Editorial decision: Major revisions 01 Nov, 2022 Reviewers agreed at journal 12 Sep, 2022 Reviewers invited by journal 18 Aug, 2022 Editor assigned by journal 26 Jul, 2022 First submitted to journal 18 Jul, 2022 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. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies 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-1680826","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":129822105,"identity":"a8791156-281d-4c72-992b-c27248933b98","order_by":0,"name":"Yukiko Yamano","email":"","orcid":"","institution":"Department of Nephrology, Kinan Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yukiko","middleName":"","lastName":"Yamano","suffix":""},{"id":129822106,"identity":"14bb7481-d9f6-4410-92a7-1d4bd457fafe","order_by":1,"name":"Tomokazu Minakata","email":"","orcid":"","institution":"Department of Nephrology, Kinan 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17:05:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37598,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1680826/v1/31c06267dc74d40c561767f9.png"},{"id":44716951,"identity":"1e8798c3-6725-4496-b57e-acb8727db3e0","added_by":"auto","created_at":"2023-10-16 18:31:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1762141,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1680826/v1/d7d051b9-d321-49ab-a84c-d51b32a02f67.pdf"},{"id":25505010,"identity":"5dc84d88-eea8-4057-baa0-eb2edfee8a4f","added_by":"auto","created_at":"2022-08-22 17:00:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":44092,"visible":true,"origin":"","legend":"\u003cp\u003eTable\u0026nbsp;Laboratory examinations on admission\u003c/p\u003e","description":"","filename":"Table.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1680826/v1/d8177cf1138ee4edfbcb97a8.pdf"}],"financialInterests":"","formattedTitle":"A case of recurrent ovarian cancer with renal dysfunction associated with the use of olaparib","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn recent years, a wide variety of drugs have been used in chemotherapy for recurrent ovarian cancer. These include cytotoxic anticancer drugs and molecular targeted drugs. Bevacizumab (BEV), a molecular drug targeting vascular endothelial growth factor (VEGF), is widely used in clinical practice; however, proteinuria and hypertension are relatively frequently observed as adverse events[1.2]. The incidence of proteinuria increases in a dose-dependent manner, and there are several reported cases of nephrotic syndrome and renal dysfunction[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although renal histopathology was not performed because of serious cancer in most of the cases, there were many reported cases of thrombotic microangiopathy (TMA) as an endothelial cell dysfunction[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] The suggested mechanism is that BEV inhibits the production of VEGF in podocytes and reduces the expression of nephrin, leading to failure of filtration function of the glomerular capillary wall, resulting in leakage of protein. It was also suggested that inhibition of VEGF that plays a role in maintaining the morphology and function of endothelial cells may cause cell damage[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe treated a patient with recurrent ovarian cancer who discontinued BEV due to development of proteinuria and renal dysfunction and was then treated with olaparib (ORB), a poly (ADP-ribose) polymerase (PARP) inhibitor. ORB exhibits an antitumor effect by inducing cell death by inhibiting PARP, an enzyme playing an important role in base excision repair of single-strand DNA breaks, and inducing DNA double-strand breaks. On the basis of the mechanism of action and clinical results, ORB is considered to have less renal toxicity, and there are no detailed reports on renal dysfunction associated with the drug. However, in the present case, the patient\u0026rsquo;s renal dysfunction progressed after switching to ORB. To our knowledge, this is the first reported case of renal dysfunction associated with ORB. It is inferred that BEV-induced renal dysfunction was exacerbated by ORB administration.\u003c/p\u003e "},{"header":"Case Report","content":" \u003cp\u003ePatient: Women in their 60s.\u003c/p\u003e \u003cp\u003eChief complaint: Renal dysfunction.\u003c/p\u003e \u003cp\u003ePast history: Not remarkable.\u003c/p\u003e \u003cp\u003eFamily history: There was no family history of renal diseases.\u003c/p\u003e \u003cp\u003eLife-style habits and other factors: There was no history of drinking alcohol, smoking, or allergy.