Mantle cell lymphoma (MCL) rarely causes glomerular disease. While immune complex-mediated and infiltrative lesions predominate, podocytopathies are exceptionally rare. We report a case of reversible focal segmental glomerulosclerosis (FSGS) occurring in the setting of blastoid-variant MCL, highlighting the paraneoplastic nature of the podocyte injury. A 69-year-old man presented with nephrotic syndrome and dialysis-dependent acute kidney injury (AKI). Kidney biopsy revealed FSGS. Subsequent diagnostic evaluation uncovered blastoid-variant MCL. Following lymphoma-directed chemotherapy, nephrotic syndrome resolved and renal function recovered, supporting a paraneoplastic mechanism of podocyte injury. This case underscores that MCL can induce a reversible paraneoplastic podocytopathy mimicking primary FSGS. Recognition of this entity is crucial to avoid unnecessary immunosuppression and to prompt early evaluation for underlying malignancy. Treating the neoplasm can result in renal recovery, emphasizing the functional connection between tumor activity and podocyte injury.
El linfoma de células del manto (LCM) causa raramente enfermedad glomerular. A pesar de predominar las lesiones mediadas por complejos inmunes e infiltrativas, las podocitopatías son excepcionalmente raras. Reportamos un caso de glomerulosclerosis focal y segmentaria (GEFS) reversible que se produjo en el ámbito de LCM con variante blastoide, destacando la naturaleza paraneoplásica de la lesión podocítica. Un varón de 69 años acudió con síndrome nefrótico y lesión renal aguda (LRA) siendo dependiente de diálisis. La biopsia renal reveló GEFS. La evaluación diagnóstica subsiguiente reveló LCM con variante blastoide. Tras quimioterapia dirigida al linfoma se resolvió el síndrome nefrótico y recuperó la función renal, respaldando un mecanismo paraneoplásico de lesión podocítica. Este caso subraya que LCM puede inducir podocitopatía paraneoplásica reversible que imita GEFS primaria. El reconocimiento de esta entidad es esencial para evitar inmunosupresión innecesaria, e impulsar la evaluación temprana de neoplasia subyacente. El tratamiento de la neoplasia puede originar recuperación renal, subrayando la conexión funcional entre la actividad tumoral y la lesión podocítica.
Paraneoplastic glomerular diseases represent a heterogeneous group of renal lesions that arise as indirect manifestations of malignancy. Membranous nephropathy (MN) is the archetypal lesion among solid tumors,1 whereas in hematologic malignancies minimal change disease (MCD) is classically associated with Hodgkin lymphoma.2 By contrast, renal involvement in non-Hodgkin lymphomas (NHL) is diverse and may include immune complex or complement-mediated glomerulopathies, crescentic patterns, and direct lymphomatous infiltration, while podocytopathies remain uncommon.3,4 This is illustrated by a multicenter retrospective series in which Kofman et al. identified only 18 cases of MCD among nearly 14,000 patients with NHL,4 and by Nael Da’as et al., who reported a single patient with FSGS among 700 NHL patients undergoing kidney biopsy.5
Mantle cell lymphoma is a mature B-cell non-Hodgkin lymphoma accounting for approximately 5–7% of all lymphomas.6 It is characterized by the translocation t(11;14)(q13;q32), leading to cyclin D1 overexpression, and displays heterogeneous clinical behavior, ranging from indolent disease to highly aggressive variants. The blastoid subtype is distinguished by a high proliferative index and rapid clinical progression. In a recent multi-institutional clinicopathologic series, Andeen et al. demonstrated that kidney injury in patients with active MCL is frequently attributable to the lymphoma itself and most commonly reflects immune complex or complement-mediated glomerular disease and/or parenchymal lymphomatous infiltration.7 Notably, podocytopathies were not identified as a primary pattern of renal injury in that cohort.
Accordingly, paraneoplastic podocytopathies associated with MCL remain exceedingly rare. To date, only four biopsy-proven cases have been reported – three with FSGS8–10 and one with MCD.11 Here, we describe the fifth reported case and the first documented in blastoid-variant MCL, in which nephrotic syndrome and dialysis-dependent acute kidney injury preceded overt hematologic manifestations and reversed following lymphoma-directed therapy.
Case presentationA 69-year-old man with hypertension medicated with an ACE inhibitor presented with a two-month history of progressive lower limb and frothy urine. He reported fatigue but denied fever, weight loss, night sweats, or recent exposure to new medications. On admission, he was hypertensive (160/90mmHg), with bilateral pitting edema but no palpable lymphadenopathy or hepatosplenomegaly.
