Glomerular Diseases Associated With Cancer and Its Treatment

Purva Sharma

Kenar D. Jhaveri

Jaya Kala

INTRODUCTION

Onconephrology is a new subspecialty of nephrology that recognizes the important intersections of kidney disease with cancer. This intersection takes many forms and includes drug-induced nephrotoxicity, electrolyte disorders, paraneoplastic glomerulonephritis (GN), and the interactions of chronic kidney disease (CKD) with cancer.¹ Paraneoplastic GN is a rare complication of malignancy, which is not directly related to the tumor burden, invasion, or metastasis. It is induced by products from tumor cells, such as hormones, growth factors, cytokines, and tumor antigens, which alter immune responses. Glomerular diseases are associated with many solid and hematologic malignancies² (Visual Abstract 19.1). These glomerular lesions are thought to be paraneoplastic, but in most cases, the exact pathogenesis is unclear. The treatment of these cancer-associated glomerular diseases is primarily targeted at the underlying malignancy. Increased cancer rates are seen with many different types of glomerular diseases.³ The increased incidence was mainly limited to − 1 to 1 year after biopsy, but skin cancer showed an increased risk over time. The risk of developing cancer 0 to 3 years after kidney biopsy for patients 45 to 64 years varied from 7.3% to 15.8%, and for patients 64 years and older from 11.8% to 20.3%. The diagnosis with the highest risk for a cancer association was membranoproliferative glomerulonephritis (MPGN).³ Figure 19.1 summarizes the various glomerular diseases and respective cancers associated with them. The diagnosis of paraneoplastic GN should be considered if it occurs in the presence of malignancy, remits after treatment of the malignancy, and recurs with recurrence of the malignancy⁴ (Visual Abstract 19.2). These conditions are of importance to the nephrologist because they may be an initial presentation of underlying malignancy and do not usually respond to usual therapies otherwise used for non-paraneoplastic GN.

SOLID TUMOR-ASSOCIATED GLOMERULAR DISEASES

Membranous Nephropathy

Membranous nephropathy (MN) is a spectrum of disease that is characterized by the presence of deposits of immunoglobulin and complement containing immune deposits in the subepithelial space. The classification into primary and secondary is based on clinical and pathologic clues. In primary MN, there is an autoimmune response to the normal podocyte antigen in the absence of any systemic disease

or agent. Secondary MN arises because of autoimmune response in the setting of systemic infections, malignancy, or drug exposure.

FIGURE 19.1: Glomerular diseases associated with solid tumors and hematologic malignancies. CLL, chronic lymphocytic leukemia; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; MGUS, monoclonal gammopathy of unclear significance; MN, membranous nephropathy; MPGN, membranoproliferative glomerulonephritis. (Adapted from Jhaveri KD. http://www.nephronpower.com/2015/01/concept-map-glomerular-diseases-seen.html; with permission.)

Several solid and hematologic malignancies have been associated with glomerular diseases. The presence of proteinuria in a known case of cancer or development of proteinuria within a few months of diagnosis of cancer should raise a strong suspicion of underlying glomerular disease, especially MN. It is commonly associated with solid malignancies such as lung and gastric tumors.⁵

Paraneoplastic GN has been explained by very few animal models. Takeda et al described one such model, which proposed that a T-cell response might be critical in the development of paraneoplastic GN (Figure 19.2).⁶

Recent advances have highlighted some features that can help distinguish primary from secondary or paraneoplastic MN. Autoantibodies to phospholipase-A2 receptor (PLA2R) may be responsible for primary MN in almost 80% of patients. This discovery has enabled the use of serologic assay for diagnosis avoiding the need of kidney biopsy in certain situations.⁷ Thrombospondin type-1 domain-containing 7A (THSD7A) accounts for 1% to 3% of MN cases in the western countries.⁸ It is also overexpressed in certain malignancies such as gall bladder and endometrial cancers. Polysomy of chromosome 7 leads
to overexpression of THSD7A in tumors. The autoimmune response toward the autoantigens causes MN. Strong THSD7A staining has also been seen in prostate, breast, kidney, and colorectal cancers.⁹ Autoantibodies to neural epidermal growth factor-like 1 (NELL-1) protein is another recent addition to the list of antigens implicated in MN. NELL-1-associated MN was identified in approximately 16% of PLA2R-negative MN cases without any identifiable secondary cause. The current literature suggests a connection between NELL-1 associated MN and malignancy.¹⁰ Yet another antigen, semaphorin-3B, was identified in infants and children, and deposits were in a segmental pattern in the glomerular tuft and in the tubular basement membrane (TBM).¹¹ Of all the biopsies with diagnosis of MN, 30% are most likely associated with secondary causes. The precise pathology and antigens have not been clearly defined.¹²

