Chronic myeloid leukemia (CML) occurring in children is a malignant blood disease that arises during the process of myeloid cells producing white blood cells. It accounts estimated to be less than 3% of all childhood leukemia cases [1]. While CML predominantly affects adults, when it occurs in children, it is categorized into childhood onset and adolescent onset forms. The disease typically manifests just before puberty. In the adult type, the Philadelphia chromosome gene plays a significant role. The BCR-ABL1 protein, a product of the Philadelphia chromosome, activates tyrosine kinases, which in turn activate multiple signaling pathways, leading to malignant transformation [2]. Consequently, the development of tyrosine kinase inhibitors (TKIs) has become a critical cornerstone in CML treatment. The 5-years relative survival rate for chronic myeloid leukemia, which was estimated to be 22% in the mid-1970s, has improved significantly after 2011, representing an improvement of over threefold and, most patients could achieve a near normal lifespan [1,3]. Specifically, in pediatric cases, we prescribe imatinib mesylate, a well-known BCR-ABL1 tyrosine kinase inhibitor, as a first-line therapy in CML patients. If patients experience relapse or resistance to imatinib mesylate, second-generation TKIs such as dasatinib [4] or nilotinib are used. Among these second-line drugs, dasatinib has been reported to have a higher likelihood of causing proteinuria compared to other TKIs [5]. However, because such cases are rare in children, it is uncommon to suspect them during the initial episode. Additionally, it becomes more challenging to consider dasatinib induced nephrotic syndrome when nephrotic syndrome occurs in patients previously treated for steroid dependent nephrotic syndrome. In this context, we report a case of relapsed nephrotic syndrome associated with dasatinib in pediatric patient who had achieved remission from idiopathic nephrotic syndrome but experienced proteinuria after taking dasatinib.

