Late effect of chemotherapy for osteosarcoma on kidney function

Takuji Enya; Tomoki Miyazawa; Kohei Miyazaki; Naoki Sakata; Keisuke Sugimoto

doi:10.4103/AJPN.AJPN_29_20

BRIEF REPORT

Year : 2021 | Volume : 4 | Issue : 1 | Page : 30-32

Late effect of chemotherapy for osteosarcoma on kidney function

Takuji Enya, Tomoki Miyazawa, Kohei Miyazaki, Naoki Sakata, Keisuke Sugimoto
Department of Pediatrics, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan

Date of Submission	08-Oct-2020
Date of Decision	27-Nov-2020
Date of Acceptance	29-Jan-2021
Date of Web Publication	30-Jun-2021

Correspondence Address:
Takuji Enya
Department of Pediatrics, Faculty of Medicine, Kindai University, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511
Japan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_29_20

Abstract

With improvement in the outcomes of chemotherapy, the management of late effects of chemotherapy is an increasingly important concern in patients with osteosarcoma. However, the risk factors for late effects on kidney function are not clear. We report seven cases of osteosarcoma, including three patients with severe or recurrent drug-induced acute kidney injury, who were diagnosed with tubulointerstitial nephritis after the treatment of osteosarcoma. Although late renal effects are considered to be dose-dependent, they are not invariable with the same protocol. The severity and frequency of acute kidney injury following chemotherapy might have influenced the occurrence of renal late effects.

Keywords: Chemotherapy, chronic kidney disease, osteosarcoma, renal late effects, tubulointerstitial nephritis

How to cite this article:
Enya T, Miyazawa T, Miyazaki K, Sakata N, Sugimoto K. Late effect of chemotherapy for osteosarcoma on kidney function. Asian J Pediatr Nephrol 2021;4:30-2

How to cite this URL:
Enya T, Miyazawa T, Miyazaki K, Sakata N, Sugimoto K. Late effect of chemotherapy for osteosarcoma on kidney function. Asian J Pediatr Nephrol [serial online] 2021 [cited 2021 Dec 2];4:30-2. Available from: https://www.ajpn-online.org/text.asp?2021/4/1/30/320183

Introduction

Tubulointerstitial nephritis (TIN) is proposed as the pathophysiological mechanism of nephrotoxic acute kidney injury (AKI) following chemotherapy. Chemotherapy-induced TIN is a major cause of AKI that may progress to chronic kidney disease (CKD) in a few patients.^[1],[2] Here, we report three cases wherein the severity and frequency of AKI during chemotherapy might have contributed to the development of renal late effects.

Cases

[Table 1] indicates the clinical features of seven cases diagnosed with osteosarcoma during April 2006 to March 2017 at a single center. Three patients developed renal late effects following chemotherapy for osteosarcoma; renal dysfunction or abnormal urinalysis were not present at admission. All cases received the neoadjuvant chemotherapy for osteosarcoma 95J (NECO 95J) protocol [Supplementary Material 1]; this multimodal therapy plan included pre-and postoperative chemotherapy using methotrexate, cisplatin, adriamycin, and ifosfamide. Ifosfamide was administered to Cases 1 and 5 who had poor therapeutic response.

Table 1: Clinical characteristics of seven patients followed after chemotherapy for osteosarcoma

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Case 1, a 16-year-old boy, was diagnosed with left femoral osteosarcoma (Enneking classification stage 2A; high grade) at the age of 14 years. He received chemotherapy in accordance with NECO 95J, including high-dose ifosfamide postoperatively. He then developed stage 2 AKI (Kidney Disease Improving Global Outcomes staging), which recovered following exclusion of ifosfamide from the chemotherapy regimen. However, he repeatedly developed stage 1 AKI after therapy with cisplatin. While renal function was normal at discharge, serum creatinine rose to 1.24 mg/dL 9 months after completion of chemotherapy. Histological findings on light microscopy of kidney biopsy included focal global sclerosis, mild mesangial proliferation, marked mononuclear cell infiltration, tubulointerstitial fibrosis and tubular atrophy [Figure 1]a and [Figure 1]b. Immunofluorescence showed no deposits of immunoglobulin or complement; electron microscopy did not show any electron dense deposits in the mesangium or basement membrane, but epithelial cell damage was observed along with cytoplasmic vacuolization in proximal tubules and rough internal structure of the tubular basement membrane [Figure 1]c and [Figure 1]d. Therapy with angiotensin-converting enzyme inhibitor (ACE-I) was initiated and continued with cautious monitoring of renal function and serum electrolytes.

