Pretransplant MGUS: prevalence, risk factors, and evolution
Patient characteristics are summarized in Table 1. Thirteen patients had pretransplant MGUS. In this group, mean age at transplantation was 59 years. The paraprotein was detected at a median time of 1.7 years before transplantation. The isotype was IgG in most patients (62%) with a median size of 2.25 g/L. Abnormal serum FLC ratio was present in 4 patients (40%). Thus, 53% had a low risk of neoplastic progression according to established criteria (IgG subtype, size <15 g/L, normal sFLC ratio).20 Two patients (15%) evolved into smoldering multiple myeloma (SMM) and 2 (15%) demonstrated progressive renal disease from light chain deposition disease (LCDD) after transplantation. Compared with patients with normal SPEP before transplantation (data not shown), patients with pretransplant MGUS were more likely to be older at the time of transplantation (58.6 versus 49.8 y, P value 0.021) and male (92.3% versus 63.1%, P value 0.037). We observed no difference in death-censored allograft survival, acute rejection episodes, and CMV and BK virus infections between patients with normal SPEP and MGUS before transplantation.
Posttransplant MGUS: Incidence, Risk Factors, and Evolution
Forty-three patients were found to have MGUS after transplantation. The paraproteins appeared after a median of 3.2 years. Most (74%) were of IgG isotype. They were characterized by a small median size (0.76 g/L) and sFLC was abnormal in 6 patients (14%). One patient progressed to MM and one was diagnosed with LCDD. The monoclonal component remained stable in 32 patients whereas it was transient in 9 patients (21%). Median time to disappearance was 2.0 years. We could not detect any statistically significant difference between transient and permanent MGUS (Table 2). However, IgG-isotype was identified in 100% of cases in the transient and 67% of cases in permanent MGUS group, and the size of the gammopathy was 0.43g/L in transient versus 2.85 g/L in permanent MGUS. No patients with transient monoclonal gammopathy had an abnormal sFLC ratio compared with 22% of patients with permanent MGUS.
Death-censored allograft survival did not differ between patients who developed MGUS posttransplant and patients without MGUS. The proportion of patients who had potentially paraprotein-related native kidney disease was low and similar in patients who developed MGUS (2%) and those who did not (4%). After adjustment for sex, race, use of ATG, acute rejection episodes and BK virus infection, age at transplantation (hazard ratio 1.05 per 1-y increase; 95% confidence intervals [CI], 1.02-1.08; P value 0.001) and CMV infections (hazard ratio 2.22; 95% CI, 1.07-4.58; P value 0.031) were associated with the development of posttransplant MGUS (Table 3). Similar results were found when patients with no previously available normal SPEP were excluded.
Progression to Hematologic Malignancies and Appearance of Paraprotein-Induced Renal Disease
Among the 56 transplant recipients with MGUS, 3 patients experienced hematologic progression and 3 developed allograft dysfunction/loss due to MGRS (Table 4). The paraprotein was identified before transplant in 4 patients and after transplant in 2 patients. Among the patients who had hematologic progression of MGUS, 2 presented with SMM and 1 developed MM. The 2 patients who were diagnosed with SMM after transplant had pretransplant MGUS. However, as pretransplant workup did not include a recent bone marrow biopsy, it remains possible that SMM was present yet undetected before transplantation. The patient who was diagnosed with MM did not have an SPEP before transplantation. However, 1 year after transplantation, a 26 g/L IgG-lambda gammopathy was identified which later evolved into MM. Further information describing the 6 patients were hematologic progression and development of MGRS are available as supplemental digital content. Of note, we observed no MGUS progression to nonplasma cell PTLD. We identified 7 cases of non plasma-cell PTLD in our cohort, but none of those were found to have a prior MGUS.
Three patients demonstrated renal insufficiency from LCDD after transplantation. As native pretransplant kidney biopsy for these patients did not include immunofluorescence staining for kappa-lambda light chains and/or paraffin immunofluorescence after pronase digestion when appropriate, we cannot exclude that MGRS may have already been present before transplantation. Figure 3 illustrates the histologic findings of 1 of the 3 patients with allograft dysfunction due to LCDD.
