Paraneoplastic glomerulopathy in hematologic malignancies
Paraneoplastic syndromes in the context of hematologic malignancies have been reported among multiple organ systems, including the nervous system, skin, bone marrow, and kidneys. Paraneoplastic glomerular injury has been demonstrated to be the result of tumoral production of cytokines, monoclonal and amyloid proteins, cryoglobulins, and the development of autoimmune diseases. Direct leukemic or lymphomatous infiltration of the kidney will not be included in this discussion, because paraneoplastic glomerulopathy (PNGN) refers to renal disease that is not a direct result of tumor burden, invasion, or metastasis.
Box 23.1 illustrates the 2016 World Health Organization classification of hematologic malignancies. The major subtypes are grouped by lineage into lymphoid, myeloid, and histiocytic/dendritic neoplasms. This chapter will focus on the lymphoid and myeloid lineages, because there are no reports of PNGN with the latter subgroup. The prevalence and types of PNGN can vary significantly among the two major subtypes. Overall, the reported incidence of PNGN related to hematologic malignancies is quite rare, with the total number of case reports in the literature only slightly in excess of 200. When compared with myeloid neoplasias, PNGN has been reported relatively more frequently in patients with the lymphoid malignancies, specifically Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL). Among the lymphoid neoplasias, paraneoplastic minimal change disease (MCD) and focal segmental glomerular sclerosis (FSGS) are more frequently reported with diseases of the T-cell lineage like HL, whereas paraneoplastic membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) are more commonly reported with B-cell lineage tumors like CLL.
Non-Hodgkin lymphoma, which includes
Mature B-cell neoplasms
Mature T and natural killer cell neoplasms
Posttransplant lymphoproliferative disorders
Chronic myeloid leukemia
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement
Chronic myelomonocytic leukemia
Acute myeloid leukemia and related neoplasms
B- and T-cell lymphoblastic leukemia
The frequency of renal involvement with lymphoid neoplasia ranges from 16% to 33%, depending upon the case series. , Varied patterns of glomerular lesions have been reported with the lymphoid malignancies, but there seems to be predilection for specific lesions. The following subsections present the paraneoplastic lesions associated with lymphoid neoplasia in their order of reported relative frequency. Fig. 23.1 illustrates the relative distribution of the patterns of PNGN based on case reports and case series in the literature. MCD and FSGS, which are glomerular lesions characterized by podocyte injury, account for more than 50% of case reports. Proliferative lesions like MPGN account for about one-third of the reported cases. Most of the discussion in this section will focus on HL, NHL, and CLL because most of the cases of PNGN have been linked with these diseases. Lymphoid neoplasias that have been less frequently associated with a PNGN are discussed in the final portion of this section.
Lymphoid malignancies: Minimal change disease and focal segmental glomerular sclerosis
MCD and FSGS are discussed together in this section because both entities present with podocyte injury, proteinuria, and minimal immune deposits. PNGN in patients with HL has been reported in up to 0.4% of cases. MCD is the most commonly reported glomerular lesion with HL. It is more frequently seen in the classic form of HL, including the mixed cellularity and the nodular sclerosing subtypes. The secondary MCD associated with HL exhibits a high degree of steroid and cyclosporine resistance, but generally goes into remission with successful treatment of the HL. The occurrence of nephrotic syndrome (NS) can precede the development of malignancy by several years, and recurrence of NS can often herald relapse of the lymphoma. The incidence of paraneoplastic FSGS is about one-tenth that of MCD. This form of secondary FSGS will also respond to chemotherapy administered for treatment of the primary lymphoma. Among patients with NHL, mantle cell lymphoma (MCL) has been reported in association with FSGS in two cases, and in both, the glomerular disease responded well to chemotherapy for the MCL. ,
The pathogenesis of paraneoplastic MCD and FSGS remains poorly defined. Both lesions are essentially the sequela of injury and dysfunction of the glomerular podocyte. As such, paraneoplastic MCD and FSGS may result from abnormal tumoral expression of proteins, which are involved with cytoskeleton organization and podocyte signaling. There are several tumoral proteins of interest in this regard. Paraneoplastic MCD in patients with HL may be related to the increased production of the T-helper 2 cell (Th2) cytokine interleukin (IL)-13. In patients with HL, T-cells tend to expand towards the Th2 cell, and IL-13 levels are increased in the serum of patients with MCD. In a rat model, increased production of IL-13 produces an MCD-type nephropathy. Another putative protein is c-mip (c-maf inducing protein). Increased expression of c-mip switches off the interaction between nephrin and tyrosine kinase-fyn. This in turn leads to defects in cytoskeleton organization and proximal podocyte signaling that may lead to the development podocyte disease. Increased production of vascular endothelial growth factor (VEGF) has also been associated with the development of podocyte dysfunction. There are cases of paraneoplastic FSGS with HL and NHL in which altered T-cell function led to abnormal secretion of VEGF, which in turn led to increased glomerular permeability. A similar pattern of podocyte injury has been observed with the tumoral cytokine, transforming growth factor beta (TGF-β). ,
Lymphoid malignancies: Membranoproliferative glomerulonephritis
Among the lymphoid neoplasias, paraneoplastic MPGN has been reported most often in association with the B-cell lineage diseases, specifically NHL and CLL. The most common etiology for NS in patients with CLL is MPGN, followed by MCD and MN. , , The T-cell lineage HL has seldom been associated with the development of paraneoplastic MPGN.
