SUBMITTED 7 NOV 22 1 REVISIONS REQ. 20 DEC 22; REVISIONS RECD. 8 JAN 23 2 ACCEPTED 5 FEB 23 3 ONLINE-FIRST: FEBRUARY 2023 4 DOI: https://doi.org/10.18295/squmj.1.2023.013 5 6 Successful Treatment of a Case of Crescentic Glomerulonephritis in a patient 7 with Primary Peritoneal Carcinoma 8 A case report 9 *Aref Zribi,1 Amro Nagy,2 Marwa Al Riyami,3 Ikram A Burney1 10 11 1Women Health Program and 2Department of Medicine, Sultan Qaboos Comprehensive Cancer 12 Care and Research Centre, Muscat, Oman; 3Department of Pathology, Sultan Qaboos University 13 Hospital, Muscat, Oman. 14 *Corresponding Author’s e-mail: arefdoc@gmail.com 15 16 Abstract 17 Crescentic glomerulonephritis (CGN) has been associated with several solid tumor malignancies. 18 Only a few cases of nephropathy have been reported in association with tubo-ovarian/peritoneal 19 malignancies. We describe a case of 55 years old female who developed combined immune 20 complex-mediated glomerulonephritis and pauci-immune necrotizing crescentic vasculitis 21 simultaneously with the diagnosis of tubo-ovarian/peritoneal cancer. The baseline estimated 22 glomerular filtration rate (eGFR) was 13 ml/min. The patient received two doses of Rituximab and 23 three doses of pulse corticosteroids, leading to significant improvement in renal function and the 24 disappearance of her proteinuria. The eGFR improved to >60ml/min, and her proteinuria gradually 25 resolved after 10 weeks of treatment. She was in a position to be given a combination 26 chemotherapy treatment for tubo-ovarian/peritoneal cancer because of normalization of her CA-27 125 after three months of therapy. 28 Keywords: tubo-ovarian/peritoneal cancer, Glomerulonephritis, Vasculitis, Chemotherapy. 29 30 Introduction 31 Glomerulopathy in the field of cancer was first described in 1922.1 Glomerulonephritis has been 32 reported in patients with solid tumors, and only a few cases have been reported in patients with 33 tubo-ovarian/peritoneal cancer.2 The most common form of secondary glomerulonephritis is 34 membranous nephropathy (MN), which is most commonly presented as nephrotic syndrome. The 35 prevalence of malignancy with MN ranges from 1% to 22%.3 The glomerular lesions are 36 considered paraneoplastic; however, the exact pathogenesis remains unclear in most cases. Renal 37 impairment is a limiting factor in the prescription of chemotherapy, especially nephrotoxic agents, 38 and thus can compromise the survival of patients. Herein, we describe the case of a woman 39 diagnosed with metastatic tubo-ovarian/peritoneal cancer and severe acute kidney injury due to 40 crescentic glomerulonephritis. 41 42 Case report 43 A 55-year-old woman was hospitalised for epigastric pain, weight loss, abdominal distension and 44 poor oral intake. She had a past medical history of hypertension (treated with amlodipine) and 45 hypothyroidism (treated with levothyroxine replacement). Ten years prior to the current 46 presentation, the patient complained of abdominal pain and distention with abdominal mass in the 47 imaging; she had undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy 48 surgery. The postoperative histopathology report was consistent with serous cystadenoma with 49 borderline malignancy. The postoperative CA-125 was carefully followed up for one year after the 50 surgery, but the patient stopped her follow-up. During the current presentation, PETCT was done, 51 and the patient was found to have supraclavicular, mediastinal, paraaortic, iliac and inguinal lymph 52 nodes with moderate pleural effusion and ascites. She underwent a cervical lymph node biopsy 53 which was consistent with a new diagnosis of metastatic high-grade serous tubo-ovarian/peritoneal 54 carcinoma: CK7: Positive (strong & diffuse), CA-125: Positive (strong and diffuse), WT1: 55 Positive, P16: Positive (Strong and diffuse.) ER: Positive (Strong and diffuse) PR: Negative. Her 56 CA-125 was 1056 KIU/L (normal 0-35 KIU/L). During her hospitalization, she was found to have 57 acute kidney injury (AKI), as she was found to have a serum creatinine of 217 umol/L (normal 45-58 84 umol/L) on presentation, and the serum urea was 10.9 mmol/L (normal 2.8-8.1 mmol/L). Her 59 electrolytes were normal. The urine dipstick showed blood 3+, protein 1+, and positive leucocytes. 