|Year : 2019 | Volume
| Issue : 4 | Page : 825-831
|Significance of paraprotein gap and β2 microglobulins in predialysis Population with multiple myeloma
Hatem Ali1, Bhuvan Kishore2, Jyoti Baharani1
1 Department of Renal Medicine, Heart of England Teaching Hospitals, Birmingham, UK
2 Department of Hematology, Heart of England Teaching Hospitals, Birmingham, UK
Click here for correspondence address and email
|Date of Submission||13-Apr-2018|
|Date of Decision||17-May-2018|
|Date of Acceptance||02-Jul-2018|
|Date of Web Publication||27-Aug-2019|
| Abstract|| |
Paraprotein gap is sometimes used as a screening tool in some autoimmune diseases, cancers, and screening for latent infections. The increase in the paraprotein gap in these diseases was hypothesized to be the result of increased levels of immunoglobulins, raising the total serum protein without any changes in serum albumin. Our aim was to assess the overall survival using novel chemotherapy, bortezomib compared to traditional ones and to assess if paraprotein gap could be used as a predictor of survival. Finally, we aimed to assess factors that could predict renal response in this population.
|How to cite this article:|
Ali H, Kishore B, Baharani J. Significance of paraprotein gap and β2 microglobulins in predialysis Population with multiple myeloma. Saudi J Kidney Dis Transpl 2019;30:825-31
|How to cite this URL:|
Ali H, Kishore B, Baharani J. Significance of paraprotein gap and β2 microglobulins in predialysis Population with multiple myeloma. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Nov 17];30:825-31. Available from: http://www.sjkdt.org/text.asp?2019/30/4/825/265458
| Introduction|| |
More than 20% of patients with multiple myeloma develop severe kidney failure., Renal impairment in this population is associated with a higher mortality rate and increased risk of chemotherapy-related toxi-city which adds to the complexity of managing this challenged population. Novel chemotherapy regimens such as bortezomib have significantly improved survival in multiple myeloma patients with renal impairment, but the effect of these agents on renal survival in those patients with significantly impaired renal function has not been comprehensively investigated., Dialysis has a significant effect on outcome of this population with an estimated survival of <1 year reported in a single-center study where over 80% of the patients required dialysis at presentation. These results are comparable to those seen in European Renal Association–European Dialysis and Transplant Association dataset where overall survival in this population was 0.91 years. Paraprotein gap is the gap between total protein and serum albumin, and it is at times used as a screening tool in some autoimmune diseases, cancers, and screening for latent infections.,,, The increase in the paraprotein gap in these conditions was hypothesized to be the result of increased levels of immuno-globulins raising the total serum protein without any changes in serum albumin. The implication of the paraprotein gap on clinical outcome and its use in clinical situations has not been extensively investigated. It is not known if the paraprotein gap can predict mortality independent of an underlying disease. In 2015, Juraschek et al attempted to assess the impact of paraprotein gap on all-cause mortality using data from NHANES study and reported that paraprotein gap is an independent risk factor of mortality with a cutoff point of 30 g/L.
In our study, we retrospectively reviewed multiple myeloma patients with severe renal impairment in two different decades. Our aim was to assess the overall survival using novel chemotherapy agents compared to traditional ones and to assess if paraprotein gap can be used as a predictor of survival. Finally, we aimed to assess factors that could predict renal response in this population.
| Materials and Methods|| |
Ninety-seven cases who were diagnosed with multiple myeloma after performing bone marrow biopsy and had estimated glomerular filtration rate (eGFR) of 30 mL or less between April 1, 2004, and August 31, 2015 at a single center were reviewed retrospectively. Patients with acute kidney injury at time of presentation, age <18 years, or patients who had a contraindication to receiving chemotherapy were excluded from the study. Patients were followed up till December 31, 2016. Thalidomide was the standard drug at Heart of England hospitals from April 1, 2004, to December 31, 2009, and bortezomib was the standard drug from January 1, 2010 to now. The initial dose of bortezomib is 1.3 g/m2 and is given twice weekly when given alone and once weekly when given in combination with prednisolone and melphalan.