There are several different mechanisms that have been suggested for the development of paraneoplastic MPGN with lymphoid neoplasia. One theory is that the glomerular lesion is caused by monoclonal immunoglobulins (Igs) that are secreted by B-cell clones. Alternatively, the tumor may produce another monoclonal Ig, specifically cryoglobulins. Chronic hepatitis C viral infection (HCV), with or without circulating cryoglobulins, is a significant infectious etiology of MPGN. It has been postulated that the HCV, which directly infects circulating peripheral blood mononuclear cells and bone marrow cells, stimulates the B lymphocytes to synthesize the type II mixed cryoglobulin. Using reverse transcriptase/polymerase chain reaction technique, investigators could detect IgM producing clonal B-cells in 38 patients with HCV infection, with and without type II mixed cryoglobulinemia. , They hypothesize that monoclonal B-cell clones may arise in a minority of patients with more severe lymphocyte dysfunction and a greater impairment of the immunoregulatory mechanisms. These clones then drive the development of both paraneoplastic MPGN and lymphoproliferative disorders. In one series of 119 consecutive HCV positive patients diagnosed with mixed cryoglobulinemia, 16 patients had mixed cryoglobulins and MPGN. Bone marrow biopsies performed on patients with MPGN and those without MPGN showed a higher prevalence of lymphoma in the group with MPGN. This leads to the speculation that MPGN in this setting may represent a PNGN because of an occult B-cell lymphoma. These investigators also observed that all patients with MPGN died of infection and/or cardiovascular disease, suggesting severe lymphocyte and dysfunction in this group. Although HCV is the major cause of mixed cryoglobulinemia, there is no evidence to suggest that viral infection is required for the pathogenesis of paraneoplastic MPGN.
Lymphoid malignancies: Membranous nephropathy
Membranous nephropathy is relatively uncommon in patients with lymphoid malignancies. MN has been described relatively more frequently in association with the B-cell lineage diseases, such as CLL and NHL, compared with the T-cell lineage neoplasias. There is a solitary case of MN in association with MCL. In a case of MN in association with CLL, the glomerulopathy responded to treatment with fludarabine.
Less common reports of paraneoplastic glomerulopathy with lymphoid neoplasia
Waldenström macroglobulinemia (WM) is a type of NHL. This B-cell lymphoid disorder constitutes about 2% of hematologic malignancies and is associated with a monoclonal IgM protein. The most common renal manifestations include hematuria and proteinuria. In a case series of 1391 patients with WM, the reported incidence of WM-associated nephropathy at 5 years was 5.1%. The diagnosis of both WM and renal disease was made concurrently in 54% of cases. Some of the lesions that were thought to be directly related to WM included, in order of frequency, light chain (AL) amyloidosis, monoclonal IgM deposition/cryoglobulinemia and lymphoplasmacytic lymphoma infiltration were the most common pathologies noted on the kidney biopsy. Lesions that were less commonly observed, and which may have represented a paraneoplastic process, included thrombotic microangiopathy (TMA), MN, and MCD. Precipitation of IgM in the capillaries, infiltration of the interstitium with malignant cells, and proliferative glomerulonephritis are some additional glomerular abnormalities described on the renal biopsy reports in patients with WM. , ,
Amyloid and lymphoid malignancies
Amyloidosis has historically been associated with HL, with most of the cases noted before 1970. The majority of these cases of amyloidosis with HL were AA or secondary amyloid, and this finding may be related to the later inflammatory stages of the disease. This is supported by the observation that, with advances in the treatment of HL, the incidence of Amyloid A (AA) amyloid has decreased. In contrast to patients with HL, patients with NHL generally present with primary, or AL-type, amyloid. , Still, there are rare case reports of NHL with AA-type amyloidosis. AL-amyloid has been reported in patients with monoclonal gammopathy in B-cell lymphomas and WM, where a single light chain type has been localized within fibrillar amyloid deposits.
