A Case of Recurrent Ovarian Cancer with Renal Dysfunction Associated with the Use of Olaparib

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 been diagnosed with recurrent ovarian cancer. She started therapy with bevacizumab (BEV). Unfortunately, BEV was discontinued due to the development of progressive renal dysfunction with proteinuria. Therefore, she started the 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 the 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. In the recent PAOLA-1 trial, the efficacy and toxicity profiles of the combination of BEV and ORB were superior to those of BEV alone. The combination of BEV and ORB is now the first-line treatment for ovarian cancer based on this result. In the present case, ORB was administered to a patient with BEV-induced renal dysfunction, resulting in further aggravation of the renal dysfunction. Here we report this case because of the adverse reaction that should be noted when ORB and BEV are used in combination therapy, which is expected to be more popular, based on the PAOLA-1 trial results.


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 [1,2]. 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 [3][4][5] 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 [6].
We treated a patient with recurrent ovarian cancer who discontinued BEV due to the 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 60 s. Chief complaint: Renal dysfunction. Past history: Not remarkable. Family history: There was no family history of renal diseases.
Lifestyle 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 tomographycomputed 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. As shown in Fig. 1, BEV was administered a total of 9 times. In July X-1, the administration of BEV was started. After the third dose of 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 Tubulointerstitium showed no major abnormalities. Immunofluorescent staining showed only diffuse non-specific deposition of fibrinogen in the glomeruli, but no deposition of immune complexes 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 were 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 1. 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. Seventeen glomeruli were obtained, and most of them showed intense mesangial proliferation, increased matrix, thickening of the glomerular tufts, and segmental lobulation, consistent with the findings of MPGN; moreover, endocapillary hypercellularity, mesangiolysis, subendothelial edema, and glomerular capillary duplication were shown. 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 the 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 the proliferation of vascular endothelial cells, controlling their survival, enhancing the permeability, and inducing the production of active substances from the endothelial cells. BEV exerts an antitumor effect by binding to and neutralizing VEGF and inhibiting angiogenesis, proliferation, and  [7][8][9]. 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 [10]. The incidence of proteinuria increases in a dosedependent manner, and there are several reported cases of nephrotic syndrome and renal dysfunction [11]. 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 [6]. In addition, since VEGF plays a role in maintaining the morphology and function of vascular endothelial cells, the disruption of the VEGF pathway may cause damage to glomerular endothelial cells [12]. 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 [1,11,13]. The incidence and mechanism of TMA have not been elucidated [14].
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 and 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 g l o m e r u l o n e p h r i t i s ( M P G N ) -l i k e f i n d i n g s . 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 [1,15]. 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 [16]. However, there are reported cases of persistent proteinuria resulting in end-stage renal failure or death even after discontinuation of the drug [1,17]. Therefore, the criteria for discontinuation of BEV have 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 the development and progression of renal dysfunction, and ORB was Fig. 2 Clinical course: Renal function exacerbated by administration of ORB and recovered after drug withdrawal 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 the repair of both single-and double-strand breaks in DNA [18]. PARP binds to DNA at sites of singlestrand 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 lead 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 the 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].
Therefore, the PAOLA-1 trial, a large study comparing ORB and BEV combination therapy with ORB alone, was then conducted, and the results were published [22]. The results revealed that the combination group had a significantly lower incidence of proteinuria and hypertension.
At first, the case herein reported appears to contradict the PAOLA-1 results.
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? In the PAOLA-1 trial, ORB was administered first, followed by BEV. As a reminder, in our case, ORB was administered after BEV. Moreover, ORB was administered after BEV-induced renal dysfunction occurred. 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. If the renal damage in the present case had been confined to the vascular endothelium, it might have been thought that ORB acted to protect the endothelium; however, it had deteriorated to the stage of MPGN lesions with intense mesangial proliferation. This may also have influenced the outcomes.
The PAOLA-1 trial also demonstrated that proteinuria can occur with prior administration of ORB, although in a very small number of patients. Although ORB is essentially a renoprotective and vascular endothelial protective agent, caution should still be exercised against 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.