Monoclonal Gammopathies and CKD Progression

Monoclonal gammopathies are a spectrum of disorders caused by aberrant clonal proliferation of plasma cells or B lymphocytes. Monoclonal gammopathy of undetermined significance (MGUS) is considered a premalignant condition, and in some patients, progressive clonality can lead to myeloma-defining events and evolve into a hematological malignancy known as multiple myeloma. During this clonal evolution, the kidneys can be affected, irrespective of disease burden, otherwise known as monoclonal gammopathy of renal significance (MGRS). Although it has become clear over the past decade that untreated MGRS is associated with poor hematologic and kidney-related outcomes, less is known about the effect of baseline CKD on outcomes among patients with MGUS and MGRS.

To understand the kidney-related consequences of monoclonal gammopathy, it is critical to first define these entities and their differences. The term MGUS was coined by Dr. Robert Kyle in 1978 in a seminal paper describing 241 patients with a detectable monoclonal protein, but without multiple myeloma. After the 34-year follow-up period, 3.2% of patients age older than 50 years developed MGUS, and the risk of progression to myeloma among these patients was 10% at 10 years.¹ In 2012, Leung et al. first described a subset of patients with circulating monoclonal proteins and unique histopathologic lesions on kidney biopsy, but without overt multiple myeloma, or so-called MGRS.² One study of 2935 patients with MGUS found that 44 (1.5%) in fact had MGRS, with the most commonly reported lesions including AL amyloidosis (27%) and light chain deposition disease (20%). Importantly, 10% of patients with MGRS progressed to multiple myeloma within the first year as compared with only 1% of patients with MGUS.³

Studies have attempted to characterize the association between MGUS and kidney-related outcomes. In a prospective study of 878 patients with detectable clones and the absence of myeloma-defining events, MGUS was not associated with a higher risk of kidney failure or death.⁴ Similarly, another study did not find that MGUS was associated with progression to kidney failure among patients with excess serum free light chains.⁵ However, these studies had limitations, such as lack of comprehensive monoclonal evaluation.

Unlike MGUS, it is well understood that untreated MGRS is associated with progressive kidney disease. In one retrospective study of 50 patients with C3 glomerulopathy and a detectable monoclonal protein, 29 patients received clone-directed therapy.⁶ Treated patients who achieved a hematologic response had superior kidney outcomes (defined by improvements in eGFR and proteinuria) compared with those receiving conservative management. Patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits, another MGRS disorder, are more likely to progress to kidney failure without treatment. In one study of 19 patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits, 16 (84%) were treated with clone-directed therapy and none progressed to kidney failure, whereas the three untreated patients all progressed.⁷

As our knowledge of monoclonal gammopathy evolves, there is a growing interest in examining the disease course of certain high-risk subsets of patients with monoclonal gammopathies, including those with underlying CKD. In this issue of CJASN, Sy-Go et al. conducted a single-center, retrospective study of 1535 patients with CKD, categorized as having MGUS (n=648), MGRS (n=59), or no monoclonal gammopathy (n=828).⁸ CKD was defined as having either an eGFR <60 ml/min per 1.73 m² or an eGFR >60 ml/min per 1.73 m² and proteinuria of >300 mg. The primary outcome was progression to kidney failure, defined as initiation of KRT or receipt of a kidney transplant, with death as a competing risk. In univariable analyses, CKD among patients with MGRS was associated with a higher risk of kidney failure compared with patients without monoclonal gammopathy, but not when compared with patients with MGUS. However, in multivariable analyses, the risk of kidney failure in the MGRS group was no longer statistically significant. MGUS was not associated with a higher risk of kidney failure compared with no monoclonal gammopathy. Finally, MGRS was associated with higher mortality as compared with no monoclonal gammopathy, whereas MGUS was not.

The authors should be applauded for carrying out one the largest studies to date of kidney and survival outcomes among patients with MGUS versus MGRS versus no monoclonal gammopathy and in a high-risk subset of patients with baseline CKD. In addition, all patients with MGRS had their diagnosis confirmed by kidney biopsy. The authors adjusted for important confounders, and they accounted for death as a competing risk, which is particularly important in studies involving patients with cancer.