\u003c/p\u003e \u003cp\u003eHistory of present illness:\u003c/p\u003e \u003cp\u003eIn X-6 (year), the patient was found to have a right ovarian tumor. In the same year, she underwent radical surgery for ovarian cancer (abdominal total hysterectomy, bilateral adnexectomy, pelvic lymph node dissection, omentectomy, and resection of peritoneal dissemination) at the department of obstetrics of our hospital, and was diagnosed with stage IIIa serous ovarian adenocarcinoma. Postoperative chemotherapy with Paclitaxel Carboplatin (PC) therapy was administered for 6 cycles and the patient was followed up. In X-3 (Year), positron emission tomography-computed tomography (PET-CT) examination showed disseminated lesions in the vicinity of the rectum, and she was diagnosed with recurrent ovarian cancer. PC therapy was continued for an additional 4 cycles, and doxorubicin therapy was performed for 20 cycles, but the disseminated lesions increased in size and a new liver metastasis was found. BEV was thus started in July X-1. In July X-1, BEV In September of the same year, proteinuria was detected for the first time. During the treatment, her qualitative tests for urinary proteins were (1+) and (2+), but hypertension developed for which an antihypertensive drug was administered. The proteinuria persisted, and her renal function deteriorated over time. Therefore, in March X, BEV was discontinued. In May of the same year, oral administration of the new drug ORB (600 mg/day) was started. However, her renal dysfunction progressed (serum creatinine 3.15 mg/dL), and thus a renal biopsy was performed in July.\u003c/p\u003e \u003cp\u003ePhysical findings on admission was as follows: Height 148 cm; weight 38.9 kg; blood pressure 118/61 mmHg; pulse rate 65 beats/minute (regular); body temperature 36.3\u0026deg;C; SpO\u003csub\u003e2\u003c/sub\u003e 97% (room air); alert and conscious; anemia in the palpebral conjunctiva; there was no discoloration of the bulbar conjunctiva; no abnormal findings were observed in the oral cavity; superficial lymph nodes were not palpated; there were no abnormal respiratory sounds or heart sounds; no abnormal findings were observed in the abdomen; and mild edema was observed in bilateral lower thighs.\u003c/p\u003e \u003cp\u003eLaboratory findings on admission are shown in Table. Serum chemistry showed severe anemia, leukocytopenia, and elevated urea nitrogen and creatinine. Urinary examination showed urinary protein (1+) and increases in urinary NAG and urinary β2-microglobulin. Regarding abdominal CT and renal echo, there were no particular abnormalities in the morphology of the kidney.\u003c/p\u003e \u003cp\u003eThe renal biopsy findings are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 17 glomeruli were obtained. Most of the glomeruli showed lobulation, endocapillary hypercellularity, mesangiolysis, subendothelial edema, and glomerular capillary duplication. The tubulointerstitium was relatively preserved. Immunofluorescent staining showed diffuse deposition of fibrinogen in the glomeruli, but there was no deposition of immune complexes. Unfortunately, glomeruli were not included in the specimen for electron microscopic studies.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe clinical course is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThereafter, ORB was temporarily discontinued twice due to an adverse drug reaction of bone marrow suppression, and improvement in renal function was observed during the discontinuation periods. In addition, the tumor increased in size during the therapy with ORB. We concluded that ORB was ineffective in the maintenance therapy and completely discontinued the drug in September X. After that her renal dysfunction improved over time. In November, the creatinine level improved to 1.48 mg/dL. Since then, there has been no deterioration in her renal function.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe treated a patient with recurrent ovarian cancer who discontinued BEV due to development of proteinuria and renal dysfunction and developed protracted renal dysfunction following treatment with ORB.\u003c/p\u003e \u003cp\u003eIn recent years, significant advances have been made in the development of molecular targeted therapies, and it has contributed to the improvement of prognosis.\u003c/p\u003e \u003cp\u003eBEV is a monoclonal antibody targeting VEGF. The functions of VEGF include promoting proliferation of vascular endothelial cells, controlling their survival, enhancing the permeability, and inducing the production of active substances from the endothelial cells. BEV exerts antitumor effect by binding to and neutralizing VEGF and inhibiting angiogenesis, proliferation, and metastasis of tumor cells[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. It also reduces stromal pressure in tumor tissue by normalizing vascular structure and reducing vascular permeability. Although BEV is widely applied to the treatment of advanced cancers, BEV inhibits not only cancerous tissue but also normal angiogenesis, and specific adverse events such as proteinuria (3\u0026ndash;36%), hypertension (21\u0026ndash;64%), bleeding, thromboembolism, and protracted wound healing have been reported[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The incidence of proteinuria increases in a dose-dependent manner, and there are several reported cases of nephrotic syndrome and renal dysfunction[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The suggested mechanism is that BEV inhibits the production of VEGF in podocytes and reduces the expression of nephrin required for maintenance of slit diaphragm structure between foot processes, leading to failure of filtration function of the glomerular capillary wall, thereby resulting in leakage of protein[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In addition, since VEGF plays a role in maintaining the morphology and function of vascular endothelial cells, the disruption of VEGF pathway may cause damage