In this study, we found a prevalence of MGUS of 3.4% before kidney transplantation and a 2.5% cumulative incidence of MGUS at 5 years after transplant. Among a total of 56 patients with a pre or posttransplant monoclonal gammopathy, 3 experienced hematologic progression to MM or SMM and 3 suffered from paraprotein-induced renal damage (LCDD). However, as pretransplant workup was incomplete, it remains possible that these were already present yet undiagnosed before transplantation. A significant proportion of MGUS appearing after transplant were transient. Our results suggest that older age at transplantation and prior CMV infection may be risk factors for MGUS appearance in kidney transplant recipients.
Previous investigators have described an increased frequency of MGUS in solid organ transplant recipients. Cumulative 5-year incidence rates of 22.5% and 30% have been reported in kidney11 and heart transplant recipients.12 In our study population, the incidence of MGUS was lower with an estimated 5-year cumulative incidence of MGUS development of 4% when all posttransplant MGUS were considered and 2.5% when omitting patients for whom posttransplant appearance could not be ascertained. This may reflect variations in immunosuppression protocols as an increased risk of MGUS has been previously described with OKT3 and cyclosporine.12,21 In Caforio’s report, in which all patients received cyclosporine, 5-year cumulative MGUS incidence after heart transplant was 21%.12 Passweg et al21 found that the risk of developing a gammopathy was 24% if OKT3 was included to induction immunosuppression as compared with 10.4% with ATG. In our study, 2.6% of patients received cyclosporine and OKT3 was never used as induction immunosuppression or rejection treatment. These agents may impair immune surveillance through inhibition of T-cell function, allowing B-cell lineage proliferation.12 Most of our patients were induced with basiliximab, which has not been linked to an increased probability of paraprotein.22 Population characteristics such as age and race may also create disparities in MGUS incidence in different reports. Lastly, we may underestimate the incidence of MGUS in our population as a protocol for serial monitoring of SPEP/IFX and sFLC after transplantation was not implemented as compared with some other studies.21,22
Thirteen patients with MGUS received a kidney transplant in our population. These patients were found to be older at transplantation with a higher male proportion compared with other transplant candidates. This is consistent with previously described risk factors for MGUS.2 Among the patients with pretransplant MGUS, 2 (15%) progressed to SMM and 2 (15%) demonstrated LCDD.23 We cannot exclude that the patients with SMM could have had increased bone marrow clonal plasmocytosis before transplant, as bone marrow biopsy was not performed in 1 patient while it had been done 6 years before transplantation in the other. The native kidney disease of the 2 patients who were diagnosed with posttransplant LCDD may have been linked to a paraprotein. The native kidney biopsy for these 2 patients had been analyzed at their referring center and had not been reviewed by our transplant center before proceeding to transplantation. However, later revision of these specimens showed that immunofluorescence staining for kappa/lambda light chains had not been performed for 1 case. In the other case, a paraffin immunofluorescence after pronase digestion study had not been completed despite a membranoproliferative pattern on light microscopy with predominant C3 deposits on immunofluorescence. In patients with pretransplant MGUS, previous studies report rates of progression to PCM that fluctuate between 0%13 and 40%.6 The extent of the pretransplant workup done to exclude MM or MGRS before transplantation in patients with MGUS in these studies was variable, which may explain the variability in progression to malignancy and appearance of paraprotein-induced allograft disease in this patient population.6-8,13
Our findings thus point to the importance of a complete evaluation to exclude hematologic malignancies and MGRS in patients with MGUS before transplantation, including the revision of native kidney pathological specimens. SMM carries a 51% cumulative probability of progression to overt malignancy over 5 years in contrast to a 4% probability in the setting of MGUS.24 Consequently, identification of SMM in a transplant candidate may influence the decision to proceed with transplantation. Alternatively, MGRS tends to recur after transplant and negatively affect allograft survival times.4,16,25 It is suggested that in the setting of an M-protein and kidney failure, the possibility of causality between these conditions should be investigated.26 Therefore, it appears important to identify it in transplant candidates. Although MGRS may not be curable, its reappearance in the allograft could be minimized by achieving a complete hematologic response.27
Previous literature has suggested a relatively benign course of posttransplant MGUS. In a report of 46 posttransplant MGUS among 390 kidney transplant recipients, none evolved to a hematologic malignancy after a median follow-up of 1 year.21 In another study of 45 posttransplant MGUS among 203 kidney transplant patients followed for >5 years, none experienced malignant transformation.11 In our study, among 43 MGUS diagnosed after transplant, 1 patient developed LCDD in the allograft and another evolved into MM. In the former, native kidney biopsy immunofluorescence did not include staining for kappa and lambda light chains. Two months after transplant, LCDD was identified in her kidney graft. Given this short lapse of time, it seems plausible that this condition may have existed before transplant and contributed to initial kidney failure. In the second patient who developed MM after transplant, no SPEP was performed before transplant, yet 1 year later, he was diagnosed with an MGUS of significant size (26 g/L). He later progressed to overt MM. It appears likely that MGUS was already present before transplant in this patient. Taken together, our results suggest that malignant evolution of MGUS in the setting of renal transplantation is low and may be similar to that of the general population as the cases of PCMs we observed may have already been present before transplantation.