FIGURE 19.2: Proposed mechanism of paraneoplastic glomerulonephritis (GN). Membranous nephropathy: The T-helper (TH-1) cells produce interferon-alpha (IFN-α), interleukin-2 (IL-2), and tumor necrosis factor-beta (TNF-β), which cause proliferative forms of GN, whereas the TH-2 cells produce IL-4, IL-5, IL-10, and IL-13, which cause membranous GN.¹¹ There have been four proposed mechanisms to explain the pathogenesis of membranous nephropathy: (A) Tumor antigens mimicking endogenous podocyte antigens lead to antigen-antibody complex formation, which deposit in the subepithelial space; (B) circulating tumor antigens may get entrapped in the glomerular capillary wall attracting circulating antibodies, forming immune-complex deposits; (C) the antigen-antibody complexes formed in circulation may get trapped in subepithelial space; and (D) external trigger such as infections may cause direct development of MN in patients with malignancy.³⁶ Minimal change disease: Studies have shown the role of vascular endothelial growth factor (VEGF) in minimal change disease, collapsing variant of focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA).¹¹ The overexpression of VEGF leads to FSGS and underexpression leads to TMA.³⁷ (Created with BioRender.com.)

All patients with MN should receive supportive management with antiproteinuric measures with angiotensin-converting enzyme inhibitors or angiotensin-receptor antagonist, blood pressure control, and dietary sodium restriction. Diuretic therapy and cholesterol-lowering agents are provided as per patient requirements. In malignancy-induced MN, the treatment of malignancy is essential, along with supportive therapy. If there is no remission in proteinuria with the treatment of cancer, then trial of immunosuppression as for primary MN is recommended.¹²

Other Glomerular Diseases

Minimal change disease (MCD) is classically associated with nodular sclerosing and mixed cellular type of Hodgkin lymphoma and in few cases of breast, gastrointestinal tract, bladder, pancreatic, ovarian, or thymoma. Nephrotic syndrome (NS) occurs early during malignancy or coinciding with the diagnosis.¹³ It is highly responsive to cancer treatment and recurs with relapse. MPGN is associated with lung, kidney, and stomach cancers. IgA nephropathy has been most frequently associated with kidney cell cancer. It is also associated with T-cell lymphoma.⁵

MPGN and rapidly progressive GN (RPGN) have been described in patients with lymphomas and solid tumors. Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have an increased risk of preceding or concurrent malignancy.¹⁴ In a series of patients with crescentic GN, prevalence of malignancy was seen in 20% of patients.¹⁵ Kidney biopsy is crucial in making accurate diagnosis, which may turn out to be different from the presumptive diagnosis.

Kidney involvement in lymphoma is often clinically silent and requires a high index of suspicion to make a diagnosis. Patients may present with acute kidney injury (AKI), but this is rare and is most commonly seen in highly malignant and disseminated disease.¹⁶ Other presentations include proteinuria in both the nephrotic and non-nephrotic range, as well as a variety of glomerular lesions including pauci-immune crescentic GN.¹⁷

It has been proposed that paraneoplastic MPGN is an immune-complex disease that is induced by the combination of tumor antigen formation and the inability of the host to effectively clear circulating antigens.¹⁸

In malignancy-induced glomerular lesions, the treatment of the cancer is important. After tumor resection, proteinuria has been noted to disappear in patients with rectal adenocarcinoma-associated MCD. The primary treatment of MPGN associated with solid tumors is tumor ablation and, in those cases, where this is not possible, a trial of prednisone treatment to control NS seems reasonable. Tumor ablation is the treatment of choice for paraneoplastic IgA nephropathy, whereas corticosteroids therapy may promote tumor growth.⁴

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA) manifests as nonimmune hemolytic anemia, thrombocytopenia, and organ dysfunction, including AKI. The presence of TMA could be a presenting feature of an underlying cancer or seen in end-stage or advanced cancer. There is also extensive involvement of bone marrow causing bone pain at presentation. They do not respond well to plasma exchange (PLEX).¹⁹ In comparison to thrombotic thrombocytopenic purpura (TTP), cancer-induced TMA has more frequent respiratory symptoms (70% of patients), abnormal liver functions (transaminases, alkaline phosphatase, direct bilirubin), elevated creatinine, infiltrating carcinomas, or bone marrow necrosis. Cancer-induced TMA occurs because of induction of coagulation cascade from the hypoxia and inflammation-induced release of tissue factors (TFs), cancer procoagulants, tumor-derived cytokines, and plasminogen activator inhibitor-1 (PAI-1) (Figure 19.3). The endothelial injury can occur from direct invasion or substances produced from the tumor.²⁰ Majority of these are seen with solid tumors such as gastric and colon cancers, but hematologic cancers such as lymphomas are seen in approximately 8% of cases.²¹