60 Urine microscopy showed no casts or crystals. The urine culture showed significant growth of 61 extended-spectrum beta-lactamase-producing Escherichia Coli with (>100.000 CFU). She was 62 commenced on intravenous Piperacillin/Tazobactam antibiotic. However, she did not complete the 63 course of antibiotics as she only had mild symptoms, her inflammatory markers were not raised, 64 and the urine sample was taken. In contrast, the patient had a urinary catheter, but the renal 65 functions declined slowly. She also was found to have nephrotic range proteinuria with a urine 66 protein to creatinine ratio (UPCR) of 436 mg/mmol (normal less 15 mg/mmol) and urine albumin 67 to creatinine ratio (UACR) of 312 mg/mmol (normal 0-3.5 mg/mmol). Serum creatinine increased 68 to 257 umol/L despite hydration and appropriate urinary tract infection treatment. In light of her 69 metastatic disease, AKI, and heavy proteinuria, a thorough workup was performed to seek possible 70 additional causes of the AKI. She had normal complements, negative hepatitis B and C serology, 71 and negative HIV serology. The serum protein electrophoresis and urine protein electrophoresis 72 showed no abnormal serum protein bands or free light chains in the urine, respectively. The ANA 73 was positive (titer 1:320) but negative anti-dsDNA antibody. All extractable nuclear antigens 74 profile was negative. She had positive IgG antibodies for Cytomegalovirus and Epstein-Barr virus 75 but negative IgM for both viruses. The CMV, adenovirus, and EBV tested negative on a 76 polymerase chain reaction. Regarding her anti-neutrophil cytoplasmic antibodies (ANCA), the 77 cytoplasmic and perinuclear forms were both positive, the anti-proteinase 3 (PR3) was expected, 78 but MPO was borderline positive (titer was 24 U/ml, normal from 0.00 – 20.00 U/ml). A clinical 79 diagnosis of rapidly progressive glomerulonephritis was made, and a kidney biopsy was 80 performed. The light microscopy report was consistent with crescentic glomerulonephritis (GN) 81 with positive staining for IgG, IgA, C3, and C1q. Later, further histopathologic examination of the 82 kidney tissue by electron microscopy revealed features consistent with immune complex-related 83 GN with mesangial and subendothelial deposits electron microscope (EM) with extensive 84 effacement of podocyte foot processes. The patient received a diagnosis of AKI secondary to 85 crescentic GN, likely due to pauci-immune GN with concomitant immune complex-mediated GN. 86 She received pulse intravenous (IV) methylprednisolone 500mg daily for three days with 87 appropriate calcium and vitamin D supplementations, then started on oral prednisone 30mg daily 88 with a gradual taper over 8 weeks and was finally maintained on prednisone 5mg daily. 89 Additionally, she received IV Rituximab 1gm once weekly for 2 weeks. Rituximab infusions were 90 without any Anaphylaxis and infusion-related reactions. Two months later, the UPCR was 43 91 mg/mmol, and UACR was 27.6 mg/mmol. Serum creatinine decreased to 98 umol/L, and her 92 eGFR was 50ml/min. The remission of her proteinuria and significant improvement in her renal 93 functions allowed for complete dose chemotherapy to be administered. She continued to show 94 significant improvement in her renal functions (serum creatinine was 78 umol/L, eGFR: 95 66.5ml/min) and had a good response to chemotherapy (CA-125: 30.2 KIU/L). Verbal and written 96 consent for publication purposes was taken from the patient. 97 Discussion 98 Historically, solid tumor malignancies, most commonly associated with nephropathy are 99 pulmonary and gastric carcinomas.3 Membranoproliferative (MPGN) injury pattern has been 100 described in association with solid tumors of the lung, kidney and stomach. Melanoma, breast 101 carcinoma, and thymoma have also been rarely reported in association with MPGN”3. Crescentic 102 glomerulonephritis (CGN) has been associated with several solid tumor malignancies.3 Only a 103 few cases of nephropathy have been reported in association with tubo-ovarian/peritoneal 104 malignancies.3 Nephropathy seems to occur irrespective of the tubo-ovarian/peritoneal tumor 105 diagnosis, either during a relapse, two years after the first diagnosis or simultaneously. The 106 underlying glomerular lesions are reported to be membranous nephropathy, MPGN, AA 107 amyloidosis, minimal change nephropathy, and mesangial-proliferative glomerulonephritis.4 In 108 the case of nephropathy associated with tubo-ovarian/peritoneal tumors, the treatment includes the 109 administration of corticosteroids, surgery and chemotherapy.5 Our patient was not fit for initial 110 debulking surgery as the disease was metastatic. Corticosteroids and rituximab were prescribed, 111 resulting in complete nephropathy remission. Chemotherapy paclitaxel and carboplatin could be 112 prescribed one month after her cancer diagnosis. The pathogenesis of secondary nephropathy has 113 not been clearly defined, but a cell-mediated immune response has been postulated; the secretion 114 of a tumoral factor and/or the appropriate production of lymphokines by T-cells to suppress tumor 115 growth could increase glomerular permeability.6 Clinically, it is difficult to differentiate primary 116 MPGN from secondary MPGN associated with solid tumors. Lefaucheur et al. 7 reported two risk 117 factors differentiating paraneoplastic MPGN from primary MPGN. These include an age of over 118 65 years and a history of smoking 20 pack-years. Our patient was a no-smoker.Beck et al. 8 119 identified circulating autoantibodies in most cases of adult primary MPGN. These autoantibodies 120 were not found in cases of secondary MPGN.4 .7 Lefaucheur et al. reported an increased number 121 of inflammatory cells (more than eight