Data about age, gender, ejection fraction%, hemoglobin, C-reactive protein, kidney function tests, bone homeostasis, β2 microglobulin, international staging score, free light chains (FLC), immunoglobulins, serum urate, lactate dehydrogenase, urine protein/creatinine ratio, serum albumin, and protein levels were retrospectively collected. Data were collected using a computerized database. Renal function was estimated and calculated using Modification of Diet in Renal Disease Study formula.
Kidney responses were defined as complete if eGFR changed and became >60 mL, limited (eGFR at time of diagnosis was <15 mL and changed to 30–59 mL), or incomplete (baseline eGFR <15 mL and became 15–29 mL or eGFR at the time of diagnosis ranging between 15 and 29 mL and change to 30–59 mL). Death was the endpoint for the study. Synthetic hollow fiber, high flux membranes (2.1 m2) were used in for patients who required dialysis. This study required no ethical approval.
| Statistical Analyses|| |
Statistical analyses were done using STATA (version 13) package (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP). Kaplan–Meier method along with Cox-hazards regression method was used for evaluation of survival rates in addition to factors affecting survival, respectively. Wilcoxon model was used to test equality between different survivor groups. Univariate and multivariate logistic regression methods identified elements that affect kidney response. Continuous variables were assessed using variable independent t-test. Chi-squared test and Fisher’s exact test were used to assess categorical variables.
| Results|| |
Cases were categorized into two groups: thalidomide group (n = 44, male = 21) and bortezomib group (n = 53, male = 25). Both groups have similar baseline characteristics as shown in [Table 1]. Bortezomib-treated patients have better survival in comparison with thalidomide-treated ones. Median survival time was 33.6 months and 8.3 months in bortezomib group and in thalidomide group, respectively (P = 0.01). Subgroup analysis revealed that chronic kidney disease patients stage 4 (CKD4) cases in bortezomib group has better survival rate in comparison with those with CKD5 in the same group, CKD4 and CKD 5 cases in the other group. Median overall survival was 62.2, 27.2, 8.3, 6.9 months in CKD 4 and CKD 5 in bortezomib group and CKD4 and CKD5 in thalidomide group, respectively (P = 0.04). These results are shown in [Figure 1].
|Table 1: Baseline characteristics between thalidomide group and bortezomib group.|
Click here to view
|Figure 1: Survival analysis in bortezomib group and in thalidomide group.|
CKD: Chronic kidney disease.
Click here to view
Cox-hazard regression method revealed that age and paraprotein gap were significant prognostic factors of survival. Hazard ratio was equal to 1.04 for age. Hazard ratio was equal to 1.03 for paraprotein gap. These are shown in [Table 2].
In both groups, 50 cases did not show kidney response, 25 demonstrated incomplete response, and five cases demonstrated limited response.
Sixteen cases showed complete kidney response. Multivariate logistic regression results are shown in [Table 3]. It revealed that β2 microglobulin is a significant prognostic factor for kidney response. Odds ratio was equal to 0.95. [Figure 2] shows that area under the curve equals 0.69.
|Figure 2: Area under the curve for logistic regression analysis assessing factors that affect renal response.|
Click here to view
A value of 24 mg or more demonstrated 835 specificity for prediction of response. Twenty-three cases in both groups started hemodia-lysis; two of them turned into dialysis independency. [Table 4] shows sensitivity and specificity according to different β2 microglobulin levels.