Although this study attempts to address an important knowledge gap regarding outcomes in patients with CKD with and without monoclonal gammopathy, there are concerns about the generalizability of these findings. There may be some selection bias because the patients were all treated at Mayo Clinic, which is well versed in comprehensive monoclonal gammopathy workup and treatment. In addition, 97% of the patients were White, which is an important consideration since one study of 4 million Black patients treated across 142 Veteran's Affairs hospitals (and of whom 2046 had MGUS) found that the incidence of myeloma was two-fold higher in Black than White patients, and the incidence of MGUS was three-fold higher.⁹ In addition, Sy-Go et al. reported that 648 (42%) of the 1535 patients had MGUS. This is substantially higher than the proportion of patients with MGUS in other studies, which reported that 11.6%, 9.6%, and 4.4% had MGUS, respectively.^4,5,10 Patients were likely identified to have MGUS during workup of other conditions, including CKD and heart failure, a phenomenon recently described by Sigurbergsdóttir et al. in a large screening study in Iceland.¹⁰

In addition, there is some question of how CKD was defined. Patients were first identified as having CKD on the basis of International Classification of Diseases codes, which are specific but insensitive for diagnosing CKD. A single eGFR <60 ml/min per 1.73 m² is insufficient to diagnose CKD, and although the authors suggest that the diagnosis was confirmed by chart review, the method by which this was done was unclear. The breakdown of patients by baseline CKD stage is also not reported; in Table 1, the authors only report the mean eGFR in each group. This is quite important in patients with MGRS with AL amyloid because eGFR <50 ml/min predicts progression to kidney failure.¹¹ There could have been a higher proportion of patients at extremes of eGFRs in one of the three groups, which would not be reflected by simply presenting the mean eGFR.

The classification of each monoclonal disorder also needs careful evaluation. Although MGRS was not associated with a higher risk of kidney failure in multivariable analyses, this analysis included adjustment for eGFR and proteinuria, both of which were higher in the MGRS group. Half of patients with MGUS had proteinuria >300 mg/24, and only 154 of 648 (23%) patients had kidney biopsy data available, raising the possibility of misclassification (e.g., patients might have been misclassified as having MGUS instead of MGRS). This is further supported by the finding of a higher incidence of kidney failure among patients with MGUS compared with those without MG at year 1 and 2 (5% versus 2% and 9% versus 6%). Nevertheless, obtaining a kidney biopsy in every patient with MGUS is impractical, and therefore, it is not surprising that these were not available in more patients.

Another consideration is that among patients with MGUS, it is important to delineate the isotype of monoclonal protein because this has bearing on prognosis. Some studies have reported both shorter overall survival and a higher risk of progression to multiple myeloma among patients with IgM MGUS versus non-IgM MGUS.¹ The authors report that only 25% of patients with MGUS and MGRS underwent a bone marrow biopsy, and cytogenetic studies were not reported. However, like kidney biopsies, patients with MGUS often do not undergo bone marrow biopsy unless they are perceived to be at higher risk for hematologic progression.

Although the authors present a sizable MGRS cohort and provide details about histopathologic findings, it is important to recognize that MGRS constitutes a very heterogeneous group of disorders. Some patients present with severe AKI, while others have a more indolent course. For most MGRS lesions, prognosis is generally better if identified early and treated.³ MGRS was not associated with a higher risk of kidney failure than those without monoclonal gammopathy, likely because these patients were all treated for their MGRS lesions. Importantly, the authors did not specify the types of treatment received. Even during the course of this study (e.g., from 2013 to 2018), new therapies were trialed for MGRS, such as daratumumab for proliferative glomerulonephritis with monoclonal immunoglobulin deposits and AL amyloidosis. Future studies should report the types of therapies received, bone marrow biopsy results, cytogenetics, and the degree of hematologic and kidney response to treatment among patients with MGRS.

Since MGUS was first characterized 50 years ago, we as clinicians and scientists have been aiming to learn about the high-risk clinical and cytogenetic features that lead to disease progression and end-organ damage. The key finding in this study is that after multivariable adjustment, treated MGRS was not associated with a higher risk of progression to kidney failure compared with MGUS or no monoclonal gammopathy, but it was still associated with higher overall mortality. Although there are some concerns regarding inherent selection bias, generalizability, and misclassification, this is a well-done study that sheds light on the kidney-related consequences of MGUS versus MGRS versus no monoclonal gammopathy.

Disclosures

S. Gupta reports consultancy for GlaxoSmithKline, Proletariat Therapeutics, and Secretome; research funding from AstraZeneca, BTG International, GE HealthCare, and NIH; and advisory or leadership role as Former President and Founder of the American Society of Onconephrology (unpaid). The remaining author has nothing to disclose.

Funding

S. Gupta: Foundation for the National Institutes of Health (K23DK125672).

Author Contributions

Writing – original draft: Raad Chowdhury, Shruti Gupta.

Writing – review & editing: Raad Chowdhury, Shruti Gupta.