A significant proportion of posttransplant MGUS were transient (21%). Although spontaneous disappearance of MGUS is relatively uncommon in the general population with a frequency of 2%,3,28 this phenomenon has been described in several solid organ transplant series with MGUS being transient in up to 37%–72% of patients.11,21,29,30 MGUS arising after transplant may thus have a different pathophysiology. Previous studies have identified an association between CMV infection and MGUS appearance.10,11,30,31 It has been hypothesized that CMV could induce paraprotein appearance through polyclonal B-cell activation.31 Our findings support this association. In contrast, in a recent retrospective report of 39 posttransplant MGUS, CMV infections did not correlate with paraprotein appearance. This discrepancy could be explained by the fact that transient MGUS were excluded22 while we considered both transient and permanent cases.
Previous studies have suggested a possible link between MGUS and the risk of nonplasma cell PTLD.7,10,12 In our cohort, none of the 7 cases of PTLD were preceded by MGUS, which is consistent with results from a larger recent study in which no PTLD developed over 6 years among 72 patients with pretransplant MGUS.9
Our study has some limitations. Current clinical practice guidelines do not provide any recommendation for or against screening for MGUS before32 or after kidney transplantation.33 Hence, SPEP was performed at the discretion of transplant physicians. Because of its retrospective nature, SPEP, immunofixation, urine immunoelectrophersis, and sFLC ratio were not available before and/or after transplant for all patients and some recipients were lost to follow-up, which may underestimate the true incidence of MGUS. There was missing data related to sFLC as this test only became available at our institution in 2006. Moreover, screening for a gammopathy was performed with SPEP and immunofixation was only added to confirm or exclude the presence of a paraprotein in the setting of a SPEP anomaly. This may have underestimated the prevalence of gammapathy as SPEP is less sensitive then immonofixation for the detection of paraprotein. Given a relatively limited sample size and associated wide CI, we cannot rule out that recipient race, BK virus infections and induction immunosuppression with ATG could increase the risk of MGUS. Finally, median follow-up after transplant was limited to 7.5 years. With longer follow-up, it is possible that additional patients with MGUS may progress to PCMs.
In conclusion, we found a prevalence of MGUS of 3.4% before transplantation, which is consistent with data obtained from the general population.1 Although this figure is low, we suggest that a complete workup (with SPEP, UPEP, and sFLC with serum and urine immunofixation) to identify a monoclonal gammopathy be performed before transplantation as this could lead to changes in the management of a transplant candidate. If a paraprotein is found, a PCM or MGRS should be excluded before transplantation. In this respect, we suggest that a bone marrow biopsy as well as a careful revision of the native kidney biopsy be performed before transplantation. The presence of SMM/MM may change the decision to proceed with transplantation, while treatment for MGRS may prevent or delay recurrent disease in the allograft. The evolution of MGUS arising in the post transplant setting seems similar to that of the general population, and a significant proportion appear to be transient. Hence, our results do not support changes in the management of MGUS in kidney transplant recipients compared with that of the general population. Consequently, we do not recommend routine screening for MGUS after renal transplantation and SPEP/IFX/sFLC should be performed when clinically indicated.
