Chronic B-cell lymphoproliferative disorder (B-CLPD) is a group of mature B-cell clonal proliferative disorders characterized by clonal proliferation of mature lymphocytes in the peripheral blood/bone marrow and diagnosed by morphological, immunophenotypic and cytogenetic features of the peripheral blood/bone marrow. It includes chronic lymphocytic leukemia (CLL), multiple myeloma (MM), Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL), and other non-Hodgkin’s lymphomas (NHL) (1). Kidney damage is a common and severe complication of B-CLPD, which often manifests as proteinuria, hematuria, nephrotic syndrome or acute kidney injury (AKI). The direct causes of AKI in B-CLPD include tumor cell infiltration, hypercalcemia, tumor lysis syndrome, and urinary tract obstruction due to lymph node enlargement (2). Moreover, the prevalence of AKI also has an association with the side effects of tumor-targeting treatment such as infection and chemotherapy toxicity. Another important presentation of LPD-related kidney dysfunction is monoclonal immunoglobulin-associated kidney injury, including light chain amyloidosis (AL), light chain deposition disease (LCDD), cryoglobulinemic glomerulonephritis, proliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID), immunotactoid glomerulonephritis, cast nephropathy, etc. The amino acid sequence and physicochemical properties of the variable regions of the pathogenic heavy and/or light chains may be major determinants of nephrotoxicity which could determine the deposition pattern in the kidney (2). However, the potential underlying mechanisms have not been elucidated clearly.

Majority of the kidney involvement in LPD were associated with pathogenic monoclonal immunoglobulin which were mainly observed in patients with indolent B-cell lymphoma or monoclonal gammopathy of undetermined significance (MGUS). The physicochemical properties of the secreted monoclonal immunoglobulin (MIg) instead of tumor masses lead to the disorders (3). Recently the term of monoclonal gammopathy of renal significance (MGRS) has been suggested when an MGUS is causing kidney disease in the absence of a malignancy warranting treatment (4). It is a new classification of pathogenic clonal proliferative disorders that produce a nephrotoxic protein, the diagnosis of which can be established only by performing a kidney biopsy (5). In addition to MIg deposition, there may be other mechanisms involved in the secretion of various biologic factors and/or MIg autoantibody activity in MGRS. For example, secreting vascular endothelial growth factor in polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome may trigger the development of renal endothelial cell injury and thrombotic microangiopathy (TMA) (6), or membrane proliferative glomerulonephritis (MPGN) which were induced by a dimeric monoclonal lambda light chain (LC) as a “micro autoantibody” to complement factor H (7). A diversity of disease manifestation has been reported in MGRS, from isolated proteinuria to the development of end stage kidney disease (ESKD), which therefore require timely clone-directed treatment targeting the B-cell monoclonal proliferation responsible for the production of nephrotoxic Ig or Ig subunits (8).

Due to the various clinical and pathological manifestations of kidney involvement in LPD, it is difficult for clinical diagnosis and subsequent treatment, and therefore the prognosis is unsatisfactory (9, 10). The whole spectrum of kidney disease in LPD is still unclear, and data on kidney prognosis is scarce. We herein retrospectively analyzed the spectrum of kidney damage in patients with LPD which were confirmed by renal biopsy to shed light on timely diagnosis and individualized therapy in LPD-related renal damage.

The single-center case series of 28 patients during an 11-year period reveals pathological diversity and clinical complexity of kidney disease associated with B-LPD. Previous studies have reported a limited number of cases with renal involvement in B-LPD, however, scarce data has been addressed the biopsy-proven renal pathological changes. Li et al. reviewed 20 patients with renal impairment in NHL and the most common type of lymphoma was CLL (40%), followed by DLBCL (20%) (24). However, Sun et al. (25) showed that the most common lymphoma subtype in China was DLBCL (36.2%). Inconsistent with previous studies, WM/LPL was more frequent in this study. While renal amyloidosis was one of the most common kidney pathological changes in this study (n=4), which was consistent with previous studies. Chauvee et al. found amyloidosis was the most common lesions in the study of 35 patients diagnosed of B-LPD, accounting for 31% of cases (26). A recent retrospective study conducted at the Mayo Clinic, including 57 patients with WM and other IgM-producing B-LPD, found that 47 (82%) patients had MIg-associated kidney damage, 19 (33%) of whom had amyloidosis (3). Amyloid is a heterogeneous group of diseases which is diagnosed by immunofluorescence, immunoelectron microscopy, or mass spectrometry examination, and the corresponding treatment and prognosis vary widely. It has been reported that the kidney damage associated with B-LPD was mainly AL amyloidosis, with EM examination showing randomly arranged fibrillar material ranging from 9 to 11 mm in diameter (27).