|Table 4: Sensitivity and specificity according to different β2 microglobulin levels.|
Click here to view
| Discussion|| |
Despite the common use of the paraprotein gap in different clinical settings, there are limited data and evidence for its routine use in clinical practice. Few studies showed that increased paraprotein gap is associated with positive serum protein electrophoresis and thereby could be used to investigate the presence of multiple myeloma., In addition, some other prospective studies have described an association between total protein and survival in transplant recipients, hospitalized patients, and cancer patients.,,,, There has also been an association described between total proteins and decreased survival in elderly patients with paraneoplastic syndromes, in hypergammaglobulinemia and rheumatological conditions.,,
Moreover, another study done on patients with severe burns found that decreased albumin to protein ratio was correlated with lower survival. Our study is the first to assess the significance of paraprotein gap in advanced CKD with multiple myeloma. The exact mechanism that expounds the association between paraprotein gap and mortality is not clear. One possibility could be that higher paraprotein gap results from higher production of immunoglobulins in multiple myeloma patients, and hence, it reflects the severity of the disease itself. Another likelihood is that the paraprotein gap reflects the degree of inflammation that leads to a rise in acute phase reactants and decline in serum albumin.,
The decreased albumin levels could also be a result of an underlying malnutrition, uremic cachexia, or nephritic syndrome.
In 1989, the MRC myelomatosis study showed high mortality rates up to 40% in the first three months in myeloma patients who presented with creatinine of 200 μmol/L or more at the time of diagnosis. Overall survival for this cohort was 380 days at two-year follow-up. Further analysis of more than 3000 patients showed that renal impairment was the responsible cause of deaths., In 2014, Uttervall et al conducted a retrospective study in Sweden that included 1538 patients with multiple myeloma, 680 patients of which had eGFR <60 mL/min. The study showed that overall survival in patients with nonrenal impairment is significantly superior to those with renal impairment. It also showed that overall survival in patients who were treated with bortezomib-based therapy was significantly better than those treated with conventional therapy. Overall survival in patients treated with bortezomib-based therapy reached 60 months. Despite the large sample size of this study, only 255 had severe renal impairment with eGFR <30 mL/min. Therefore, the results of this study could not entirely reflect the overall survival in patients with severe renal impairment whose eGFR is <30 mL/min. In our study, the eGFR for the whole cohort sample was 30 mL/min or less, and the overall survival in the bortezomib-based group was significantly better than the thalidomide-based group. This could reflect improved control of multiple myeloma with novel chemotherapy. However, the estimated survival of the borte-zomib group in our study (33.6 months) might not reflect the actual overall survival due to relatively small sample size in this group (n = 53) and different follow-up period among each individual given that the starting point was not the same.
The Vista study compared the renal response and overall survival in multiple myeloma patients who received bortezomib-based therapy versus those who received melphalan-based therapy and found superiority of bortezomib-based treatment over melphalan-based treatment in terms of these factors. Subgroup analysis showed better survival in patients with eGFR >30 mL/min compared to those with eGFR <30 mL/min. There was no enough number of patients in this study to compare those with eGFR <15 mL/min and those with eGFR between 15 mL/min and 30 mL/min (n = 15). Our study showed significant overall survival in CKD 4 patients in bortezomib group compared to those with CKD 5 in the same group and those in thalidomide group. This could be explained by that the degree of renal impairment reflects the severity of the disease and the degree of renal response and thereby affects overall survival.
β2 microglobulins have been used as a marker for the activation of cellular immunity and as a tumor marker for plasma cell tumors, especially multiple myeloma. Few studies showed significant relationship between β2 microglo-bulins and renal impairment., In 2008, Hofstra et al proved that β2 microglobulins could be used as a prognostic factor for certain types of glomerulonephritis. Serum β2- microglobulins are filtered in the glomeruli; however, >99% are reabsorbed in the proximal convoluted tubules ending up in minimal amount of β2 microglobulins in urine. In our study, we found a significant relationship between β2 microglobulin levels and renal response in multiple myeloma patients with severe renal impairment (odds ratio = 0.95). Our analysis showed that a level of 24 mg is 83.3% specific of having poor renal response. We suggest that β2 microglobulins could be used as a clinical biomarker for prognosis of renal response in this group of patients.