Other lymphoid malignancies
Although most of the paraneoplastic glomerular lesions have been reported in HL, NHL, and CLL, there are scattered case reports of PNGN more rarely associated with other lymphoid neoplasia. In patients with MCL, glomerular involvement can be seen in the form of proliferative glomerulonephritis and immune complex mediated glomerulonephritis. Among patients with small lymphocytic lymphoma, antineutrophil cytoplasmic antibody-mediated crescentic glomerulonephritis (about than eight cases till date), as well as focal necrotizing glomerulonephritis, has been reported. B-cell lymphomas have also presented with extracapillary proliferative glomerulonephritis in association with granulomatosis and polyangiitis. Isolated MPGN with C3 deposits has been reported in patients with HCL. With angiotrophic lymphomas, which are characterized by the presence of primarily B-lymphocytes in small vessels, neoplastic lymphoid cells have been shown to infiltrate the glomeruli and peritubular capillaries. Large cell lymphoma has been shown to cause extensive deposition of IgM kappa monoclonal Ig in the glomerular capillary lumen and can lead to the finding of amorphous material on renal biopsies. Patients generally present with NS and may have enlarged kidneys on renal ultrasound. This could be related to the production of a local lymphocyte factor also referred to as a vascular permeability factor and altered glomerular hemodynamics. , “Crystal-storing histiocytosis” whose renal involvement is characterized by mesangial infiltration with mononuclear/multinuclear cells with rhomboid shaped crystals can be seen in the setting of a low-grade lymphoproliferative disorder. IgA nephropathy has been described in association with cutaneous T-cell lymphomas.
Myeloid neoplasia constitutes a heterogeneous group of clonal hematopoietic stem cell disorders, which can be subdivided into acute and chronic myeloid neoplasia based on peripheral blood findings or bone marrow findings. Based on the 2016 World Health Organization classification (see Box 23.1 ), the myeloid neoplasms are further subdivided into myeloproliferative neoplasias (MPN), myeloid/lymphoid neoplasms with eosinophilia with various rearrangements, myelodysplastic syndrome (MDS), and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The MPN are further subcategorized into chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis. ,
In comparison with the lymphoid malignancies, the reported incidence of PNGN among patients with myeloid malignancies is much less common. Fig. 23.2 illustrates the relative percentages of paraneoplastic glomerular lesions reported with the types of PNGN among myeloid malignancies. Overall, mesangioproliferative glomerulonephritis is the lesion that has been most commonly reported on renal biopsy, followed by FSGS. In MDS, the incidence of PNGN has been reported to be from 0.5% to 4% with a wide variety of presentations, including mesangioproliferative glomerulonephritis, MN, IgA nephropathy, and rapidly progressive glomerulonephritis (RPGN). , , Among patients with myeloproliferative neoplasia, the incidence of PNGN has been reported to be around 3.6%. The pattern of renal involvement in patients with MPN is quite variable and is referred to as MPN-related glomerulopathy . , , Some of the pathologic findings include mesangial/segmental sclerosis, hypercellularity, chronic TMA, and intracapillary hematopoietic cell infiltration. The differential diagnosis of MPN-related glomerulopathy includes primary FSGS, diabetic glomerulosclerosis, smoking related glomerulopathy, TMA, and MPGN.
In patients with acute myeloid leukemia (AML) who were biopsied for the evaluation of nephrotic range proteinuria, FSGS, MPGN, mesangioproliferative glomerulonephritis, and MCD have been identified. In patients with CML and nephrotic range proteinuria, the renal biopsy showed a range of glomerular lesions similar to those observed with AML, with the exception of FSGS. Owing to the indolent nature of CML, the development of PNGN may be coincidental. , In isolated case studies where MCD and RPGN were diagnosed in the setting of CML, the glomerular lesion was treated effectively with immunosuppression without any effect on the underlying CML.