Figure 1: Histology in kidney biopsy specimens of three patients. Light microscopy specimen from patient 1 shows (a) marked mononuclear cell infiltration, interstitial fibrosis, and tubular atrophy and (b) sclerosis in a few glomeruli. On electron microscopy, (c) epithelial cell injury and (d) vacuolization of mitochondria were observed. (e and f) Findings on light microscopy in patient 2 included interstitial fibrosis and tubular atrophy; without any glomerular pathology. (g) Electron microscopy showed renal tubular injury in patient 3

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Case 2 was an 18-year-old boy who was diagnosed with right tibial osteosarcoma at the age of 15 years. Therapy with cisplatin was associated with AKI twice during chemotherapy. Kidney biopsy demonstrated tubulointerstitial fibrosis accompanied by mild tubular atrophy and altered tubular epithelial cell morphology [Figure 1]e and [Figure 1]f. Serum creatinine remained elevated at 1.05 mg/dL, 5 months after completion of chemotherapy. Therapy with ACE-I was initiated cautiously.

Case 3 was a 10-year-old boy with localized osteosarcoma of the left humerus. He developed stage 3 AKI transiently after therapy with methotrexate. The levels of urinary β2-microglobulin were persistently elevated 3 months after the completion of chemotherapy; serum level of creatinine was normal until after therapy with ACE-I. Kidney biopsy revealed interstitial infiltration of mononuclear cells, tubular atrophy, and mild tubulointerstitial fibrosis; electron microscopy indicated renal tubular cell damage [Figure 1]g. Cases 4 and 5 experienced one episode each of stage 1 AKI, but did not develop late renal effects of chemotherapy.

Discussion

Following improved long-term survival after the treatment of pediatric malignancies, the management of late effects of chemotherapy is an increasingly important concern. Patients undergoing chemotherapy for pediatric malignancies are at risk of renal late effects which has varied manifestations that are attributed to chemotherapy and diverse sets of risk factors.^[3] While the prognosis of osteosarcoma has improved considerably since the use of the NECO-95J protocol,^[4] dosage reduction and prolonged administration intervals in response to drug-induced nephrotoxicity attributed to cisplatin, ifosfamide, or methotrexate, might impact outcomes adversely. Megalin, an endocytic receptor expressed on the apical membranes of proximal tubules, mediates intracellular signal transduction and the reabsorption of various molecules.^[5],[6] Megalin also mediates the proximal tubular uptake of nephrotoxic drugs such as cisplatin, which accumulates therein to cause irreversible proximal tubular epithelial cell injury.

Drugs and infections are the chief causes of TIN.^[7],[8] Drug-induced TIN accounts for 70% of cases,^[9] presenting chiefly as AKI. While previously considered transient and innocuous, AKI is now recognized to often progress to CKD.^[1],[2] In one series, almost 60% of pediatric patients with TIN developed CKD.^[2] It is likely that patients in the present series of patients with osteosarcoma had the progression of renal dysfunction as a late renal effect of chemotherapy, as we could not identify any other triggers of AKI, such as surgery, infection or other nephrotoxic drug administration. Conversely, renal late effects might have followed severe or repetitive AKI in the present patients. Our patients showed diverse features of nephron injury, ranging from tubulointerstitial fibrosis, to proximal tubule injury and glomerular sclerosis. Repetitive proximal tubular and capillary vessel injury by various chemotherapy drugs might lead to their delayed excretion and/or excessive elevated blood levels. Inflammation in the tubulointerstitium causes renal tubular atrophy and increased production of extracellular matrix. The severity and frequency of proximal tubular injury is relevant to progression to CKD, as the former promotes the transformation of fibroblasts leading to fibrosis, glomerular sclerosis, and distal tubule injury in genetically modified animal models.^[10]

Hydration is used to prevent drug-induced nephrotoxicity by chemotherapy, but might have modest preventive efficacy. Early diagnosis and appropriate treatment are important to prevent irreversible renal dysfunction. The first two patients in this series showed progression of renal dysfunction after administering of ACE-I. Patients on chemotherapy should be jointly supervised by oncologists and nephrologists, with the latter providing guidance on measures to prevent AKI, adjust drug doses, and monitor for renal late effects. Careful observation for renal late effects is essential in patients with severe or repetitive drug-induced nephropathy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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