Our study has several limitations. First, its retrospective design that could have led to selection bias. Second, the relatively small sample size that could have caused underestimation of significant results. Finally, due to the retrospective design, there were some missing data that were not included in the analysis such as data about serum FLC, immu-noglobulin levels, toxicity profile between both groups, and residual renal functions.
In conclusion, multiple myeloma patients with severe renal impairment have better survival when treated with bortezomib compared to thalidomide. In multiple myeloma population, patients with CKD4 have better survival compared to those with CKD5. Age and paraprotein gap are significant prognostic factors for survival. β2 microglobulin is a strong prognostic factor for kidney response in this population. More randomized controlled studies with bigger sample size are needed to confirm the significance of paraprotein gap and β2 microglobulins in this group of patients.
Conflict of interest: None declared.
| References|| |
Alexanian R, Barlogie B, Dixon D. Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 1990;150: 1693-5.
Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003;78:21-33.
Augustson BM, Begum G, Dunn JA, et al. Early mortality after diagnosis of multiple myeloma: Analysis of patients entered onto the United Kingdom medical research council trials between 1980 and 2002 – Medical research council adult leukaemia working party. J Clin Oncol 2005; 23:9219-26.
Kastritis E, Terpos E, Dimopoulos MA. Current treatments for renal failure due to multiple myeloma. Expert Opin Pharmacother 2013;14: 1477-95.
Harousseau JL, Shaughnessy J Jr., Richardson P. Multiple myeloma. Hematology Am Soc Hematol Educ Program 2004:237-56.
Dimopoulos MA, Kastritis E, Rosinol L, Bladé J, Ludwig H. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia 2008;22: 1485-93.
Laubach J, Richardson P. Hematology: Bortezomib and dexamethasone induction for multiple myeloma. Nat Rev Clin Oncol 2011; 8:8-10.
Haynes RJ, Read S, Collins GP, Darby SC, Winearls CG. Presentation and survival of patients with severe acute kidney injury and multiple myeloma: A 20-year experience from a single centre. Nephrol Dial Transplant 2010;25: 419-26.
Tsakiris DJ, Stel VS, Finne P, et al. Incidence and outcome of patients starting renal replacement therapy for end-stage renal disease due to multiple myeloma or light-chain deposit disease: An ERA-EDTA registry study. Nephrol Dial Transplant 2010;25:1200-6.
Thakkinstian A, Tran H, Reeves G, Murch S, Attia J. A clinical decision rule to aid ordering of serum and urine protein electrophoresis for case-finding of paraproteins in hospitalized inpatients. J Gen Intern Med 2008;23:1688-92.
Salt HB. Serum globulin fractions in chronic rheumatic diseases; an electrophoretic study. Clin Chem 1956;2:35-44.
Suh B, Park S, Shin DW, et al. Low albuminto-globulin ratio associated with cancer incidence and mortality in generally healthy adults. Ann Oncol 2014;25:2260-6.
Dispenzieri A, Gertz MA, Therneau TM, Kyle RA. Retrospective cohort study of 148 patients with polyclonal gammopathy. Mayo Clin Proc 2001;76:476-87.
Juraschek SP, Moliterno AR, Checkley W, Miller ER 3rd
. The gamma gap and all-cause mortality. PLoS One 2015;10:e0143494.
Dupuis MM, Li Z, Tuchman SA, Kang Y. The gamma gap: A point-of-care test that correlates with disease burden and treatment response in multiple myeloma. Blood 2017;130 Suppl 1: 4407.
Sormani MP, Oneto R, Bruno B, et al. A revised day +7 predictive score for transplant-related mortality: Serum cholinesterase, total protein, blood urea nitrogen, gamma glutamyl transferase, donor type and cell dose. Bone Marrow Transplant 2003;32:205-11.
