ACRT Journal

Discussion

In 2012, for the first time, kidney diseases related to MG were referred to as “monoclonal gammopathy of renal significance” (MGRS); since then, the attention given to MG as being a potentially significant cause of kidney injury has progressively increased [5]. The epidemiology of MGRS is still a topic of discussion, and there is a high discordance between prevalence rates according to various studies. In general, the likelihood of finding an MGRS disorder in patients affected by MG ranges from 6% to 40-45% [6-8]. Our study is in conjunction with the data recorded by Kyle and colleagues, who reported a 44.7% prevalence of MGRS in patients affected by MGUS [7]. Kidney biopsy represents the cornerstone for the diagnosis of MGRS because it permits the identification of Ig deposits and the classification of histological lesions. In the majority of cases, the histological evidence of a monoclonal deposit and its correspondence with the Ig found in serum and/or urine are the keys to establishing a diagnosis [2,9]. C3 glomerulopathy and thrombotic microangiopathy (TMA) are exceptions because they are not always characterized by the deposition of monoclonal immunoglobulin, even though monoclonal Ig can act through indirect mechanisms, such as the activation of the complement system [2]. The main indications for kidney biopsy in patients with MG are at least one of the following conditions: AKI, eGFR < 60 ml/min/1.73 m2, urinary albumin creatinine ratio (UACR) between 3 and 30 mg/mmol if eGFR > 60 ml/min, hematuria if eGFR < 60 ml/min and/or evidence of light chain proteinuria [2]. However, established guidelines on this topic are still unavailable. Our Center applies these indications to identify all patients who require kidney biopsy at earlier times among the cohort of MG patients proposed by hematologists. The aim of this strategy was to diagnose MGRS early in patients with a recent diagnosis of MG. From a hematological standpoint, the acknowledged gold standard for the diagnosis of MG is serum and urine protein electrophoresis and immunofixation, whereas serum immunofixation helps to confirm the presence of monoclonal Ig [10,11, p. 3]. In those cases in which monoclonal Ig is not detectable via electrophoretic methods, a urine sample should be analysed because its positivity for monoclonal light chain is diagnostic for MG [10,12]. However, routine employment of urine protein electrophoresis and immunofixation is not always performed due to its increased costs [13,14]. The International Myeloma Workshop Consensus Panel 3 recommends routine testing of serum free light chain (SFLC) for the screening of MG [10], [11]. However, abnormal SFLC and κ/λ ratios taken alone are not sufficient to prove the presence of MG and need to be confirmed by using electrophoretic methods and/or bone marrow biopsy [12]. Singh compared the diagnostic performance of SFLC, serum and urine protein electrophoresis and immunofixation with the objective of assessing their relative diagnostic contributions. He observed that protein electrophoresis was concordant with the already established diagnosis of MG significantly more often than the κ/λ ratio [12]. From a nephrological standpoint, the evaluation of SFLC is not included among the criteria for performing kidney biopsy in patients with MG. In one Mayo clinic study, the authors reported that younger age, elevated serum creatinine and higher levels of proteinuria were the clinical and laboratory factors that increased the likelihood of receiving a kidney biopsy, and an altered κ/λ ratio did not seem to influence this odd discordance. This may suggest that nephrologists should not consider an abnormal κ/λ ratio when deciding whether to perform kidney biopsy, although it is considered a predictor of MGRS [4]. In our study, the κ/λ ratio was neither diagnostic nor exclusionary for the MGRS. Only 18.4% of patients with MGUS had both an altered κ/λ ratio and MGRS-associated disease, whereas the majority of patients (26.3%) had MGRSs in the context of a normal κ/λ ratio. However, we adopted the “conventional κ/λ ratio”, while for patients with an eGFR < 60 ml/min, other authors used the “renal κ/λ ratio”, which is greater than the conventional κ/λ ratio. These data reinforce the association that we found between a normal κ/λ ratio and MGRS lesions, even if it was not statistically significant (p = 0.06). Concerning the possibility of an elevated κ/λ ratio in our patients who were diagnosed with MGRS, we could propose a different hypothesis. First, we cannot exclude that MGRS has been detected in an early stage of the disease in which the κ/λ ratio is still normal, whereas in advanced stages, it may become altered as a consequence of the increased production of SFLC. This hypothesis reflects our attempt to make an early diagnosis.

