Chronic lymphocytic leukemia (CLL) is derived from neoplastic B-cell lymphocytes mostly involving the bone marrow and lymph nodes. Other lymphatic organs are infiltrated less frequently (1). Moreover, renal involvement in CLL is increasingly recognized as a clinically relevant complication, occurring in approximately 7.5% of patients at diagnosis and more frequently throughout the course of the disease (2–5). The underlying mechanisms of renal impairment are diverse, including direct leukemic infiltration of the renal parenchyma, obstructive uropathy from lymphadenopathy, treatment-related nephrotoxicity, tumor lysis syndrome, and immune-mediated glomerular injury (2–5).

Among renal complications, immune-mediated glomerulonephritis is a particularly important subset. Two large retrospective studies of renal biopsies in CLL and small lymphocytic lymphoma (SLL) have identified membranoproliferative glomerulonephritis (MPGN) as the most frequent histological finding (2, 4, 5).

Due to the rarity of these renal manifestations, treatment recommendations are largely based on individual case reports and small case series, and no standardized therapeutic approach has been established to date. Chemoimmunotherapy with agents such as rituximab, chlorambucil, and fludarabine has previously been reported as an effective treatment option (2, 6). However, data on the efficacy of newer agents routinely used in CLL therapy such as venetoclax or Bruton’s tyrosine kinase (BTK) inhibitors in the management of autoimmune renal complications remain scarce (7–10).

Here, we present two cases of CLL-associated nephrotic syndrome that responded rapidly and completely to treatment with obinutuzumab and venetoclax, without the need for additional immunosuppression.

Glomerulonephritis in chronic lymphocytic leukemia (CLL) is observed in approximately 7.5% of patients at diagnosis, with an increasing incidence over the course of the disease (2, 5). Despite this, clinically relevant renal involvement remains rare and is frequently underrecognized. Nephrotic syndrome may precede the diagnosis of CLL or occur at any stage of the disease and should be suspected in patients presenting with unexplained proteinuria, atypical glomerulonephritis, or disease refractory to standard immunosuppressive therapy, particularly in the presence of discordant serological findings.

According to current guidelines, treatment of CLL is recommended in cases of symptomatic or progressive disease (1). CLL-associated glomerular disease is not considered an independent criterion for therapy initiation, likely due to its rarity. Nevertheless, it is well established that successful treatment of the underlying leukemia often leads to improvement or resolution of renal involvement (2, 7–9, 12).

In our first case, the patient had an early-stage CLL without any formal indication for treatment based on hematologic criteria alone. However, she presented with a significant nephrotic syndrome that was initially suspected to be associated with lupus nephritis and therefore treated with immunosuppression. Due to insufficient response, CLL-induced MPGN was suspected. Despite Binet stage A/low-risk chronic lymphocytic leukemia, the presence of organ-threatening autoimmune renal disease was considered a sufficient indication to initiate systemic therapy to prevent irreversible renal damage. The iwCLL criteria recommend initiation of therapy in the presence of clinically relevant autoimmune complications, including autoimmune hemolytic anemia and immune thrombocytopenia (1). While severe autoimmune renal involvement is not explicitly addressed, we considered the organ-threatening nature of the disease sufficient justification for systemic treatment to avoid progressive renal impairment.

The second patient had a clear hematological indication for specific CLL therapy in addition to renal complications. Since the CLL did not present with high-risk features in both cases, treatment with obinutuzumab in combination with venetoclax was selected and administered as a time-limited approach with deep hematologic responses, rapid disease control, and a favorable safety profile (11, 13).

In both of our cases, treatment with venetoclax and obinutuzumab resulted in a rapid and profound hematologic and renal response, with complete resolution of the nephrotic syndrome and normalization of proteinuria within weeks of therapy initiation. Notably, this was achieved without the need for additional immunosuppressive therapy.

Historically, treatment strategies for CLL-associated MPGN included immunosuppression or chemoimmunotherapy with agents such as rituximab, chlorambucil, or fludarabine (2, 6). These approaches often resulted in partial or delayed responses and were associated with significant toxicities, especially in elderly or comorbid patients due to prolonged immunosuppression or myelosuppression.

In contrast, modern treatment approaches for CLL increasingly rely on targeted therapies such as Bruton’s tyrosine kinase inhibitors or the BCL2 inhibitor venetoclax, often in combination with monoclonal antibodies like obinutuzumab. However, data on the efficacy of these agents in treating autoimmune renal complications like MPGN remain limited to anecdotal case reports (8–11).

Our observations contribute to the growing body of evidence, suggesting that modern targeted therapies may offer a more effective and better-tolerated treatment option for patients with CLL-associated glomerulonephritis, particularly MPGN (8–11). The rapid clinical improvement observed in our patients highlights the importance of early recognition of renal involvement in CLL and the potential reversibility of kidney injury when appropriate systemic therapy is promptly initiated.

In patients presenting with unexplained nephrotic syndrome, particularly when the clinical course is atypical or refractory to immunosuppressive therapy, CLL should be considered as a potential underlying cause, and careful evaluation including peripheral blood smear and flow cytometry may facilitate early diagnosis.

Nephrotic syndrome due to CLL-associated MPGN is a rare but serious complication. In these two cases, treatment with the combination of venetoclax and obinutuzumab was associated with both hematologic response and improvement of renal manifestations. While these observations suggest a potential role for targeted therapies in the management of autoimmune renal complications of CLL, larger studies are required to better define their efficacy and generalizability.