cells per glomeruli) on the kidney biopsy of patients with 122 paraneoplastic MPGN as compared to patients with primary MPGN. In our case, biopsy showed 123 mixed inflammatory cell infiltrate consisting mainly of lymphocytes and a few neutrophils, which 124 is consistent with the paraneoplastic origin of glomerulonephritis. Beck et al. 8 explain the possible 125 mechanisms, whereby solid tumors may be associated with MPGN. These include: (a) in-situ 126 immune-complex formation in which antibodies are formed against a tumor antigen that is 127 localized in the subepithelial location or to podocyte antigen that is identical or similar to the tumor 128 antigen, (b) tumor antigens may form circulating immune complexes that are subsequently trapped 129 in glomerular capillaries, and (c) external factors such as infections with oncogenic viruses or 130 altered immune function that can cause both the malignancy and MPGN. 131 132 The degree of proteinuria varies among patients with myeloperoxidase (MPO) vasculitis but is 133 usually subnephrotic. 9. 10 Proteinuria of 1g per day or less in patients with ANCA-associated 134 vasculitis (AAV) is most likely the consequence of fibrosed glomeruli or tubular fibrosis in an 135 individual who may or may not be in remission. Higher amounts of proteinuria, including 136 proteinuria of more than 3g/day, may be more common in patients who present later in the course 137 of the disease and who have had previous necrotizing glomerulonephritis.11 In our patient, 138 although the biopsy had a limited number of glomeruli, all glomeruli were intact and showed a 139 mild increase in the mesangial matrix. All glomeruli showed cellular crescents with segmental 140 fibrinoid necrosis in the tuft. There were no signs of endocapillary hypercellularity or thrombosis 141 on light microscopy. Capillary walls showed normal thickness with no spikes or double contours. 142 There was no tubular atrophy or interstitial fibrosis. Further examination by EM revealed 143 numerous small subendothelial deposits in the basement membrane with extensive effacement of 144 podocyte foot processes with mesangial expansion and mesangial deposits. In some patients with 145 AAV with high amounts of proteinuria, there may be a second concurrent glomerular disease or 146 an atypical histologic pattern like a glomerular immune-complex deposition.12.13 The nephrotic 147 range proteinuria was most likely due to the extensive foot processes effacement found on 148 histopathologic analysis of the renal biopsy. 149 150 Conclusion 151 We describe the case of a patient diagnosed with tubo-ovarian/peritoneal cancer and associated 152 with glomerulonephritis and vasculitis. Clinical history, physical examination, laboratory data, and 153 kidney biopsy revealed the correct diagnosis. Corticosteroids combined with Rituximab resulted 154 in an improvement in renal functions, and the patient was able to receive a combination of 155 chemotherapy paclitaxel and carboplatin for tubo-ovarian/peritoneal cancer. The treatment of 156 paraneoplastic glomerulonephritis requires a multidisciplinary approach to monitor both cancer 157 and glomerular lesions. 158 159 Authors’ Contribution 160 AZ, AN and IAB managed the case. MR provided the details of histopathology. AZ, AN and MR 161 drafted the manuscript. IAB critically reviewed the manuscript. All authors approved the final 162 version of the manuscript. 163 164 Acknowledgements 165 We would like to thank Dr Mohammad Athar Khan for kindly reviewing the manuscript, and 166 giving useful suggestions to improve its quality. 167 168 References 169 1. Galloway J. Remarks on Hodgkin's disease. Br Med J. 1922 Dec 23; 2(3234): 1201-1204 170 2. Meyrier A, Delahousse M, Callard P, Rainfray M. Minimal change nephrotic syndrome 171 revealing solid tumors. Nephron. 1992; 61(2):220-223. 172 3. Bacchetta J, Juillard L, Cochat P et al. Paraneoplastic glomerular diseases and 173 malignancies. Crit Rev Oncol Hematol. 2009; 70: 39–58. 174 4. 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Nephrol Dial Transplant. 2003 Mar;18(3):524-31. 200 201 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/abstract/13,19 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/abstract/13,19 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/abstract/13,19 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/contributors https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/contributors https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-clinical-manifestations-and-diagnosis/contributors 202 Figure1: A: shows two glomeruli, one with fibrinoid necrosis (arrow) and the other with a cellular 203 crescent (H&E stain). B: higher magnification of a glomerulus with a cellular crescent (Jones 204 stain). C and D: Electron micrograph highlighting mesangial and subendothelial deposits, 205 respectively (arrows). There is also extensive foot process effacement of podocytes. 206 Magnifications: Image A: 200X, Image B: 400X, Image C: 12,000X, Image D: 10,000X. 207