Second, according to the Consensus Statement, the definition of MGRS does not include any mention of an overproduction of the immunoglobulin, which better reflects the tumour burden rather than kidney involvement. In this context, the nephrotoxicity of immunoglobulin in MGRS seems not to result from the amount of immunoglobulin itself but rather from its intrinsic pathogenic properties [15,16]. Proteomic studies, which permit the investigation of the intrinsic characteristics of pathological immunoglobulin to identify possible common aspects, are potentially useful in the treatment of MGRS. In this context, urinary exosomes are a potentially powerful tool for studying cellular proteomics in the urinary tract. In patients with amyloidosis, urinary exosomes contained monotypic light chains in vesicles, which later disappeared in patients who achieved complete remission. This suggests that urinary exosomes could be an excellent alternative biomarker to the κ/λ ratio for the diagnosis and monitoring of kidney responses in patients with MGRSassociated disorders. The disadvantages are the excessive costs and the nonavailability on a large scale [17,18]. When referring to our study, we subsequently conducted a sub analysis assessing the burden of the predominant light chain (κ or λ) in MGRS patients, and we did not find a statistically significant association between the prevalence of a single light chain and the presence of MGRS (p = 0.059, not shown). However, we observed that the concomitant presence of λ predominance and proteinuria ≥ 1 g/ day were strongly associated with MGRS lesions (p value of the chi-square test= 0.030). Moreover, we found that the highest level of proteinuria (3.89 g/day, p = 0.027) was significantly associated with MGRS lesions. In contrast to our results, some authors have shown that the κ/λ ratio is greater in lesions with λ chains [12]. When considering the longer half-life of λ chains than that of κ chains, a lambda-dominant κ/λ ratio is expected to be more prevalent. However, λ chain lesions have a greater false-negative rate for the κ/λ ratio than κ chain lesions, and approximately 90% of MGUS patients with λ light chain evidence have a normal κ/λ ratio [19]. This effect could be explained by the greater tendency of λ light chains to polymerize and consequently possibly hide the epitopes that are normally detected by the antibodies that are used in the laboratory assay [12]. Another potential explanation for the high false-negative rate of the κ/λ ratio for λ chain lesions could be the overproduction of polyclonal κ chains and the underproduction of excess free λ light chains in patients with neoplastic monoclonal gammopathies with λ chain lesions [20,21]. It is important to correctly interpret the κ/λ ratio when considering the clinical context. In fact, there are many conditions that can possibly alter the κ/λ ratio, such as primary antibody deficiency and polyclonal gammopathy [18]. The latter condition is typical of inflammatory states and is characterized by the overproduction of κ light chain, which interferes with the interpretation of the κ/λ ratio if an underlying MG is suspected [19]. In our study, a review of clinical data did not suggest the presence of concomitant diseases that could influence the production of free light chains. All of these data raise questions about the clinical usefulness of SFLC in routine testing as a predictor for the diagnosis of MGRS. Making a correct diagnosis of MGRS is fundamental due to its impact on kidney function and survival. A combined hematological and nephrological approach is crucial. These results highlight the complexity of making a correct diagnosis of this family of clonal proliferative disorders and the need to evaluate both the laboratory findings and the histological data. A high risk of progression of MG to a related hematological malignancy, a low response to immunosuppressive therapies and a 90% risk of recurrence on kidney grafts are recognized if MG is not correctly treated during the perioperative period. From a “tumoral” viewpoint (i.e., their bulk and proliferative rate), even patients with MGRS should not require treatment. However, the prevention of renal deterioration makes therapy mandatory and sometimes urgent. In the MGRS, the normalization of the SFLC is included among the factors predicting a complete response to treatment [21]. The principal limitation of our study is the limited sample size. In addition, in contrast with other authors, we used the conventional κ/λ ratio, which limits the possibility of comparison. Our study has the strength of possessing a nephrological perspective, as it was conducted at a single Center, thus mirroring the daily practice of kidney biopsy decision-making. Our study also demonstrated that collaboration may allow for an early and optimal diagnosis of the disease. In conclusion, our single-Center experience revealed a high percentage of biopsies demonstrating MGRS among patients affected by MGUS. Immunoglobulin-related amyloidosis is the most common pattern of renal involvement. Serum-free light chain assays and altered κ/λ ratios are not sufficient for detecting MGRS, and kidney biopsy remains fundamental for diagnosis. Accurate monitoring of patients affected by MGUS is key for the early diagnosis of MGRS. Increased proteinuria is the main factor predictive of kidney involvement. 

Declarations

Conflict of interest: All of the authors confirm that they have contributed to the intellectual content of this paper and that they have no competing interests.

