Next-Generation Bruton’s tyrosine kinase Inhibitors plus Rituximab for Chronic Lymphocytic Leukemia-associated Membranoproliferative Glomerulonephritis: A Case Report

doi:10.21203/rs.3.rs-8195069/v1

Renal involvement in chronic lymphocytic leukemia (CLL) is rare but clinically significant. Among the various pathological types, membranoproliferative glomerulonephritis (MPGN) is the most common and often presents as nephrotic syndrome. Early recognition of the association between renal lesions and CLL is crucial for guiding treatment and improving both renal and hematologic outcomes.

We report two biopsy-proven cases of CLL-associated MPGN successfully treated with next-generation Bruton’s tyrosine kinase inhibitors (BTKis). Both patients presented with nephrotic-range proteinuria. In Case 1, initial treatment with rituximab plus chlorambucil was discontinued due to severe infection and intolerance; the patient subsequently achieved sustained hematologic and renal remission with orelabrutinib monotherapy. In Case 2, zanubrutinib monotherapy led to partial improvement, followed by the addition of rituximab to accelerate proteinuria reduction and enhance renal response. To our knowledge, this is the first report of successful treatment of CLL-associated MPGN with next-generation BTKis. These cases underscore the critical role of kidney biopsy in confirming diagnosis and identifying underlying mechanisms. BTK inhibitors offer a safe and effective backbone for controlling systemic CLL activity, while adjunctive anti-CD20 monoclonal antibodies may further promote renal recovery. This combined approach may serve as a promising strategy for managing this rare but challenging complication.

Chronic lymphocytic leukaemia

Membranoproliferative glomerulonephritis

Nephrotic syndrome

Bruton’s tyrosine kinase inhibitors inhibitors

kidney biopsy

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent B-cell malignancy, often diagnosed incidentally and without an immediate need for treatment in most patients [1]. While extramedullary involvement is not uncommon in CLL, clinically significant renal complications are rare and frequently under-recognized. Renal biopsies are performed in fewer than 2% of CLL cases, limiting our understanding of the full spectrum of CLL-associated renal pathology [2].

Membranoproliferative glomerulonephritis (MPGN) is one of the most frequently reported glomerular diseases associated with CLL. Proposed pathogenic mechanisms include immune complex deposition, monoclonal immunoglobulin-related injury, complement pathway dysregulation, cryoglobulinemia, and direct leukemic infiltration of renal tissue. The clinical presentation is heterogeneous, ranging from asymptomatic proteinuria to nephrotic syndrome, acute kidney injury, or even end-stage renal disease, highlighting the indispensable role of renal biopsy in accurate diagnosis and treatment planning [2–4].

Prompt recognition of CLL-associated renal disease and early initiation of targeted therapy are crucial for optimizing both renal and hematologic outcomes. We report two cases of biopsy-confirmed MPGN in CLL patients, including one with renal disease as the initial manifestation and another in which renal involvement developed as a late complication. Both achieved dual hematologic and renal remission following treatment with next-generation Bruton’s tyrosine kinase inhibitors (BTKis), zanubrutinib or orelabrutinib. Rituximab was used in different therapeutic contexts: discontinued early in one patient due to intolerance, and added sequentially in the other after initial BTKi monotherapy to enhance proteinuria control. This is the first report of CLL-associated MPGN treated successfully with next-generation BTK inhibitors and rituximab, emphasizing the diagnostic value of early renal biopsy and the potential of targeted therapy for this rare but serious complication.

In September 2022, a 29-year-old man presented with diarrhea, progressive bilateral lower extremity edema, and oliguria. Laboratory tests (Table 1) revealed moderate anemia (Hb 67 g/L), thrombocytopenia (43×10⁹/L), and features consistent with nephrotic syndrome, including massive proteinuria (24-hour urinary protein: 7643 mg; urine albumin-to-creatinine ratio [uACR]: 209.9 mg/mmol), marked hypoalbuminemia (25 g/L), and impaired renal function (serum creatinine 103 µmol/L, uric acid 709 µmol/L). Immunological workup showed isolated low complement C3 (0.68 g/L) with normal C4, and hypogammaglobulinemia (IgG, IgA, IgM all below normal range). Serum immunofixation electrophoresis identified an IgG-κ monoclonal protein (1.2 g/L), and urine tested positive for free κ light chains. Serum β₂-microglobulin was markedly elevated at 6038 ng/mL. Imaging demonstrated generalized lymphadenopathy and splenomegaly (84×224 mm). Lymph node biopsy confirmed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Bone marrow flow cytometry showed abnormal mature B cells comprising 63.4% of lymphocytes, with the following phenotype: CD19⁺, CD5⁺, CD23⁻, CD22⁺, CD200⁺, FMC7⁻, Kappa⁻, Lambda⁻—consistent with CLL/SLL. Fluorescence in situ hybridization (FISH) analysis revealed no abnormalities in TP53 (17p13.1), ATM (11q22.3), trisomy 12, or deletion 13q14 (D13S319/RB1). Sanger sequencing identified unmutated IGHV status. The disease was staged as Rai IV / Binet C, with a high-risk CLL-IPI score of 5.