Laboratory studies showed normocytic normochromic anemia (hemoglobin 11.6g/dL), leukocytosis (14,000/μL, 82% neutrophils), hypoalbuminemia (2.5g/dL), dyslipidemia, and nephrotic-range proteinuria (6g/24h), predominantly albuminuria. Serum creatinine was elevated (5.99mg/dL). Urinalysis showed no hematuria. Renal ultrasound with doppler was unremarkable.
Serum protein electrophoresis revealed a monoclonal spike in the gamma region (monoclonal protein 0.51g/dL) identified as IgM lambda on immunofixation. Free light chain (FLC) lambda was 287mg/L and kappa 174mg/L. FLC ratio was 0,61. Urinary immunofixation was negative. Autoimmune testing (ANA, antidsDNA, ANCA, anti-GBM, anti-PLA2R, anti-THSD7A), cryoglobulins and viral serologies (HIV, HBV, HCV) were negative. The patient was immune to CMV, EBV and parvovirus B19. Complement levels were normal.
A kidney biopsy was performed. Light microscopy revealed 14 glomeruli, two of which exhibited segmental sclerosis lesions (Figs. 1 and 2), while the remaining glomeruli were morphologically unremarkable. Columbia classification of FSGS was not feasible, as the vascular and tubular poles were not clearly identifiable, precluding reliable subclassification. There was extensive diffuse acute tubular necrosis (ATN) and intense interstitial lymphoid infiltration (Fig. 3). Immunofluorescence (IF) showed no granular immune deposits in the mesangium or along the capillary walls, no complement deposition, and no light-chain restriction. Polyclonal IgM staining was limited to sclerotic lesions. Immunohistochemical characterization of the interstitial infiltrate revealed positivity for CD20, CD5, and CD22, and negativity for CD10. Congo red staining was negative. Electron microscopy (EM) was not performed.
Given the presence of a IgM lambda intermediate-low risk monoclonal gammopathy, a bone marrow biopsy was performed as part of the standard diagnostic evaluation to exclude an underlying lymphoproliferative disorder or plasma cell dyscrasia. Bone marrow examination demonstrated a hypercellular marrow with preserved trilineage hematopoiesis and nodular aggregates of CD20-positive B lymphocytes. Flow cytometry identified a small IgM lambda-restricted lymphoplasmacytic population. Molecular testing for the MYD88 L265P mutation was negative.
Whole-body 18F-FDG PET/CT revealed hypermetabolic supra- and infradiaphragmatic lymphadenopathy and increased uptake at the esophagogastric junction. An initial gastric biopsy was nondiagnostic owing to extensive tissue necrosis. A repeat biopsy performed fifteen days later confirmed blastoid-variant MCL, with tumor cells expressing CD20, CD5, and cyclin D1 and a Ki-67 proliferation index exceeding 90%. SOX11 immunohistochemical staining was not performed.
Following the diagnosis of MCL, the kidney biopsy was re-evaluated. Additional immunohistochemical staining for cyclin D1 confirmed that the interstitial lymphoid infiltrate represented lymphomatous renal involvement (Fig. 4).
During hospitalization, intravenous diuretic therapy was initiated due to clinical signs of hypervolemia. Serum albumin and hemoglobin reached nadir values of 2g/dL and 8g/dL, respectively. Renal function progressively deteriorated, with a peak serum creatinine of 9mg/dL, accompanied by oliguria, diuretic-refractory fluid overload, and metabolic acidosis, prompting initiation of hemodialysis. No episodes of hypotension were documented.
The patient was treated with high-dose prednisone for tumor debulking, followed by VR-CAP chemotherapy (rituximab, cyclophosphamide, doxorubicin, prednisone, and bortezomib). This resulted in partial hematologic remission, accompanied by normalization of serum albumin within one month of treatment initiation. Proteinuria progressively decreased to 760mg/day over four months, and renal function recovered, allowing discontinuation of hemodialysis six months after presentation.
DiscussionRenal histopathology in mantle cell lymphomaThis case illustrates a reversible paraneoplastic podocytopathy manifesting as FSGS in the context of blastoid-variant MCL. MCL is a B-cell neoplasm characterized by the translocation t(11;14), cyclin D1 overexpression, and coexpression of CD5 and CD20, with a clinical spectrum ranging from indolent disease to highly aggressive forms such as the blastoid and pleomorphic variants, which are often associated with high Ki-67 proliferation indices and rapid clinical progression.
Renal involvement in MCL most commonly reflects immune complex- or complement-mediated glomerular disease. This is best illustrated by the largest clinicopathologic series of MCL-associated kidney disease published by Andeen et al., in which immune complex- and complement-mediated glomerulopathies accounted for the majority of glomerular lesions, encompassing a heterogeneous spectrum of light-microscopy patterns – including membranoproliferative, mesangial proliferative, endocapillary proliferative, and membranous forms – with immune deposits confirmed by IF and EM.7 Notably, podocytopathies were not identified in that cohort.