to glomerular endothelial cells[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough renal histopathology was not performed because of serious cancer in most of the cases developing proteinuria or renal dysfunction, there were many reported cases of renal-limited TMA as an endothelial cell dysfunction[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The incidence and mechanism of TMA have not been elucidated[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTypical histopathological findings of TMA include: endothelial cell swelling and edematous expansion of the subendothelial space, platelet thrombosis, fibrin thrombosis, mesangiolysis, and fibrinoid necrosis in the acute stage; base membrane duplication, mesangial interposition, proliferative change, and segmental sclerosis in the chronic stage.\u003c/p\u003e \u003cp\u003eRenal histopathology showed diffuse mesangial proliferation, lobulated appearance with endocapillary hypercellularity, mesangiolysis, and glomerular capillary duplication, showing membranoproliferative glomerulonephritis (MPGN)-like findings. Immunofluorescent staining showed no significant deposition of immune complexes, and this was considered to be the morphology of pauci-immune MPGN. It is known that chronic TMA presents with cell proliferation and lobulation, and sometimes forms glomerular lesions that are difficult to be differentiated from MPGN[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. On the basis of renal histopathological findings, the lesion was considered to be TMA secondary to BEV therapy.\u003c/p\u003e \u003cp\u003eIt is reported that proteinuria caused by BEV improves after discontinuation of the drug in most cases[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, there are reported cases of persistent proteinuria resulting in end-stage renal failure or death even after discontinuation of the drug[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Therefore, the criteria for discontinuation of BEV has been established in order to prevent irreversible renal dysfunction due to long-term leakage of protein in urine. The Clinical Practice Guidelines for the Management of Kidney Disease in Cancer Survivors in 2016 in Japan recommend as follows: When the level of proteinuria is 2\u0026thinsp;+\u0026thinsp;or higher or 1.0 g/day or higher, BEV should be discontinued or reduced, and specialists should be consulted, as necessary.\u003c/p\u003e \u003cp\u003eIn the present case, hypertension and proteinuria developed after starting BEV, but the drug was not discontinued at that time because the qualitative tests for urinary proteins were 1\u0026thinsp;+\u0026thinsp;and 2\u0026thinsp;+\u0026thinsp;and the quantitative results were around 0.5 g/day. Then BEV was discontinued due to development and progression of renal dysfunction, and ORB was started. However, as exacerbation of renal function was noted, we suspected the involvement of ORB and performed a renal biopsy.\u003c/p\u003e \u003cp\u003eORB is a PARP inhibitor and it blocks the enzyme involved in repair of both single- and double-strand breaks in DNA[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. PARP binds to DNA at sites of single-strand breaks. The activated PARP promotes DNA repair by inducing poly-ADP ribosylation of proteins involved in DNA repair by chain addition polymerization of ADP-ribose residues using oxidative nicotinamide adenine nucleotide (NAD\u003csup\u003e+\u003c/sup\u003e) as a substrate. However, excessive activation of PARP can deplete NAD\u003csup\u003e+\u003c/sup\u003e and ATP and induces the release of apoptosis-inducing factors (AIF) from mitochondria. The AIF released to the cytoplasm together with endonuclease G from mitochondria translocate to the nucleus, resulting in segmentation of the nucleus and cell death.\u003c/p\u003e \u003cp\u003eWhen DNA single-strand break repair is blocked by PARP inhibitors, cell death does not usually occur in normal cells because DNA breaks are usually repaired through homologous recombination repair. However, when cells with homologous recombination defects, such as BRCA mutations, are present, the defects in homologous recombination together with PARP inhibition leads to synthetic lethality. Thus, PARP inhibitors selectively act on cells with homologous recombination defects.\u003c/p\u003e \u003cp\u003eApproximately 50% of patients with ovarian cancers have abnormalities in genes involved in homologous recombination repair, such as BRCA genes. In addition, platinum anticancer drugs exert their cytotoxic effect by increasing DNA double-strand breaks through generation of interstrand DNA crosslinks. It is therefore expected that patients with recurrent ovarian cancers who responded to postoperative chemotherapy with platinum drugs have a deficiency in homologous recombination repair, for whom PARP inhibitors can induce synthetic lethality and exert antitumor effects.