In November 2022, the patient was enrolled in a clinical trial (CTR20201980) and randomized to the control arm. He received rituximab (375 mg/m² on day 1 of cycle 1; 500 mg/m² on day 1 of cycles 2–6) in combination with chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle, for 6 cycles), along with valsartan to control proteinuria. After the first treatment cycle, the patient experienced complete resolution of edema, normalization of serum albumin, and a significant reduction in proteinuria (24-hour urinary protein: 202 mg), meeting the criteria for complete renal remission. However, the patient continued to exhibit persistent cytopenias along with no reduction in lymphadenopathy or splenomegaly, suggesting inadequate hematologic response. A renal biopsy was performed to clarify the underlying cause of the nephrotic syndrome. Histological evaluation revealed diffuse mesangial cell proliferation with capillary loop narrowing and occlusion, segmental endocapillary hypercellularity, and focal glomerular basement membrane thickening with “double-contour” formation (Fig. 1A). Immunofluorescence was negative for IgG, IgA, IgM, C3, C1q, and κ/λ light chains. Electron microscopy showed sparse subendothelial electron-dense deposits (Fig. 1B), and a final diagnosis of MPGN was made.

During treatment, the patient developed grade 4 pneumonia complicated by sepsis (per CTCAE criteria), leading to discontinuation of therapy. After two treatment cycles, the hematologic response was assessed as stable disease (SD). In April 2023, the patient withdrew from the study and was switched to orelabrutinib monotherapy (150 mg daily). Four months later, blood counts normalized, and both splenomegaly and lymphadenopathy resolved (Fig. 1C and 1D). Minimal residual disease (MRD) in peripheral blood decreased to 0.46%, and further follow-up in July 2025 showed a decline to 0.11%. The patient remains on orelabrutinib monotherapy with no treatment-related adverse events reported to date.

A 70-year-old man was diagnosed with CLL in 2007 at the age of 53 and had been under regular follow-up with stable disease for 17 years. In August 2024, he presented to the nephrology clinic with bilateral ankle edema and foamy urine. Laboratory tests revealed nephrotic-range proteinuria (24-hour urine protein: 3964 mg; uACR: 242.73 mg/mmol) with normal serum creatinine (95 µmol/L). Anti-PLA2R antibodies were negative, and serum and urine immunofixation electrophoresis did not detect monoclonal proteins. The patient was started on telmisartan for proteinuria control and referred to the hematology department. At that time, he did not meet the iwCLL criteria for treatment initiation and was managed conservatively with close monitoring.

By November 2024, his edema had worsened. Laboratory studies demonstrated a marked increase in proteinuria (24-hour urine protein: 9917 mg) and severe hypoalbuminemia (serum albumin: 18 g/L). Serum immunoglobulin levels (IgG, IgA, IgM) were all decreased, but complement C3 and C4 remained within normal ranges. Immunofixation continued to show no detectable monoclonal bands in serum or urine. Serum β2-microglobulin was elevated to 4660 ng/mL (Table 1). Ultrasound examination revealed splenomegaly (68 × 172 mm) and generalized lymphadenopathy.

Renal biopsy was performed, which revealed marked mesangial and endocapillary proliferation under light microscopy, with diffuse glomerular basement membrane (GBM) thickening and characteristic double-contour (“tram-track”) appearance. Masson’s trichrome stain showed magenta subendothelial deposits, and Congo red staining was negative (Fig. 1E). Immunohistochemistry showed CD20⁺ B-cell infiltration in the interstitium, supporting CLL-related leukemic infiltration.