Treatment of kidney failure and TMA in cancer patients from any etiology is mainly supportive with initiation of dialysis as necessary. The role of PLEX is controversial because it has not been uniformly beneficial. Low ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type-1 motif, member 13) activity (<5%) indicates TTP and should be treated with PLEX. With normal ADAMTS13 levels, diagnosis of atypical-hemolytic uremic syndrome (aHUS) is likely, and strong consideration should be given to administering eculizumab, a humanized
monoclonal antibody that inhibits terminal complement activation by binding to complement C5 and preventing formation of the terminal membrane attack complex.²²,²³

FIGURE 19.3: Possible mechanisms in cancer-associated thrombosis and thrombotic microangiopathy (TMA) induced by drugs. Multiple, overlapping, and interacting mechanisms explain the increased incidence of thrombosis in patients with malignancies. In cancer-associated thrombosis, hypercoagulability is the result of products arising from the tumor itself. Auto-ab, auto-antibody; DIC, disseminated intravascular coagulation; NBTE, nonbacterial thrombotic endocarditis; PAI-1, plasminogen activator inhibitor-1, UL-vWF, ultra-large von Willebrand factor; VEGF, vascular endothelial growth factor. (Created with BioRender.com.)

HEMATOLOGIC CANCERS-ASSOCIATED GLOMERULAR DISEASES

Myeloma and paraprotein-related glomerular diseases are the most common glomerular diseases seen with hematologic cancers.

Paraproteinemia-Associated Glomerular Diseases

Multiple myeloma (MM) can be found in the kidney in various forms with tubular injury being the most common.²⁴ Table 19.1 summarizes the known glomerular diseases associated with myeloma. Although MM is traditionally associated with tubular and glomerular disease, there are also associations of kidney diseases with monoclonal gammopathy of undetermined significance (MGUS), monoclonal B-cell lymphocytosis, smoldering myeloma, Waldenstrom macroglobulinemia (WM), and low-grade lymphoma. These non-MM glomerular diseases are broadly defined as monoclonal gammopathy of renal significance (MGRS).²⁵

Although circulating light chains can lead to cast nephropathy (as discussed) and light chain-associated proximal tubular dysfunction (Fanconi syndrome), they may also deposit in the glomeruli leading to organized and nonorganized patterns of immunoglobulin deposits that can be seen with electron microscopy along with the clinical features of proteinuria, NS, microscopic hematuria, hypertension, and deterioration of kidney function. Organized deposits include AL amyloidosis, cryoglobulinemic GN, immunotactoid GN, and ostensibly fibrillary GN. Nonorganized deposits include monoclonal immunoglobulin deposition disease and proliferative GN with monoclonal immunoglobulin deposits (PGNMID). TMA can also be rarely associated with monoclonal proteins.²⁴,²⁶

Classification of MGRS is highly complex, and Table 19.2 describes the incidence, kidney biopsy findings, clinical presentation, associated hematologic disorders, mechanism of injury, and treatment outcomes (where available) for each type of kidney biopsy finding associated with MGRS (see also Chapter 15).²⁷,²⁸ Once the pathologic diagnosis is made, the next challenge is detecting a clonal cell line responsible for the production of the monoclonal protein.²⁹ Figure 19.4 is an algorithm for the diagnosis of MGRS. The most common glomerular diseases seen with WM are AL amyloidosis and cryoglobulinemic GN.³⁰

TABLE 19.1 Paraproteinemia-Related Glomerular Renal Diseases

Monoclonal immunoglobulin deposition disease (light chain/heavy chain), amyloidosis

Immunotactoid glomerulopathy

C3 glomerulonephritis

Proliferative glomerulonephritis with monoclonal deposits

Cryoglobulinemic glomerulonephritis

Monoclonal crystalline glomerulonephritis

Membranous-like glomerulopathy with masked IgG-κdeposits

Thrombotic microangiopathy (paraprotein- or treatment-related)

Fibrillary glomerulonephritis(?)