\u003c/p\u003e \u003cp\u003eSerious adverse reactions of ORB include bone marrow suppression, such as anemia, neutropenia, leukocytopenia, and thrombocytopenia, and interstitial lung disease. Other adverse reactions include skin symptoms and digestive symptoms; however, renal dysfunction has not been reported as an adverse reaction to ORB. According to clinical trial data, hypercreatinemia was observed in 2 patients and elevated blood creatinine was observed in 21 patients. It is recognized that ORB is less likely to cause renal dysfunction, In fact, an animal experiment showed that a PARP inhibitor was protective against acute kidney injury[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, in the present case, the patient\u0026rsquo;s renal function deteriorated after treatment with ORB, and improved after discontinuation of the drug, and the same pattern was repeated. This clinical course strongly suggested that ORB was related to the renal dysfunction. What could be the underlying mechanism for ORB to cause exacerbation of renal dysfunction? The suggested mechanism is that BEV-induced secondary TMA decreased the glomerular blood flow, resulting in transient tubular damage. Then ORB inhibited the repair mechanism and prevented the recovery from tubular damage, resulting in protracted renal dysfunction.\u003c/p\u003e \u003cp\u003eTo our knowledge, this is the first report of renal dysfunction associated with ORB. The use of ORB after developing BEV-induced TMA was considered to be the cause of the drug-induced renal dysfunction. Given that ORB can be used in the treatment of intractable cancers, clinicians should be aware of the risk of developing renal dysfunction.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe described a patient with recurrent ovarian cancer who developed protracted renal dysfunction after discontinuation of BEV and administration of ORB. The ORB is known as a drug with almost no renal impairment, but physicians should be careful that renal impairment may occur due to the relationship with other drugs such as BEV.\u003c/p\u003e \u003cp\u003ePostscript:\u003c/p\u003e \u003cp\u003eThe abstract of this paper was presented at the 50th Annual Meeting of the Japanese Society of Nephrology (Western Meeting). At that time, this paper was awarded the Excellent Presentation Award.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge the patient and the patient\u0026rsquo;s family for allowing the case to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: Not applicable. (No funding)\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThe authors have declared no competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval/\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Ethical standards:\u0026nbsp;\u003c/strong\u003eThis article does not contain any studies with human participants or animals performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication/\u003c/strong\u003e\u003cstrong\u003eInformed consent:\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from the patients mentioned in this study. Informed consent is given in writing. Also, although this patient is dead, her husband has given her consent even after her death.\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003eThe data used to support the findings of this study are available from the corresponding author upon request. We will disclose all information except personally identifiable information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u0026nbsp;\u003c/strong\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u0026nbsp;\u003c/strong\u003eall authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. YY is the chief editor of this paper. YY, TM, SH and SH are the doctors who actually treated. TT performed a pathological analysis. SH is the corresponding author of this paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevasizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE. VEGF Inhibition and Renal Thrombotic Microangiopathy. N Engl J Med. 2008;358:1129\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStokes MB, Erazo MC, D\u0026rsquo;Agati VD. Glomerular disease related to anti-VEGF therapy. Kidney Int. 2008;74:1487\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStylianou K, Lioudaki E, Papadimitraki E, Kokologiannakis G, Kroustalakis N, Liotsi C, Giannakakis K, Georgoulias V, Daphnis E. Crescentic glomerulonephritis associated with vascular endothelial growth factor(VEGF) inhibitor and bisphosphonate administration. Nephrol Dial Transplant. 2011;26:1742\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE. VEGF inhibition and renal thrombotic micro- angiopathy. N Engl J Med. 2008;358:1129\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdvani A. Vascular endothelial growth factor and the kidney: something of the marvellous. Curr Opin Nephrol Hy-pertens. 2014;23:87\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOllero M, Sahali D. Inhibition of the VEGF signalling pathway and glomerular disorders. Nephrol Dial Transplant. 2015;30:1449\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOstendorf T, Vriese ASD, Floege J. Renal side effects of anti-VEGF therapy in man: a new test system. Nephrol Dial Transplant. 2007;22:2778\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23:1011\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGerber HP, Ferrara N. Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies. Cancer Res. 2005;65:671\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6:465\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu S, Kim C, Baer L, Zhu X. Bevacizumab increases risk for severe proteinuria in cancer patients. J Am Soc Nephrol. 