Paraneoplastic glomerular diseases

Introduction

Paraneoplastic syndromes refer to manifestations of cancer that are not related to tumor burden, invasion, or metastatic disease. The manifestations may be systemic or organ-limited and can involve virtually any organ system. There is a paucity of literature on paraneoplastic kidney disease (PnKD), likely because of the rarity of these conditions. This narrative review will focus on PnKDs that occur in the setting of solid tumors and hematologic malignancies.

Because most of the literature on the epidemiology of PnKD comprises case reports and case series, the incidence and prevalence of PnKD are difficult to ascertain. Some data have shown that the risk for cancer is higher in patients with glomerular disease than in the general population. For example, the Danish Kidney Biopsy Registry, which includes all kidney biopsies performed in Denmark since 1985, reported that the risk for cancer at 1 year and 1 to 4 years after the diagnosis of glomerulopathy was increased by 2.4- and 3.5-fold, respectively, compared with the general population. In a population-based study in Tromsø, Norway (originally designed to evaluate cardiovascular disease), the albumin-creatinine ratio at baseline for patients with glomerular disease significantly correlated with the incidence of cancer during 10 years of follow-up. Further, those with albumin-creatinine ratios in the highest quintile were 8.3- and 2.4-fold more likely to be diagnosed with bladder cancer and lung cancer compared with the lowest quintile. ^,

The pathophysiology of PnKD is usually linked to products of tumor cells or from paraneoplastic autoimmune manifestations that cause kidney damage. ^, This mechanism is well-characterized in certain paraneoplastic neurologic syndromes. For example, anti-Hu (ANNA1) antibody in the setting of small cell lung cancer is associated with encephalomyelitis, sensory neuropathy, and paraneoplastic cerebellar degeneration, and anti-Yo (PCA1) antibody in ovarian and breast cancers is associated with paraneoplastic cerebellar degeneration. However, with the exception of monoclonal gammopathies, the exact pathomechanisms linking tumor products and renal disease are poorly understood.

In patients diagnosed with PnKD, the temporal profile of the cancer diagnosis and kidney manifestations may be asynchronous. It is generally accepted that malignancies are present for up to several years before becoming clinically apparent. Patrone et al. applied a modified version of Collins’ law, which was originally used to estimate the time-to-recurrence of Pediatric Wilms tumors, in order to estimate the time-to-recurrence of adult solid tumors. Further, if more than 6 years have elapsed since remission of the cancer, it is unlikely that a glomerulopathy is related to the malignancy. To illustrate this point further, in the study by Lefaucher et al., the tumor was clinically evident in only 52% of the patients, underscoring the fact that cancers may be clinically silent and unless looked for systemically, may lead to unnecessary treatment of membranous nephropathy (MN).

The lack of published criteria for PnKD makes it challenging to distinguish between kidney disease occurring coincidentally in a patient with cancer and true PnKD. Box 21.1 summarizes “criteria” that have been suggested to help strengthen the link between cancer and kidney disease, when suspected. There are several case reports that satisfy criteria 1 and 2, but criteria 3 is generally lacking. The exceptions are plasma cell dyscrasias and B-cell disorders, which produce monoclonal antibodies that are directly toxic to the kidney.

Among the PnKD, and despite not meeting criteria 3, solid tumor-associated MN and Hodgkin lymphoma-associated minimal change disease (MCD) have become recognized as typical forms of paraneoplastic glomerulonephritides. Other glomerular diseases mentioned in this chapter are rarely associated with cancer, with the association between the kidney lesions and cancer infrequently fulfilling the criteria listed.

Finally, it is important to note that treatment paradigms for PnKD may be quite different from noncancer-related glomerular disease, in that the main strategy in PnKD is treatment of the underlying cancer. Patients with Hodgkin disease-associated podocytopathy and solid cancer-associated MN are frequently resistant to immunosuppressive regimens that are traditionally used in these entities but respond well to treatment of the cancer.

Paraneoplastic kidney diseases in patients with hematologic malignancies

Paraprotein-associated disorders are caused by clonal plasma or B-cell populations that produce monoclonal immunoglobulins (Igs), which may cause kidney damage. These antibodies have physiochemical properties that lead to specific types of kidney injury, leading to a variety of histologic patterns on kidney biopsy ( Box 21.2 ). An important point to emphasize is that the presence of end-organ damage may prompt treatment even if the underlying clone does not officially meet criteria for cancer. This necessitates familiarity with the criteria for overt multiple myeloma, smoldering multiple myeloma, and monoclonal gammopathy of undetermined significance (MGUS) ( Box 21.3 ). For example, the majority of patients with AL (light chain) amyloidosis have >10% clonal plasma cells found on bone marrow biopsy, and thus do not meet criteria for multiple myeloma. Nonetheless, the kidneys are commonly affected by AL amyloidosis, and the disease itself is associated with significant morbidity and mortality. Similarly, in other paraprotein diseases of the kidney, the presence and detection of renal involvement may be the factor that prompts treatment of the underlying clone. In this section, we will highlight selected paraprotein-mediated disorders. Many of these are discussed in Chapter 6, Chapter 7, Chapter 8, Chapter 9 .