Woo J, Mak YT, Lau J, Swaminathan R. Prediction of mortality in patients in acute medical wards using basic laboratory and anthropometric data. Postgrad Med J 1992;68: 954-60.
Azab B, Kedia S, Shah N, Vonfrolio S, Lu W, Naboush A, et al. The value of the pre-treatment albumin/globulin ratio in predicting the long-term survival in colorectal cancer. Int J Colorectal Dis 2013;28:1629-36.
Azab BN, Bhatt VR, Vonfrolio S, et al. Value of the pretreatment albumin to globulin ratio in predicting long-term mortality in breast cancer patients. Am J Surg 2013;206:764-70.
Duran AO, Inanc M, Karaca H, et al. Albumin-globulin ratio for prediction of long-term mortality in lung adenocarcinoma patients. Asian Pac J Cancer Prev 2014;15:6449-53.
Torisu T, Takata Y, Ansai T, et al. IgA level is associated with risk for mortality in an eighty-year-old population. Gerontology 2009;55:179- 85.
Vollertsen RS, Conn DL, Ballard DJ, Ilstrup DM, Kazmar RE, Silverfield JC. Rheumatoid vasculitis: Survival and associated risk factors. Medicine (Baltimore) 1986;65:365-75.
Lehtinen K. The mortality and causes of death of patients with “hypergamma type” of ankylosing spondylitis. Scand J Rheumatol 1983;12:3-4.
Kumar P. Grading of severity of the condition in burn patients by serum protein and albumin/ globulin studies. Ann Plast Surg 2010;65:74-9.
Killingsworth LM. Plasma protein patterns in health and disease. CRC Crit Rev Clin Lab Sci 1979;11:1-30.
Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 1999;340:448-54.
Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O, Ledue TB, Craig WY. Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: A practical, simple and clinically relevant approach in a large cohort. J Clin Lab Anal 1999;13:273-9.
MacLennan IC, Cooper EH, Chapman CE, Kelly KA, Crockson RA. Renal failure in myelo-matosis. Eur J Hematol Suppl 1989;51:60-5.
Uttervall K, Duru AD, Lund J, et al. The use of novel drugs can effectively improve response, delay relapse and enhance overall survival in multiple myeloma patients with renal impairment. PLoS One 2014;9:e101819.
Bladé J, Fernández-Llama P, Bosch F, et al. Renal failure in multiple myeloma: Presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 1998; 158:1889-93.
Dimopoulos MA, Richardson PG, Schlag R, et al. VMP (Bortezomib, melphalan, and predni-sone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: Cohort analysis of the phase III VISTA study. J Clin Oncol 2009; 27:6086-93.
Bethea M, Forman DT. Beta 2-microglobulin: Its significance and clinical usefulness. Ann Clin Lab Sci 1990;20:163-8.
Kals J, Zagura M, Serg M, et al. B2- microglobulin, a novel biomarker of peripheral arterial disease, independently predicts aortic stiffness in these patients. Scand J Clin Lab Invest 2011;71:257-63.
Wilson AM, Kimura E, Harada RK, et al. Beta2- microglobulin as a biomarker in peripheral arterial disease: Proteomic profiling and clinical studies. Circulation 2007;116:1396-403.
Hofstra JM, Deegens JK, Willems HL, Wetzels JF. Beta-2-microglobulin is superior to N-acetyl-beta-glucosaminidase in predicting prognosis in idiopathic membranous nephropathy. Nephrol Dial Transplant 2008;23:2546-51.
Peterson PA, Evrin PE, Berggård I. Differentiation of glomerular, tubular, and normal proteinuria: Determinations of urinary excretion of beta-2-macroglobulin, albumin, and total protein. J Clin Invest 1969;48:1189-98.
Department of Renal Medicine, Heart of England Teaching Hospitals, Birmingham
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
| Article Access Statistics|
| Viewed||273 |
| Printed||0 |
| Emailed||0 |
| PDF Downloaded||35 |
| Comments ||[Add] |