Rev. Nefrol. Dial. Traspl.2026, 46(2):99-105
Casuística
Bosutinib and Membranous Nephropathy in
Chronic Myeloid Leukemia: Coincidence or Drug-Related İnjury?
Bosutınıb y Nefropatía Membranosa en Leucemıa
Mıeloıde Crónıca: ¿Coıncıdencıa o Lesıón Relacionada con el Fármaco?
1) Department of Pathology, Antalya Training and Research Hospital, Antalya,
Turkey
2) Department of Nephrology, Health Sciences University, Antalya Training and
Research Hospital, Antalya, Turkey
3) Department of Hematology, Antalya City Hospital, Antalya, Turkey
Fecha entregado: 5 de enero de 2026
Fecha corregido: 26 de febrero de 2026
Fecha aceptado: 29 de abril de 2026
Autor: Şenay Yıldırım
ORCID: 0000-0002-1457-7957
Mail: dr_senayyildirim@hotmail.com
RESUMEN
Los inhibidores de
tirosina quinasa (ITKs) han mejorado significativamente los resultados en la
leucemia mieloide crónica (LMC), aunque los efectos adversos renales son cada
vez más reconocidos. Se describe un varón de 32 años con LMC que desarrolló
proteinuria en rango nefrótico dos años después de iniciar tratamiento con
bosutinib. Los análisis mostraron creatinina sérica elevada, hipoalbuminemia y
proteinuria grave. La biopsia renal reveló nefropatía membranosa con
positividad granular gruesa para PLA2R e IgG4, acompañada de inflamación
intersticial compatible con nefritis túbulo-intersticial aguda. El bosutinib se
suspendió temporalmente y luego se reanudó bajo supervisión multidisciplinaria
estrecha, asociado a rituximab y tacrolimus. A los seis meses, la función renal
y la proteinuria mejoraron significativamente. Este caso cuestiona el impacto
del bosutinib en el daño glomerular y tubular en el riñón. El reconocimiento
temprano, la biopsia renal y el manejo multidisciplinario individualizado son
esenciales. En casos seleccionados, la continuación del ITK junto con terapia
inmunomoduladora adyuvante puede ser una estrategia factible.
ABSTRACT
Tyrosine kinase
inhibitors (TKIs) have significantly improved outcomes in chronic myeloid
leukemia (CML), but renal adverse effects are increasingly recognized. We
report a 32-year-old male with CML who developed nephrotic-range proteinuria two
years after starting bosutinib. Laboratory tests showed elevated serum
creatinine, hypoalbuminemia, and severe proteinuria. Renal biopsy revealed
membranous nephropathy with coarse granular PLA2R and IgG4 positivity,
accompanied by interstitial inflammation consistent with acute
tubulointerstitial nephritis. Bosutinib was temporarily discontinued and then
resumed under close multidisciplinary supervision, combined with rituximab and
tacrolimus. At six months, renal function and proteinuria had significantly
improved. This case questions the impact of bosutinib on glomerular and tubular
damage in the kidney. Early recognition, renal biopsy, and individualized
multidisciplinary management are crucial. In selected cases, continuing TKI
with adjunct immunomodulatory therapy may be a feasible strategy.
INTRODUCTION
Chronic myeloid
leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL
fusion gene resulting from the Philadelphia (Ph) chromosome translocation.
Although renal involvement in CML is rare, paraneoplastic glomerulopathies or
treatment-related nephrotoxicity can occur. Adverse drug reactions (ADRs)
affecting the kidneys due to tyrosine kinase inhibitors (TKIs) used in CML are
relatively uncommon, and no standardized management protocol currently exists
for these complications(1).
The introduction
of the first-generation TKI, imatinib, significantly improved prognosis and
overall survival in patients with CML. Subsequently, second-, third-, and
fourth-generation TKIs, including bosutinib, dasatinib, nilotinib, ponatinib,
and asciminib, further increased response rates and enabled individualized treatment
selection (2,3).
Less than 4% of bosutinib is recovered in the urine, with approximately 1%
excreted unchanged, indicating minimal renal clearance of the active drug and
increased risk of accumulation and nephrotoxicity in patients with impaired
renal function (4).
TKIs can induce a
range of glomerular diseases, including IgA nephropathy, minimal change disease
(MCD), focal segmental glomerulosclerosis (FSGS), thrombotic microangiopathy
(TMA), and membranous nephropathy (MN), as well as tubular/interstitial
injuries such as acute tubular necrosis (ATN) or acute tubulointerstitial
nephritis (TIN). MN is particularly rare in patients with CML and usually
manifests several years after diagnosis (1). Here, we present a
unique case of simultaneous MN and acute TIN in a patient with CML receiving
long-term bosutinib therapy, highlighting the diagnostic challenges and
therapeutic considerations.
CASE PRESENTATION
A 32-year-old male
patient diagnosed with CML was initially treated with imatinib 600 mg daily.