TABLE 19.2 Dysproteinemia-Associated Kidney Diseases, Incidence, Pathology, and Clinical Presentations

Kidney Biopsy Diagnosis	Clinical Presentation	Pathology	Most Common Protein	Heme Disorder	Clone Detection Rate	Paraprotein Detection Rate	Renal Outcomes
Cast nephropathy	AKI, non-nephrotic proteinuria	Tubular damage, intraluminal obstruction, interstitial nephritis	κ	MM, CLL, SMM, WM	100%	100%	Excellent renal recovery with chemotherapy agents with or without plasmapheresis
LCPT	AKI, Fanconi syndrome	Tubular damage, non-nephrotic range proteinuria	κ	MM, MGUS, SMM, CLL, NHL, WM	90%-100%	90%-100%	ESKD not defined but medial renal survival 64 mo
Crystalglobulinemia	AKI, proteinuria?	Tubular and vascular damage	κ	MM, LPL	100%	100%	ESKD not defined, median renal survival 135 mo
AL/AH amyloidosis	Proteinuria, AKI	Glomerular and vascular deposition, Congo red positive, 8-12 nm randomly arranged fibrils	Lambda, IgG (if heavy chain) and IgG lambda (if combined)	MM, CLL, LPL,	100%	100%	Overall patient survival 5 yr, proteinuria >5 g and eGFR < 50 mL/min best predictor of dialysis at 3 yr
LCDD	AKI, CKD, proteinuria	Deposition of pathologic LC in the glomeruli, tubules and vasculature	κ	MM (50%), MGUS, SMM	90%-100%	90%-100%	53% renal response if heme response achieved, median renal survival 5.4 yr, overall survival 67%, 5 yr 57% ESKD risk 53%
HCDD	AKI, CKD, proteinuria	Deposition of truncated HC in glomeruli, tubules, and vasculature	IgG1	MM (29%), MGUS, SMM	100%	100%	Renal survival 5.5 yr, overall survival 67% at 5 yr
LCHDD	AKI, CKD, proteinuria	Deposition of both heavy and light chain in glomeruli, tubules, and vasculature	IgG1 κ	MM (50%), MGUS, SMM	90%-100%	90%-100%	Median time to dialysis 2-3 yr, mean survival of 4-5 yr
Cyro-GN (type 1)	AKI, HTN, RPGN	Glomerular and vascular deposition of (Congo red negative, paired microtubules 25-40 nm) monoclonal protein	IgG/IgM with κ	MM, WM, CLL, B-NHL, MGUS, HCL	76%-82%	90%-100%	>78% in partial or complete remission
Cyro-GN (type 2)	AKI, HTN, RPGN	Glomerular and vascular deposition of (Congo red negative, paired microtubules 25-40 nm) monoclonal protein	IgM κ	LPL, WM, B-CLPD	40%-90%	NA	Not available
ITG	Proteinuria, hematuria, CKD	Glomerular deposition of protein (Congo red negative, 30-60 nm microtubules)	IgG1	CLL (19%), MM, LPL	63%-71%	63%	ESKD risk 17%, remission 50%
PGNMID	AKI, HTN, proteinuria, hematuria	Glomerular deposition of protein	IgG3 κ	None to some cases of MGUS, SMM	20%-30%	30%-40%	If clonal treatment, no ESKD; else ESKD risk is 38%-100%
C3 GN	AKI, RPGN, proteinuria, HTN	Alternative pathway activation and non-monoclonal deposits	IgG-κ	MGUS, SMM, MM, CLL, lymphoma	33%-83%	100%	ESKD risk 56%
Fibrillary GN(?)^a	AKI, HTN, proteinuria	Glomerular deposition of protein (Congo red negative, DNAJB9 negative, 15-20 nm randomly arranged fibrils)	IgG	MM, CLL	15%-17%	NA	ESKD risk 44%
TMA	AKI, HTN, CKD	Direct endothelial injury	IgG	MM, SMM, MGUS	NA	NA	ESKD risk 50%
AKI, acute kidney injury; B-CLPD, B-cell chronic lymphoproliferative disorder; CLL, chronic lymphocytic leukemia; CKD, chronic kidney disease; Cyro, cryoglobulinemia; ESKD, end-stage kidney disease; GN, glomerulonephritis; HC, heavy chain; HCDD, heavy-chain deposition disease; HCL, hairy cell leukemia; HTN, hypertension; ITG, immunotactoid glomerulopathy; LC, light chain; LCDD, light-chain deposition disease; LCPT, light-chain proximal tubulopathy; LPL, lymphoplasmacytic lymphoma; MM, multiple myeloma; MGUS, monoclonal gammopathy of unclear significance; NHL: non-Hodgkin lymphoma; PGNMID, proliferative GN with monoclonal deposits; RPGN, rapidly progressive glomerulonephritis; SLL, small lymphocytic lymphoma; SMM, smoldering myeloma; TMA, thrombotic microangiopathy; WM, Waldenstrom macroglobulinemia. ^{^a}The association of fibrillary GN with dysproteinemias is a subject of controversy. Adapted and modified from Rosner MH, Jhaveri KD, McMahon BA, Perazella MA. Onconephrology: the intersections between the kidney and cancer. CA Cancer J Clin. 2021;71:47-77. doi:10.3322/caac.21636