In light of these data, an immune complex or complement-mediated glomerulopathy was considered in the differential diagnosis. However, kidney biopsy revealed an FSGS pattern without proliferative features or capillary wall remodeling, and IF demonstrated no granular immune deposits, showing only segmental IgM staining confined to sclerotic lesions, consistent with nonspecific passive entrapment. These findings effectively ruled out immune complex-mediated entities such as membranoproliferative and membranous nephropathy, supporting the interpretation of a paraneoplastic podocytopathy rather than immune complex-driven glomerular injury.
Although an identifiable paraprotein on serum and/or urine protein electrophoresis has been reported in patients with MCL, clinicopathologic series – including that of Andeen et al.7 – demonstrate that monoclonal glomerular deposits are uncommon, thereby distinguishing MCL-associated kidney disease from monoclonal gammopathy of renal significance. In our patient, the absence of the MYD88 L265P mutation argued against lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.
Paraneoplastic podocytopathy and spectrum of podocyte injuryAs outlined in the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases,12 distinguishing primary from secondary FSGS requires integration of clinical presentation, laboratory findings, exclusion of secondary causes, and ultrastructural assessment. Primary FSGS typically presents with abrupt-onset nephrotic syndrome, marked hypoalbuminemia, and diffuse podocyte foot-process effacement on EM, in the absence of an identifiable underlying trigger. In contrast, secondary FSGS occurs in association with an identifiable cause – such as maladaptive stress, viral infection, drug exposure or systemic disorders – and is usually characterized by nephrotic or subnephrotic proteinuria, often without full nephrotic syndrome, and segmental rather than diffuse podocyte foot-process effacement when ultrastructural evaluation is available.
In the present case, the identification of a systemic trigger (active MCL), the subacute evolution of nephrotic syndrome, and its resolution following lymphoma-directed therapy favor a secondary, paraneoplastic form of FSGS rather than primary disease.
To date, only a limited number of biopsy-proven podocytopathies have been reported in MCL (Table 1). The earliest case, published in 2007, described a 68-year-old man who developed nephrotic syndrome and AKI due to FSGS.8 His condition improved following plasma exchange and chemotherapy. The second case, reported in 2014, involved a 55-year-old woman with MCD associated with newly diagnosed MCL.11 Her nephrotic syndrome initially responded to corticosteroids and remained in remission after CHOP chemotherapy and autologous stem cell transplantation. In 2015, a 67-year-old man presented with FSGS that preceded the diagnosis of MCL by almost a year.9 Despite treatment with standard immunosuppressive therapy, his nephrotic syndrome was refractory and relapsed, prompting further investigation. Lymphocytosis was the key finding that led to the diagnosis of MCL, and renal function improved only after initiation of R-CHOP chemotherapy. In 2023, a 73-year-old man with newly diagnosed MCL and FSGS was successfully treated with ibrutinib monotherapy,10 an irreversible inhibitor of Bruton's tyrosine kinase, a critical enzyme in the B-cell receptor signaling pathway. This therapy led to hematologic remission, resolution of nephrotic syndrome, and complete normalization of renal function.
Summary of reported podocytopathies occurring in the context of MCL.
| Reference | Age (years)/sex | Histology | Findings that prompted the hematologic diagnosis | Treatment | Renal outcome | Hematologic outcome |
|---|---|---|---|---|---|---|
| (8) | 68M | FSGS | Lymphocytosis | Hemodialysis, MTP, AZA, PEX and CYC. Later R-CVP | Normalisation of kidney function and proteinuria | Complete remission |
| (11) | 55F | MCD | Lymphocytosis and proptosis with intraconal mass | PDN, CHOP, MTX and autologous HSCT | MCD remission | Complete remission |
| (9) | 67M | FSGS | Lymphocytosis and relapsing nephrotic syndrome | PDN, CsA, R-CHOP | Normalisation of kidney function and proteinuria | Partial remission |
| (10) | 73M | FSGS | Peripheral lymphadenopathies and hepatosplenomegaly | Ibrutinib monotherapy | Normalisation of kidney function and proteinuria | Complete remission |
| Current case | 69M | FSGS | Gastric hypercaptation on PET/CT | Hemodialysis, PDN, VR-CAP | Proteinuria and kidney function improvement with dialysis independence | Partial remission |
FSGS: focal segmental glomerulosclerosis; MTP: methylprednisolone; AZA: azathioprine; PEX: plasmapheresis; CYC: cyclophosphamide; R-CVP: rituximab, cyclophosphamide, vincristine and prednisolone; MCD: minimal change disease; PDN: predinosolone; CHOP: cyclophosphamide, hydroxydaunorubicin (doxorubicin), oncovin (vincristine) and prednisolone; MTX: methotrexate; HSCT: hemopoietic stem cell transplantation; CsA: ciclosporin; VR-CAP: rituximab, cyclophosphamide, doxorubicin, prednisone, and bortezomib.