Ethical approval: This study was approved by the local Ethics Committee and was performed according to the Declaration of Helsinki. The participants received an explanatory statement and provided written informed consent to participate in the study (Protocol number 204/2020/Oss/AOUBo).

Author contributions: Conceptualization: GV, Data curation, Formal analysis: GP, AC, MP, Investigation, Project administration, Supervision: GV, GP, AC, MP, OB, GC, EZ, GLM, Writing– original draft: GV, GP, AC. All of the authors have read and approved the final manuscript. AC and GP participated equally.

References

1. Leung N, Bridoux F, Nasr SH. (2021) Monoclonal Gammopathy of Renal Significance. N Engl J Med. 384:1931-1941.
2. Leung N, Bridoux F, Batuman V, Cahidos A, Cockwell P, et al. (2019) The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 15:45-59.
3. Klomjit N, Leung N, Fervenza F, Sethi S, Zand L. (2020) Rate and Predictors of Finding Monoclonal Gammopathy of Renal Significance (MGRS) Lesions on Kidney Biopsy in Patients with Monoclonal Gammopathy. J Am Soc Nephrol. 31:2400-2411.
4. Yong ZH, Yu XJ, Liu JX, Zhou FD, Wang SX, et al (2022) Kidney Histopathologic Spectrum and Clinical Indicators Associated with MGRS. Clin J Am Soc Nephrol. 17:527-534.
5. Glavey SV, Leung N. (2016) Monoclonal gammopathy: The good, the bad and the ugly. Blood Rev. 30:223-31.
6. M. Shaik e A. Al-Janadi. (2014) Long Term Survival of Monoclonal Gammopathy of Renal Significance (MGRS): An Analysis of Nhanes III.Blood 124: 4849–4849,
7. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, et al. (2006) Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 354:1362-9.
8. Ciocchini M, Arbelbide J, Musso CG. (2017) Monoclonal gammopathy of renal significance (MGRS): the characteristics and significance of a new meta-entity. Int Urol Nephrol. 49:2171-2175.
9. Jain A, Haynes R, Kothari J, Khera A, Soares M, et al (2019) Pathophysiology and management of monoclonal gammopathy of renal significance. Blood Adv. 3:2409-2423.
10. Singh G. (2020) Serum and Urine Protein Electrophoresis and Serum-Free Light Chain Assays in the Diagnosis and Monitoring of Monoclonal Gammopathies. J Appl Lab Med. 5:1358-1371.
11. Dimopoulos M, Kyle R, Fermand J, Rajkumar SV, Miguel JS, et al. (2011) Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 117:4701-5.
12. Singh G. (2017) Serum Free Light Chain Assay and κ/λ Ratio: Performance in Patients With Monoclonal Gammopathy-High False Negative Rate for κ/λ Ratio. J Clin Med Res. 9:46-57. .
13. Rajkumar SV, Bimopoulos MA, Palumbo A, Blade J, Merlini G, et al. (2014) International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 15:e538-48.
14. Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, et al. (2002) Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem. 48:1437-44.
15. Basnayake K, Stringer SJ, Hutchison CA, Cockwell P. (2011) The biology of immunoglobulin free light chains and kidney injury. Kidney Int. 79:1289-301.
16. Rengers JU, Touchard G, Decourt C, Deret S, Michel H, et al (2000) Heavy and light chain primary structures control IgG3 nephritogenicity in an experimental model for cryocrystalglobulinemia. Blood. 95:346772.
17. Leung N, Barnidge DR, Hutchison CA. (2016) Laboratory testing in monoclonal gammopathy of renal significance (MGRS). Clin Chem Lab Med. 54:929-37.
18. Tosi P, Tomassetti S, Merli A, Polli V. (2013) Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol. 4:37-41.
19. Singh G. (2016) Serum Free Light Chain Assay and κ/λ Ratio Performance in Patients Without Monoclonal Gammopathies:  High False-Positive Rate. Am J Clin Pathol. 146:207-14.
20. Lee WS, Singh G. (2018) Serum Free Light Chains in Neoplastic Monoclonal Gammopathies: Relative Under-Detection of Lambda Dominant Kappa/Lambda Ratio, and Underproduction of Free Lambda Light Chains, as Compared to Kappa Light Chains, in Patients With Neoplastic Monoclonal Gammopathies. J Clin Med Res. 10:562-569.
21. Gozzetti A,Guarnieri A, Zamagni E, Zakharova E, Coriu D, et al. (2022) Monoclonal gammopathy of renal significance (MGRS): Real-world data on outcomes and prognostic factors. Am J Hematol. 97:877-884.