2010;21:1381\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimamura Y, Maeda T, Takizawa H. Bevacizumab-induced thrombotic microangiopathy and nephrotic syndrome. Clin Exp Nephrol. 2019;23:142\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrocklebank V, Wood KM, Kavanagh D. Thrombotic Microangiopathy and the Kidney. Clin J Am Soc Nephrol. 2018;13:300\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSethi S, Fervenza FC. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin Nephrol. 2011;31:341\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerazella MA. Onco-nephrology: renal toxicities of chemotherapeutic agents. Clin J Am Soc Nephrol. 2012;7:1713\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHou WH, Chen SH, Yu X. Poly-ADP ribosylation in DNA damage response and cancer therapy. Mutat Res. 2019;780:82\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKapoor K, Singla E, Sahu B, Naura AS. PARP inhibitor, olaparib ameliorates acute lung and kidney injury upon intratracheal administration of LPS in mice. Mol Cell Biochem. 2015;400(1\u0026ndash;2):153\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKalmar-Nagy K, Degrell P, Szabo A, Sumegi K, Wittmann I, Gallyas F Jr, Sumegi B. PARP inhibition attenuates acute kidney allograft rejection by suppressing cell death pathways and activating PI-3K-Akt cascade. PLoS One. 2013; 3; 8(12).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu S, Liu J, Liu D, Wang XT, Yang RL. Inhibition of Poly-(ADP-Ribose) Polymerase Protects the Kidney in a Canine Model of Endotoxic Shock. Nephron. 2015;130:281\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\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":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Olaparib, Bevacizumab, membranoproliferative glomerulonephritis, thrombotic microangiopathy, poly ADP-ribose polymerase (PARP) inhibitor","lastPublishedDoi":"10.21203/rs.3.rs-1680826/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1680826/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMany anticancer drugs have been reported to damage the kidneys. Olaparib (ORB) is known not to largely affect renal function due to its specific pharmacological mechanism, and there are no reports on renal dysfunction associated with the drug. The patient was found to have diagnosed with recurrent ovarian cancer. She started therapy with Bevacizumab (BEV). Unfortunately, BEV was discontinued due to development of progressive renal dysfunction with proteinuria. Therefore, she started administration of ORB. However, after switching to ORB, her renal dysfunction progressed. Renal histopathology revealed membranoproliferative glomerulonephritis (MPGN) and thrombotic microangiopathy (TMA). During the clinical course, her renal function deteriorated after administration of ORB and improved after the drug was discontinued because of bone marrow suppression. Moreover, sustained improvement of renal function was observed after complete discontinuation of the drug. This case is considered to be the first report of renal dysfunction due to ORB. Although ORB is not considered to cause renal damage when administered alone, it can be considered to further exacerbate the preceding BEV-induced renal dysfunction. Since switching of anticancer drugs is common, clinicians should be aware of the risk of developing renal dysfunction.\u003c/p\u003e","manuscriptTitle":"A case of recurrent ovarian cancer with renal dysfunction associated with the use of olaparib","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-08-22 17:00:43","doi":"10.21203/rs.3.rs-1680826/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2022-11-02T03:32:51+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2022-09-12T09:52:52+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-08-18T09:17:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-07-26T04:33:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"SN Comprehensive Clinical Medicine","date":"2022-07-18T08:40:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"sn-comprehensive-clinical-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sncm","sideBox":"Learn more about [SN Comprehensive Clinical Medicine](https://www.springer.com/journal/42399)","snPcode":"42399","submissionUrl":"https://submission.nature.com/new-submission/42399/3","title":"SN Comprehensive Clinical Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"307cc5e2-3e61-46d0-b423-cdb9eb2a0c5e","owner":[],"postedDate":"August 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T18:26:59+00:00","versionOfRecord":{"articleIdentity":"rs-1680826","link":"https://doi.org/10.1007/s42399-023-01390-7","journal":{"identity":"sn-comprehensive-clinical-medicine","isVorOnly":false,"title":"SN Comprehensive Clinical Medicine"},"publishedOn":"2023-01-13 18:16:58","publishedOnDateReadable":"January 13th, 2023"},"versionCreatedAt":"2022-08-22 17:00:43","video":"","vorDoi":"10.1007/s42399-023-01390-7","vorDoiUrl":"https://doi.org/10.1007/s42399-023-01390-7","workflowStages":[]},"version":"v1","identity":"rs-1680826","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1680826","identity":"rs-1680826","version":["v1"]},"buildId":"CiT4i_kKBbxQbnFL0ufpk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}