MGUS is a low-grade B-LPD manifested by monoclonal protein <3 g/dl and bone marrow plasma cells <10%. Kidney disease has been reported as a common complication of MGUS and the pathological pattern was mainly determined by the physicochemical properties of the pathogenic MIg rather than its concentration (8). In the present study, we reported a case of membranous nephropathy and two cases of AIN, representing cases of MGUS. Those biopsy-diagnosed AIN had performed immunohistochemistry examination, the results of which suggested renal infiltration were unrelated to tumor cells (Table S1). And other factors such as nephrotoxic drugs could be taken into account. When intrinsic nephrotoxic properties of certain monoclonal Igs or their subunits induce kidney diseases, it is referred to as MGRS which implies that the pathological consequences of MIg should take priority over the hematological status (28). The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify either the monotypic immunoglobulin deposits or infers their involvement in the case of C3 glomerulonephritis or TMA with a circulating monoclonal immunoglobulin (5).

C3 glomerulonephritis is a typical MGRS-related disease primarily caused by dysregulation of the alternative complement pathway. Recent studies have reported an unusually high prevalence of MIg and TMA in patients with C3 glomerulonephritis compared to the age-matched general population (29, 30). In our study, we observed one patient with MGRS had typical renal pathology of C3 glomerulonephritis combined with TMA. Light microscopy examination showed glomerular mesangial hyperplasia, sclerosis while immunofluorescence examination showed C3 deposition without other MIg deposits. Another case of biopsy-proven, kidney-limited TMA combining with diffuse proliferative sclerosing glomerulonephritis, had coexisting paraproteins which are potentially causative in our opinion. In addition to our cases, others have reported that kidney-biopsy TMA with a clone of B-lineage cells insufficient to diagnose a malignancy, represent cases of MGRS and the presumed mechanism of which is disordered complement regulation (31–34). Previous studies suggested that MGRS strongly associated with renal prognosis, so early clone-directed intervene may be essential (7, 35). However, all three patients with MGRS in our study were untreated. The available disease-modifying treatments for MGRS are to target a monoclonal Ig-producing proliferation whose existence is frequently speculative, and therefore identifying whether kidney pathological patterns are related to paraproteinemia may shed light in designing optimal treatment strategies (28). Another major difficulty for nephrologists in clinical practice is to convince hematologists to administer timely and effective chemotherapy to patients with MGRS. It is urgent to aware the necessity of the clone-specific therapy for MGRS which need the cooperation of hematologists and nephrologists (7).

Currently, MIg-related glomerulonephritis has been widely studied, but the association between non-MIg-associated glomerulonephritis, such as FSGS, diabetic nephropathy, and B-LPD has not reached consistent results (10, 36). It has been suggested that these entities were not associated with B-LPD and may have a diagnosis consistent with hematological disease (10). Malignant lymphoma was rarely concurrent with secondary IgAN. The incidence of IgAN has been reported in association with T-cell lymphoma (37), Hodgkin’s lymphoma (38) and B-cell lymphoma in several cases (36, 39). The timing of the onset of IgAN and remission after chemotherapy suggest that IgAN may be a result of a paraneoplastic phenomenon in these cases. Studies have suggested that B-cell lymphoma may be involved in the pathogenesis of IgAN through the direct production of abnormal IgA1 and autoantibodies by dysregulated clonal B-cell populations (40). In this study, there were two cases of IgAN, diagnosed almost simultaneously with hematological disease, in which the main clinical manifestation was microhematuria rather than nephrotic-range proteinuria. One case died of multiorgan failure and the other patient reached complete response after treatment, considering that this patient had IgAN secondary to lymphoma.