A 14-year-old boy presented at the outpatient clinic with nephrotic range proteinuria. This patient had experienced proteinuria since the age of 4 years. Initially diagnosed with childhood onset nephrotic syndrome, he received standard treatment with steroids. However, the patient relapsed every 3 to 4 months and was subsequently diagnosed with steroid dependent nephrotic syndrome. The patient initially received cyclophospha-mide as an alternative immunosuppressive therapy for steroid dependent nephrotic syndrome. After experiencing remission of one year while on cyclosporine, there was another relapse three months later. Due to frequent recurrences, combination treatment with rituximab and steroids was started, and fortunately, the patient was in successful remission within 2 weeks of treatment. The patient was subsequently followed up through outpatient care. The platelet count in the patient’s complete blood count performed at the time of remission was 667,000/mL, but thrombocytosis worsened to 985,000/mL 2 months later. At this time, other values were normal, including hemoglobin 14.5 g/dL and white blood cell count 9,570/mL How-ever, in the complete blood count performed 1 month later, hemoglobin 13.5 g/dL, white blood cell count 25,110/mL, and platelet count 1,371,000/mL. As thrombocytosis continued without improvement and leukocytosis was also accompanied, a bone marrow examination was performed. As a result, BCR-ABL1 rearrangement was observed in 95% of cells, leading to a diagnosis of chronic myelogenous leukemia (CML). The patient was referred to a pediatric hematology specialist and initiated treatment with imatinib mesylate, a first-generation tyrosine kinase inhibitor (TKI), for CML. The patient had a good response to CML while being treated with imatinib mesylate, but two years after starting the drug, he developed severe side effects such as leg pain and gastrointestinal disor-ders. The drug was then changed to dasatinib, a second-generation TKI, and the side effects, including leg pain were resolved thereafter. Four months after starting dasatinib treatment, the patient developed proteinuria, leading to a visit to the pediatric nephrology outpatient clinic for assessment and management. The urine protein/creatinine ratio before dasatinib treatment was 0.12 g/g, but when proteinuria was confirmed after treatment, it was 7.5 g/g. Prior to taking dasatinib, the patient had been on cyclosporine, a calcineurin inhibitor prescribed for idiopathic nephrotic syndrome, and had maintained good remission. However, despite this, the patient continued to experience persistent nephrotic range proteinuria, with no other signs of infection. Consequently, we strongly suspected a relapse of nephrotic syndrome. Ini-tially, the patient received oral steroids at a standard dose that previously alleviated symptoms. However, the symptoms worsened, characterized by increased proteinuria, edema, and hypoalbuminemia. As a result, the patient was admitted for re-evaluation and management of the nephrotic syndrome. The laboratory findings upon admission were as follows: hemoglobin 12.6 g/dL, white blood cell count 10,260/mL, platelet count 567,000/mL, C3/C4 levels 117/39.7 mg/dL, C-reactive protein (CRP) 0.22 mg/dL, blood creatinine 0.45 mg/dL (estimated glomerular filtration rate 139.7 mL/min/1.73 m²), total protein 6.0 g/dL, albumin 2.9 g/dL, total cholesterol 328 mg/dL, urinalysis blood 1+, protein 4+, urine red blood cells 1-3/HPF, urine protein/creatinine ratio 10.26 g/g. After admission, kidney ultrasound and kidney biopsy were performed to confirm and evaluate the cause of relapsed nephrotic syndrome. The kidney sonography revealed normal kidney size and normal parenchyma, and histologic examination confirmed minimal change disease (Fig. 1). Considering the patient’s prior diagnosis of CML following rituximab treatment, we planned high-dose steroid therapy [6]. Methylprednisolone at a dose of 1 g/day was administered every other day until the histological examination results became available. Despite administering methylprednisolone two times, proteinuria worsened, and other glomerular disease were unlikely based on histological and serological examination. So, rather than continuing treatment and waiting for progress, we first tried to stop taking drugs that could be causative to nephrotic syndrome. We stopped to taken dastinib consider of the possibility of a dasatinib-induced renal disease, rare. Upon discontinuing dasatinib, the patient’s proteinuria rapidly improved (Fig. 2). Following steroid pulse therapy and subsequent steroid reduction, the patient remained in remission. Imatinib mesylate which had previously elicited a favorable response for CML, was resumed at a lower dose with closed monitoring of adverse effect such as leg pain. Subsequently, the patient has been successfully maintaining remission for proteinuria while being monitored in the pediatric nephrology outpatient clinic, without medication for nephrotic syndrome, while taking low-dose imatinib mesylate for CML.

Figure 1. Kidney biopsy. (A) Glome-rulus had no cellular proliferation or capillary wall thickening are unremarkable on Toluidine blue staining (×200). (B) Electron mi-croscopy, most foot process showed effacement. Electron dense deposits are not present (×3,000).

Figure 2. Urine protein/creatinine ratio and serum albumin change. Steroid pulse was administered on days 6 times for 12 days after admission, and dasatinib was discontinued from day 4.

Most of pediatric CML cases, imatinib mesylate is commonly used as a first line therapy. However, for patients who experience relapsed or resistance to imatinib mesylate, second generation TKIs are used. Currently, second generation TKIs are also frequently used as first line treatments in adults. Notably, dasatinib has been associated with a higher risk of proteinuria compared to other TKIs [7]. The mechanism of kidney damage caused by dasatinib is not fully elucidated, but it has been associated with the vascular endothelial growth factor (VEGF). VEGF is a factor produced by kidney podocytes and plays a crucial role in the development and maintenance of normal glomerular function. Dasatinib disrupts the VEGF signaling pathway, leading to kidney damage and, consequently, proteinuria [7,8]. While some cases of dasatinb induced nephrotic syndrome have been reported in adults, pediatric cases are rare, making early suspicion less common.