Immunofluorescence revealed granular IgG (+++) and lambda (++) deposition along the glomerular capillary loops, with negative kappa staining. C3 (++) and C1q (+~++) were also detected (Fig. 1F). Electron microscopy confirmed abundant subepithelial and intramembranous electron-dense deposits,as well as segmental mesangial and subendothelial electron-dense deposits (Fig. 1G), consistent with a diagnosis of MPGN.

Bone marrow flow cytometry revealed 92.5% clonal mature B lymphocytes (CD19⁺, CD5⁺, CD10⁻, CD23dim⁺, CD79b⁻, FMC7⁻, CD200⁺), consistent with CLL/SLL. FISH analysis did not identify high-risk cytogenetic abnormalities, and IGHV sequencing showed a mutated status. The patient was staged as Rai III / Binet B, with a CLL-IPI score of 4 (high-risk group).

In December 2024, zanubrutinib (160 mg twice daily) was initiated. During early treatment, the white blood cell (WBC) count increased from 127×10⁹/L to 181×10⁹/L, prompting the addition of chlorambucil (4 mg daily for 8 days). After two weeks, peripheral edema improved. By one month, serum albumin normalized (39 g/L), 24-hour urine protein decreased to 3869 mg, WBC normalized (5.6×10⁹/L), and absolute lymphocyte count was 2.99×10⁹/L. After four months of zanubrutinib, proteinuria further declined to 1068 mg/24h (Fig. 1H and 1I). To accelerate renal remission, rituximab (375 mg/m², once monthly) was added in April 2025. After two cycles, proteinuria declined further to 267 mg/24h. No significant treatment-related adverse events were observed other than grade 2 thrombocytopenia and occasional skin petechiae. As of the last evaluation in August 2025, the patient had achieved complete remission of nephrotic syndrome and partial hematologic remission of CLL.

Membranoproliferative glomerulonephritis (MPGN) represents a histopathological pattern of glomerular injury rather than a distinct disease entity. It is primarily driven by two mechanisms: immune complex deposition and dysregulation of the alternative complement pathway. The former requires thorough evaluation for potential infections, autoimmune diseases, or monoclonal gammopathies, while the latter is further classified into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) based on electron microscopy findings [3, 4].

In this report, we present two cases of CLL-associated MPGN, each reflecting a distinct clinical course. One case involved simultaneous diagnosis of CLL and MPGN, while the other developed MPGN as a late complication 17 years after CLL diagnosis. In Case 1, kidney biopsy revealed typical MPGN features with negative immunofluorescence and sparse subendothelial electron-dense deposits on electron microscopy. The patient had isolated low C3, IgG-κ monoclonal proteinemia, and no evidence of DDD or C3GN per strict criteria. The clinical and pathological findings suggested a mechanism of monoclonal immunoglobulin-mediated activation of the alternative complement pathway, resulting in glomerular endothelial injury and acute inflammation. Case 2 exhibited classic immune complex–mediated MPGN. Immunofluorescence showed strong granular deposition of IgG, C3, and C1q along the glomerular capillary walls, accompanied by CLL cell infiltration in the interstitium. Combined immunopathologic and ultrastructural findings supported the pathogenesis of either circulating immune complexes induced by tumor-associated antigens or in situ formation of immune complexes derived from locally secreted immunoglobulins by infiltrating CLL cells.

These cases highlight the heterogeneity of CLL-associated MPGN and the indispensable role of renal biopsy in confirming the diagnosis and underlying mechanism. In CLL patients presenting with new-onset proteinuria or renal dysfunction—especially with concurrent immune abnormalities or monoclonal proteins—early renal biopsy is crucial to guide management. According to iwCLL guidelines, renal parenchymal involvement alone can serve as an indication to initiate CLL-directed therapy [1].

The treatment of MPGN hinges on addressing the underlying disease. Previous reports describe the use of corticosteroids, chemotherapy (e.g., chlorambucil, cyclophosphamide), and anti-CD20 monoclonal antibodies (e.g., rituximab) in CLL-associated MPGN, but outcomes have been variable and often limited by poor tolerability [2, 4, 5]. Recently, BTK inhibitors have transformed the treatment landscape of CLL, demonstrating superior efficacy and tolerability in high-risk subgroups such as those with unmutated IGHV or TP53 mutations. Compared with ibrutinib, next-generation BTK inhibitors such as zanubrutinib and orelabrutinib offer improved selectivity and reduced adverse effects, and are now recommended as first-line therapies [6, 7].