Following an insufficient response at 8 months, the regimen was switched to
bosutinib 400 mg daily. Two years into the bosutinib therapy, the patient was
referred to the nephrology clinic for newly onset proteinuria. Laboratory
evaluation revealed a serum creatinine level of 1.76 mg/dL, an estimated glomerular filtration rate (eGFR) of 50 mL/min/1.73 m²,
proteinuria of 14536 mg/g, albuminuria of 8377 mg/24h, and a serum albumin
level of 16.50 g/L. Urinalysis demonstrated 4+ proteinuria, with a spot urine
protein-to-creatinine ratio of 12716 mg/g and an albumin-to-creatinine ratio of
7848 mg/g, consistent with nephrotic-range proteinuria. The hemogram showed an
eosinophilia of 5.7%. Microscopic examination of the urine sediment for
eosinophils was not performed. The patient had no history of diabetes mellitus
or hypertension.
A percutaneous
renal core biopsy was performed. Light microscopy revealed diffuse thickening of
the glomerular basement membranes (GBM) in all glomeruli (Figure 1).
Crescent formation and glomerular necrosis were absent. Hematoxylin and Eosin
staining demonstrated diffuse GBM thickening (Figure 1A), Masson trichrome
staining revealed fine eosinophilic granular deposits (Figure 1B), and Jones
methenamine silver staining showed characteristic spike formations along the
GBM (Figure 1C). Congo red and crystal violet stains were negative for amyloid deposition.
Immunohistochemical staining for myeloperoxidase showed no evidence of tumor
cell infiltration in the interstitium. Further immunohistochemical analysis
demonstrated linear C4d positivity along the GBM (Figure 1D) and coarse granular
positivity for PLA2R (Figure
1E) and IgG4 (Figure 1F) along the GBM. DNAJB9
staining, used to differentiate from fibrillary glomerulonephritis, was negative.
The interstitium showed moderate inflammatory infiltration predominantly
composed of lymphocytes and polymorphonuclear leukocytes, with focal tubular
epithelial infiltration (Figure 2A-2B). Immunofluorescence could not
be evaluated due to the presence of only medullary tissue. Based on these
findings, the biopsy was reported as membranous nephropathy concomitant with
acute tubulointerstitial nephritis.
Figure 1: Diffuse Thickening of the Glomerular Basement Membranes (GBM) and Corresponding
Immunohistochemical Staining Results
Fig
1A: Diffuse thickening of the GBMs (Hematoxylin and Eosin, X200)
Fig 1B: Eosinophilic deposits along the thickened GBMs
(Masson's Trichrome, X400)
Fig 1C: Spikes formation within the thickened GBMs (Jones
Hematoxylin Eosin, X400)
Fig 1D: C4d positivity along the GBM (X200)
Fig 1E: PLA2R positivity along the GBM (X100)
Fig 1F: IgG4 positivity along the GBM (X100)
Figure 2: Interstitial
Inflammation Infiltrating the Tubular Epithelium.
Fig 2A: Inflammatory cells in the interstitium have infiltrated some tubules, entering
the lumen.
Fig 2B: Inflammatory cells have caused damage to certain tubules. Regenerative atypical
changes were observed in the epithelial cells lining the other tubules.
Bosutinib
treatment was temporarily discontinued for one month; however, no improvement
in renal function was observed. Following a multidisciplinary consultation with
the hematology department, bosutinib was restarted due to the critical need for
continued hematologic control. Immunosuppressive therapy with rituximab and
tacrolimus was initiated based on the renal biopsy diagnosis of membranous
nephropathy. The treatment regimen consisted of two doses of rituximab 1 g
administered 15 days apart, combined with tacrolimus 2 mg/day (1 mg twice
daily) for a total duration of 12 months. The patient received no nonsteroidal
anti-inflammatory drugs (NSAIDs) or corticosteroids.
At six-month
follow-up, significant clinical improvement was observed, with serum creatinine
of 1.03 mg/dL, eGFR of 94 mL/min/1.73 m², serum
albumin of 36.2 g/L, spot urine protein-to-creatinine ratio of 2074 mg/g, and
albumin-to-creatinine ratio of 1517 mg/g.
DISCUSSION
TKIs have
revolutionized the treatment of hematologic malignancies such as CML,
significantly improving patient survival and quality of life. These agents
primarily target the BCR-ABL fusion protein, but they may also inhibit other
tyrosine kinases expressed in renal tissue, including vascular endothelial
growth factor receptors, platelet-derived growth factor receptor beta (PDGFR),
c-KIT, and SRC family kinases, thereby contributing to nephrotoxicity (5).
Bosutinib inhibits PDGFR, which is expressed in glomeruli, tubules, renal
interstitium, and arteries, playing a role in tubular cell repair, as well as
c-KIT, which is expressed at low levels in collecting ducts and distal tubules.