The pediatric cases of dasatinib-induced nephrotic syndrome, including this case, total five cases reported [9-12]. These cases presented clinical characteristics in Table 1. In this case, a pediatric patient with idiopathic nephrotic syndrome concurrently developed CML. The situation was challenging because the patient was already at risk for nephrotic syndrome relapse, and it was difficult to immediately suspect dastinib induced nephrotic syndrome. Notably, the patient who had been diagnosed with idiopathic nephrotic syndrome during childhood and received first line steroid standard therapy. Subsequently, the experienced recurrent relapses and steroid dependence. As a second line treatment, the patient received cyclo-sporine. Later, after rituximab use, the patient was diagnosed with CML. Given the possibility of nephrotic syndrome relapsed due to the patient’s medical history, it was initially challenging suspect dasatinib induced nephrotic syndrome. However, since the patient exhibited progressive proteinuria unresponsive to standard steroid therapy, it was crucial to differentiate secondary causes of relapsed nephrotic syndrome. The highlights the need for further evaluation, including additional tests such as serum complement level, specific antibody for certain glomerular disease, markers of vasculitis, and especially kidney biopsy. Considering the potential coexistence of secondary causes of nephrotic syndrome in pediatric patients with a history of primary idiopathic nephrotic syndrome, kidney biopsy results play an important role in determining the therapeutic plan. Upon reviewing the previously reported pediatric cases [9,10], which included only two cases with histologic findings, it was observed that foot process effacement was consistently associated with dasatinib induced nephrotic syndrome including this case. However, in adult’s cases, diverse finding presented, such as focal global glomerulosclerosis, mild chronic tubulointerstitial changes, diffuse segmental corrugation or double contouring [13]. This discrepancy may be attributed to difference in the mechanisms of kidney damage between pediatric and adult populations or variations related to exposure to nephrotoxic medications. Though, given the limited nature of this pediatric case, generalizing the biopsy results is challenging. Further research will be necessary in the future. This case biopsy results confirmed minimal change disease, and the possibility of other secondary glomerular disease based on laboratory blood tests was low. Ultimately, considering dasatinib induced nephrotic syndrome, discontinuation of dasatinib fortunately led to an improvement in pro-teinuria. However, in some cases where CML is poorly controlled or treatment is initiated early, stopping the medication may not be feasible. Consequently, some adult patients have reported improvement in proteinuria after switching to the second generation TKI nilotinib [14].

Table 1 . Clinical characteristics of dasatinib induced nephrotic syndrome in pediatric patients.

Case	Age	Sex	Diagnostic disease	Previous TKI	Dasatinib duration	Urine PC ratio	Kidney biopsy	Prognosis
[9]	3	F	Ph+CML	Imatinib	17 months	17 g/g	Global sclerosis, segmental mesangial proliferation, focal foot processes effacement	Discontinued, prednisone, ACE inhibitor remission
[10]	5	M	Ph+ALL	Imatinib	26 days	15.24 g/g	Fusion of foot processes	Discontinued, remission
[11]	8	F	Ph+ALL	Imatinib	2 months	15.29 g/g	N/A	Continuation, intermittent proteinuria
[12]	14	M	Ph+pre B ALL	N/A	10 months	N/A	N/A	Dose reduction, recovery
Index	14	M	Ph+CML	Imatinib	4 months	11.7 g/g	Focal foot process effacement	Discontinued, prednisone, remission

TKI, tyrosin kinase inhibitor; PC, protein/creatinine; Ph+, philadelphia positive; CML, chronic myelogenous leukemia; ACE inhibitor, angiotensin converting enzyme inhibitor; ALL, acute lymphoblastic leukemia; N/A, not available; Pre B ALL, precusor B cell lymphoblastic leukemia..

In conclusion, this case serves as a valuable example, highlighting the need to consider dasatinib induced neph-rotic syndrome when proteinuria occurs in patients using dasatinib and monitoring proteinuria. Therefore, when starting dasatinib treatment, it is necessary to inquire about the patient’s kidney function and history of kidney-related diseases. Additionally, it underscores the importance of individualized treatment decisions, including medication discontinuation or switching to alternative drugs. Furthermore, this case emphasized the need to approach histological difference between dasatinib induced nephrotic syndrome in pediatric and adults’ patients.

The authors have no conflict of interest to declare.