Several pathogenic mechanisms for glomerular injury have been postulated for PNGN associated with myeloid neoplasias. Increased concentrations of lysozyme in the urine of patients with chronic myelomonocytic leukemia has been described to produce nephrotic range proteinuria. This has been referred to as pseudonephrotic syndrome . Other possible etiologies include splenomegaly-induced immunosuppression, autoimmune dysregulation, and increased production of platelet derived growth factor (PDGF) and TGF-β. ,
Myeloid neoplasia: Mesangioproliferative glomerulopathy
Among the myeloproliferative neoplasms, mesangioproliferative glomerulopathy is more commonly associated with primary myelofibrosis as compared with ET, PV, or CML. The presence of MPN-related glomerulopathy is generally detected late in the course of the disease and is characterized by the development of proteinuria that is refractory to the usual treatments for proteinuria. , Histologically speaking, mesangioproliferative glomerulopathy is characterized by the presence of mesangial hypercellularity and duplication of the glomerular basement membrane with a subendothelial electron lucent layer. These features are similar to those seen with chronic TMA. Rarely, nodular mesangial sclerosis has been observed. There are no immune complexes on electron microscopy and immunofixation studies are also negative. On occasion, intracapillary hematopoietic cells can be seen. , , Increased levels of TGF-β, and PDGF, are thought to be responsible for this mesangioproliferative pattern by promoting mesangial cell expansion and extracellular matrix proliferation. Upregulation of PDGF-A within the mesangial cells and PDGF-D have been demonstrated in animal models of anti-Ty 11 mesangioproliferative glomerulonephritis. Blockade of these pathways has been shown to reduce mesangial cell proliferation and tubulointerstitial fibrosis. Concurrent to the aforementioned findings, rat models have also demonstrated an upregulation in PDGF receptor messenger ribonucleic acid between days 3 and 5 of disease induction, which corresponds to the time of mesangial cell proliferation.
Myeloid neoplasia: Focal segmental glomerular sclerosis
In patients with myeloproliferative neoplasia, the pathogenesis of FSGS may be related to alterations in lymphocyte function, which may in turn lead to increased production of “permeability factors.” Purported permeability factors include cytokines such as TGF β-1, PDGF, basic fibroblast growth factor (BFGF), VEGF, epidermal growth factor (EGF), endothelial cell growth factor, and IL-1. These cytokines have been related to both the development of myelofibrosis and FSGS. In addition to these systemic cytokines, locally produced cytokines such as PDGF, tumor necrosis factor (TNF), and IL-1β are also associated with FSGS. PDGF is a major cytokine, whose synthesis can be induced by PDGF itself, EGF, and TGF-β. Under hypoxic conditions, the glomerular endothelial cells are stimulated to produce PDGF. Under conditions of hyperfiltration, hepatocyte growth factor and TGF-β are ultrafiltered in the glomerulus and stimulate the production of PDGF. In concert with other cytokines such as TGF-β, PDGF promotes extracellular matrix synthesis and mesangial cell contraction, leading to alterations in the glomerular hemodynamics. , In animal models, PDGF and TGF-β play an important role in the development of glomerulosclerosis, promoting podocyte apoptosis, and the development of FSGS-like lesions. These strong profibrotic stimuli act in concert with other members of the TGF family, including thrombospondin 1 and phosphorylated Smad2/Smad3. Increased expression of BFGF in addition to VEGF has also been implicated in the development of FSGS among these patients.
In the setting of MPN, increased production of PDGF, Platelet-Activating Factor (PAF), and TGF-β has been shown to stimulate intense fibrosis in the mesangial cells. In patients with ET, there is increased production and abnormal function of platelets. The increased intraglomerular accumulation of platelets has been associated with the release of TGF-β which, in addition to producing fibrosis, also serves as a mitogen for glomerular cell proliferation. In patients with PV, alterations in glomerular hemodynamics including renal vasodilatation and an increase in effective renal blood flow have been observed. Patients with PV can also develop hyperviscosity, which predisposes to the development of microvascular thrombi. Both of these processes can lead to endothelial cell injury, activation of macrophages, and extension of the extracellular matrix.
Myeloid neoplasia: Membranous nephropathy and membranoproliferative glomerulonephritis
Both MN and MPGN have only rarely been reported in association with the myeloproliferative disorders. They are relatively much more commonly seen with lymphoid neoplasias. , , MN has been described in association with AML and chronic myelomonocytic leukemia (CMML). , Because of the indolent nature of CMML, the association of membranous nephropathy may or may not be related to the neoplasia. Patients have shown response to treatment with imatinib and mycophenolate mofetil in rare cases. MPGN has been described in association with CML as well as PV. ,