The present case represents the fifth reported biopsy-proven podocytopathy associated with MCL and the fourth exhibiting an FSGS pattern, but uniquely the first described in the blastoid variant. Unlike previously reported cases, our patient had no B-symptoms, lymphocytosis, or peripheral lymphadenopathy at presentation, and the diagnosis of MCL was established only after 18F-FDG PET/CT prompted gastric biopsy. Immunohistochemical analysis confirmed CD20, CD5 and cyclin D1 positive lymphoid infiltration in the kidney, consistent with direct parenchymal involvement by MCL.
Given the aggressive biology of blastoid-variant MCL, rapid cytoreduction is important. In patients ineligible for autologous stem cell transplantation, the phase 3 LYM-3002 trial demonstrated that VR-CAP, compared with R-CHOP, was associated with a shorter median time to response and significantly higher duration of complete response.13 In post-hoc subgroup analyses, VR-CAP was also associated with improved overall survival in patients with Ki-67-positive tumors, particularly those with high Ki-67 expression,14 supporting its use in aggressive MCL subtypes where rapid disease control and durable remission are critical given the unfavorable prognosis.
The AKI requiring initiation of hemodialysis was multifactorial. Nephrotic syndrome-related changes in effective circulating volume, together with severe anemia and hypoalbuminemia, may have contributed to renal hypoperfusion and acted as precipitating factors for intrinsic kidney injury. This is supported by kidney biopsy findings of extensive diffuse ATN. In addition, direct lymphomatous interstitial infiltration represented an independent and concomitant mechanism of intrinsic renal damage. Improvement in renal function likely reflected resolution of these overlapping processes, including correction of nephrotic syndrome–associated hemodynamic disturbances, gradual tubular recovery and chemotherapy-induced control of lymphomatous infiltration.
Importantly, the concomitant presentation of nephrotic syndrome and AKI underscores the mandatory role of histopathological evaluation in patients with suspected lymphoproliferative disorders. In this case, kidney biopsy was indispensable to delineate overlapping mechanisms of renal injury, identify potentially reversible lesions, define therapeutic strategy, and inform about renal prognosis.
In this case, persistent subnephrotic proteinuria is best interpreted as a marker of chronicity rather than ongoing disease activity. In FSGS, podocyte dysfunction may resolve with lymphoma-directed therapy, whereas sclerotic lesions are not expected to regress and can account for residual proteinuria, as observed in other glomerulopathies. Although histologic confirmation would require repeat kidney biopsy, this was not pursued given clinical stability and resolution of nephrotic syndrome, with no expected impact on therapeutic decision-making.
LimitationsA limitation of this case is the absence of electron microscopy, which could have provided ultrastructural confirmation of podocyte foot-process effacement. No tissue fragment was fixed in glutaraldehyde at the time of kidney biopsy, and ultrastructural evaluation from paraffin-embedded tissue is not routinely performed at our institution. Nevertheless, the concordance between the clinical presentation, light microscopy, immunofluorescence findings, and the renal response to lymphoma-directed therapy strongly supports the diagnosis of a paraneoplastic podocytopathy.
Learning pointsEven in aggressive subtypes of MCL, such as the blastoid variant, renal manifestations may precede overt hematologic features, and nephrotic syndrome or AKI may constitute the initial presentation. In adults with nephrotic syndrome or biopsy-proven FSGS – particularly when unresponsive to standard immunosuppressive therapy – secondary causes, including occult lymphoproliferative disorders, should be actively considered. Recognition of a paraneoplastic podocytopathy is crucial, as timely initiation of lymphoma-directed therapy may reverse podocyte dysfunction, resolve nephrotic syndrome, and control lymphomatous renal infiltration, thereby enabling recovery of kidney function. Histopathological evaluation plays a central role in integrating multifactorial mechanisms of renal injury and identifying potentially reversible lesions.
ConclusionThis case expands the spectrum of renal involvement in MCL by documenting a reversible paraneoplastic podocytopathy presenting with an FSGS pattern. Importantly, this pattern of renal involvement extends beyond the immune complex– and complement-mediated glomerulopathies most frequently described in MCL, underscoring the heterogeneity of lymphoma-associated kidney disease and the need for careful histopathologic evaluation.
CRediT authorship contribution statementAll authors made a significant contribution to the work reported, whether in the conception; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interestThe authors declare no conflicts of interest.