Anti-CD20 monoclonal antibodies (e.g., rituximab) may serve as adjuncts to BTKi-based regimens, particularly in patients requiring rapid tumor debulking or enhanced renal remission. However, their use should be carefully weighed against the increased risk of infection, especially in immunocompromised or renally impaired patients.

In our cases, both patients received BTKi-based treatment with favorable outcomes. Case 1 initially received rituximab combined with chemotherapy and achieved rapid renal remission but developed severe infection with persistent CLL activity. Switching to orelabrutinib resulted in hematologic improvement. In Case 2, zanubrutinib monotherapy significantly improved proteinuria and hematologic parameters, and subsequent addition of rituximab further enhanced renal recovery, ultimately achieving dual remission of CLL and MPGN.

In summary, renal biopsy plays an essential role in diagnosing and characterizing CLL-associated MPGN. BTKi-based regimens demonstrate excellent efficacy and safety in this setting, and timely incorporation of anti-CD20 antibodies may further optimize treatment responses. These findings support the broader clinical application of BTKis in managing CLL patients with renal involvement.

Author contributions

L.C., JQ.M. and XX.P. designed the study. L.C., YT.H., QY.Z., FL.H. collected the data and administered the study. J.X., SN.H. and XX.P. performed renal pathological examination and analysis. L.C., YT.H., J.X., SN.H. wrote the paper. JQ.M. and XX.P. revised the manuscript. All authors reviewed and approved the manuscript.

Ethical approval

This study was approved by the Ethics Committee of Ruijin Hospital in Shanghai (Approval number 2025–2) and conducted in accordance with the Declaration of Helsinki.

Conflict of interest statement

The authors declare no competing interests and approve the manuscript for publication.

Funding

This work was supported by Innovative research team of high-level local universities in Shanghai.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Patient consent to publish declaration: Written informed consent was obtained from both patients for publication of this case report and any accompanying images.

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Table 1 Baseline characteristics at treatment initiation

	Case 1	Case 2
Age (years) / Sex	29 / Male	70 / Male
CLL presentation	First manifestation	17 years after diagnosis
White blood cell count (× 10⁹/L)	4.29	127
Absolute lymphocyte count (× 10⁹/L)	3.56	115
Hemoglobin (g/L)	67	101
Platelet (× 10⁹/L)	43	145
Serum albumin (g/L)	25	18
Serum creatinine (μmol/L)	103	89
Uric acid (μmol/L)	709	466
eGFR (mL/min/1.73 m²)	84.2	77.9
Serum β₂-microglobulin (ng/mL)	6038	4660
Proteinuria (mg/24h)	7643	9917
uACR (0-2.5 mg/mmol)	209.9	242.73
Complement C3 (0.74-1.4 g/L)	0.68	0.78
Complement C4 (0.1-0.4 g/L)	0.16	0.28
IgG (8.6-17.4 g/L)	4.55	2.91
IgA (1-4.2 g/L)	1.05	0.49
IgM (0.3-2.2 g/L)	0.09	0.18
Serum monoclonal protein	IgG-κ (1.2 g/L)	Negative
Urine monoclonal protein	κ-type Bence Jones proteinuria	Negative
ANCA	Negative	Negative
Anti-PLA2R Ab	Negative	Negative
Serum viral testing*	Negative	Negative
FISH (TP53, ATM, CSP12, RB1, D13525)	Negative	Negative
IGHV status	Unmutated	Mutated
Rai stage	IV	III
Binet stage	C	B
CLL-IPI score	5	4

Viral panel* (Hepatitis B surface antigen, Hepatitis C virus antibody, Human immunodeficiency virus antibody and Treponema pallidum antibody).

Abbreviations：CLL, Chronic lymphocytic leukemia; eGFR, estimated glomerular filtration rate; uACR, Urinary Albumin-to-Creatinine Ratio; ANCA, antineutrophilic cytoplasmic antibody; PLA2RAb, phospholipase A2 receptor antibody.

No competing interests reported.

Next-Generation Bruton’s tyrosine kinase Inhibitors plus Rituximab for Chronic Lymphocytic Leukemia-associated Membranoproliferative Glomerulonephritis: A Case Report

Status:

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Abstract

Figures

Introduction

Case 1: CLL initially presenting with MPGN in a young patient

Case 2: Late-onset MPGN in a patient with long-standing CLL

Discussion

Declarations

References

Table

Additional Declarations

Status:

Version 1