Additionally, bosutinib inhibits SRC family kinases, predominantly expressed in
renal tubules and, to a lesser extent, in vascular structures (6).
Previous studies
have shown improvement in renal function when patients were switched from
imatinib to dasatinib or nilotinib, whereas bosutinib use has been associated
with a nonsignificant trend toward declining eGFR (1). Hirano et al. suggested that proteinuria severity may be dose-dependent,
as dose reduction effectively decreased proteinuria in their cohort (7).
Literature reports indicate that the main management strategy for
TKI-associated nephrotic syndrome or tubulointerstitial injury involves dose
reduction or discontinuation of the offending agent, with switching to an
alternative TKI, particularly in dasatinib-related cases. In contrast,
continuation of the suspected TKI is rarely reported and is typically reserved
for situations in which hematologic disease control is critical.
Renal adverse
effects associated with bosutinib predominantly include increases in serum
creatinine and reductions in eGFR, with partial or complete recovery following
drug discontinuation (8).
Although these findings do not constitute strong direct evidence for
bosutinib-induced nephrotic syndrome or MN, they support the concept of
reversible TKI-related renal toxicity. For drug-induced acute
tubulointerstitial nephritis, standard management generally involves
discontinuation of the offending agent and consideration of corticosteroid therapy
in selected cases.
The distinguishing
feature of the present case is the simultaneous occurrence of membranous
nephropathy and acute tubulointerstitial nephritis during bosutinib therapy, a
combination rarely reported. Unlike most reported cases, bosutinib was not
permanently discontinued in our patient. Instead, following a brief
interruption, treatment was resumed after careful multidisciplinary
risk–benefit assessment, and immunomodulatory therapy was initiated. This
approach led to stabilization and subsequent improvement of renal function and
proteinuria at six months of follow-up.
Bosutinib is a
second-generation TKI used in newly diagnosed or resistant/intolerant
Ph-positive CML (9).
Analyses based on 45 dysregulated IIMATs identified in MGN indicate that
several anticancer drugs, including tamoxifen, bosutinib, ponatinib, and
nintedanib, may represent potential therapeutic candidates for MN, and that
these IIMATs are associated with critical biological processes, particularly the
chemokine signaling pathway (10). These findings
support the potential nephrotoxic effects of bosutinib and its possible
association with MN development in our case.
This case
demonstrates that automatic discontinuation of the TKI is not always the only
option when TKI-associated nephrotic syndrome develops. Especially when
alternative treatment options are limited, a clear diagnosis via renal biopsy,
multidisciplinary (nephrology–hematology) risk–benefit assessment, and close monitoring
may allow continuation of the suspected TKI with adjunct immunomodulatory
therapy as a defensible strategy in selected cases.
MN is a common
cause of nephrotic syndrome in adults; while it typically presents as a primary
kidney disease, approximately 20% of cases are secondary to systemic diseases
(SLE, infections, malignancies) or drug exposure (11). In our case, PLA2R
immunostaining, associated with primary (idiopathic) MN, showed coarse granular
positivity along the GBM. PLA2R-positive MN associated with bosutinib has not
been previously reported; however, PLA2R-positive MN has been reported in
patients treated with sunitinib, another TKI. The present study reports that,
while sunitinib exacerbated the underlying MN, it did not cause it (12).
The PLA2R
positivity suggests an underlying idiopathic membranous nephropathy (MN);
however, the concomitant development of acute tubulointerstitial nephritis
(TIN) suggests a potential drug-induced component. Due to the limited
literature, a definitive causal relationship between bosutinib and
PLA2R-positive MN cannot be firmly established. It remains unclear whether the
drug directly induced these findings or acted as a trigger in a genetically
predisposed individual. Therefore, larger-scale cohort studies and additional
clinicopathological evidence are required to elucidate the precise role of
bosutinib in the pathogenesis of these complex renal presentations.
CONCLUSION
We present a rare
case of nephrotic syndrome characterized by the coexistence of PLA2R-positive
membranous nephropathy and acute tubulointerstitial nephritis in a patient
receiving bosutinib therapy. While the PLA2R positivity indicates an idiopathic
MN pattern, the concurrent TIN suggests a possible association with
bosutinib-related nephrotoxicity. At this stage, it is not possible to
definitively attribute the glomerular pathology to bosutinib, and our findings
should be interpreted as a potential association rather than confirmed
causality. Further studies involving larger patient populations are essential
to confirm the renal safety profile of bosutinib. This case underscores the
importance of renal biopsy in TKI-treated patients and highlights the need for
vigilant monitoring of renal function and proteinuria to detect potential
adverse effects early.
DECLARATİONS
Funding: This
research received no specific grant from any funding agency in the public,
commercial, or not-for-profit sectors.
CONFLİCTİNG İNTERESTS
The authors
declare that they have no conflicts of interest.
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