It has been reported that 80% of lymphomas invading the kidney presenting as AKI, but limited studies elaborated on the type of B-cell lymphoma (41). In one study conducted by Javaugue V et al, the incidence of AKI was 56%, with the highest incidence in DLBCL (75%), and 58% and 67% for the presentation of hematuria and proteinuria respectively (10). However, in another study by Chauvet S et al. (26), hematuria (74%) and proteinuria (>50%) were found to be more frequent, whereas the incidence of AKI was only 29%. The findings of the current study were consistent with the results by Chauvet S et al. (26), with a 29% prevalence of AKI and a higher incidence of proteinuria (82%), possibly due to the similarity in the number of cases. The study by Chauvet S. et al. (26) did not include patients with DLBCL, while two patients with DLBCL were included in our study, with renal pathological changes of biopsy-proven lupus nephritis and IgAN.

Previous studies found that the most common lesions involving the kidney in BLPD were lymphoma malignant infiltration in renal tubulointerstitial, severe infiltration of tumor cells, combined with acute tubular necrosis, which may lead to severe renal involvement (10, 26). Javaugue V (8) performed an immunophenotypic analysis of renal infiltration in 50 patients with BLPD, of whom 49 patients stained positive for a B-cell marker (CD20), consistent with bone marrow immunohistochemical findings, confirming that the cells infiltrating the interstitial tissue were malignant cells. In our study, lymphocytic infiltration of interstitial tissue was observed in all 28 patients by light microscope. Further immunohistochemistry examination was performed in eight patients including five cases with biopsy-proven AIN, showing confirmed interstitial infiltration as tumor cells in three of them, with the corresponding immunophenotypes in bone marrow. The other three patients showed chronic interstitial inflammatory reaction and no lymphoma infiltration was observed. Immunohistochemistry examination is necessary to identify the type of infiltrating cells, as factors such as infection, toxicity and chemotherapeutic agents may also contribute to the development of AIN.

The study population size was too small to statistically assess the prognostic impact of chemotherapy on B-LPD related kidney damage. Three patients died within 4 months after the diagnosis of kidney disease, suggesting that the survival rates of patients with kidney diseases may be very low. However, three of the five patients who achieved hematological response developed renal response, indicating that early introduction of chemotherapy specifically targeting potential B cell clones may have the potential to prolong the survival time of patients. In this study, one patient with WM combined with cryoglobulinemic glomerulonephritis was prescribed with ibrutinib after unremarkable regimen of rituximab, cyclophosphamide and dexamethasone) (RCD). And the patient got off dialysis and achieved renal remission in a very short time. Further well-planned large prospective studies of the efficacy of ibrutinib on lymphoma concurrent with kidney disease may get more useful and reliable information.

In conclusion, the clinicopathological features of renal involvement in B-LPD are diverse and complex. MIg-associated kidney disease has been relatively well studied previously, whereas less attention has been drawed on non-MIg-associated glomerulonephritis which requires distinction from primary to secondary forms. Renal biopsy and immunohistochemistry examination have the necessity for early diagnosis and prognostic assessment. Additionally, for MGRS early and proper diagnosis is essential to maximize the chance of disease-modifying treatments targeting a monoclonal Ig-producing proliferation. Further large, randomized controlled, prospective studies are still needed to ascertain the short- and long-term efficacy of kidney lesions on MGRS.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

The study was reviewed and approved by ethics committee of the First Affiliated Hospital of Nanjing Medical University (2022-SR-083).

GN designed the research and contributed to the writing. LS analyzed the data and performed statistical analysis. CZ, YY, HM, ZW, and JL reviewed the manuscript. CX and SD conceived, coordinated the study, and had responsibility for its final content. BZ is the guarantor of this work who had complete access to all the data in the study and takes ultimate responsibility for the study design and integrity of data analysis. All authors contributed to the article and approved the submitted version.

This work was supported by grants from the National Natural Science Foundation of China (82170699, 81870469 to YY, No. 82100767 to SD), the Natural Science Foundation of Jiangsu Province (No. BK20131030 to YY, BK20191075 to SD), the China Scholarship Council (CSC, File No. 201608320124), Chinese Society of Nephrology (17010060675 to YY, 17010090678 to SD), “PRO•Run” Fund of the Nephrology Group of CEBM(KYS2021-03-02-14 to BZ), Project of clinical capability improvement of the First Affiliated Hospital of Nanjing Medical University(to SD), the Clinic Research Center of Jiangsu Province (No. BL2014080) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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