The authors thank Dr Alexandra Laforest-Renald for providing additional data pertaining to certain patients included in this study.
1. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance.N Engl J Med20063541362–1369
2. Wadhera RK, Rajkumar SV. Prevalence of monoclonal gammopathy of undetermined significance: a systematic review.Mayo Clin Proc201085933–942
3. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance.N Engl J Med2002346564–569
4. Leung N, Bridoux F, Hutchison CA, et al; International Kidney and Monoclonal Gammopathy Research GroupMonoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant.Blood20121204292–4295
5. Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution.Clin J Am Soc Nephrol20127231–239
6. Rostaing L, Modesto A, Abbal M, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance in transplant patients.Am J Nephrol199414187–191
7. Naina HV, Harris S, Dispenzieri A, et al. Long-term follow-up of patients with monoclonal gammopathy of undetermined significance after kidney transplantation.Am J Nephrol201235365–371
8. Redfield RR, Naji A. Progression of monoclonal gammopathy of undetermined significance to multiple myeloma in a solid organ transplant.Transplantation201192e65–6author reply e66
9. Goebel TE, Schiltz NK, Woodside KJ, et al. Neoplastic and non-neoplastic complications of solid organ transplantation in patients with preexisting monoclonal gammopathy of undetermined significance.Clin Transplant201529851–857
10. Badley AD, Portela DF, Patel R, et al. Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder.Liver Transpl Surg19962375–382
11. Regamey N, Hess V, Passweg J, et al. Infection with human herpesvirus 8 and transplant-associated gammopathy.Transplantation2004771551–1554
12. Caforio AL, Gambino A, Belloni Fortina A, et al. Monoclonal gammopathy in heart transplantation: risk factor analysis and relevance of immunosuppressive load.Transplant Proc2001331583–1584
13. Jimenez-Zepeda VH, Heilman RL, Engel RA, et al. Monoclonal gammopathy of undetermined significance does not affect outcomes in patients undergoing solid organ transplants.Transplantation201192570–574
14. Lemoine A, Pham P, Azoulay D, et al. Detection of gammopathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants.Blood2001981332–1338
15. Czarnecki PG, Lager DJ, Leung N, et al. Long-term outcome of kidney transplantation in patients with fibrillary glomerulonephritis or monoclonal gammopathy with fibrillary deposits.Kidney Int200975420–427
16. Nasr SH, Sethi S, Cornell LD, et al. Proliferative glomerulonephritis with monoclonal IgG deposits recurs in the allograft.Clin J Am Soc Nephrol20116122–132
17. Leung N, Lager DJ, Gertz MA, et al. Long-term outcome of renal transplantation in light-chain deposition disease.Am J Kidney Dis200443147–153
18. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Lancet Oncol201415e538–e548
19. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood20161272375–2390
20. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance.Blood2005106812–817
21. Passweg J, Thiel G, Bock HA. Monoclonal gammopathy after intense induction immunosuppression in renal transplant patients.Nephrol Dial Transplant1996112461–2465
22. Alfano G, Fontana F, Colaci E, et al. Monoclonal gammopathy of undetermined significance after kidney transplantation: single-center experience.Transplantation2017101e337–e342
23. Bancu I, Cañas L, Juega FJ, et al. Outcomes of monoclonal gammopathy of undetermined significance in patients who underwent kidney transplantation.Transplant Proc2015472344–2345
24. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.N Engl J Med20073562582–2590
25. Nambirajan A, Bhowmik D, Singh G, et al. Monoclonal gammopathy of renal significance with light-chain deposition disease diagnosed postrenal transplant: a diagnostic and therapeutic challenge.Transpl Int201528375–379
26. Bladé J, Cibeira MT. M-protein-related disorders: MGCS.Blood20181321464–1465
27. Fermand JP, Bridoux F, Kyle RA, et al; International Kidney and Monoclonal Gammopathy Research GroupHow I treat monoclonal gammopathy of renal significance (MGRS).Blood20131223583–3590
28. Kyle RA, Larson DR, Therneau TM, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance.N Engl J Med2018378241–249
29. Galioto A, Morando F, Rosi S, et al. Monoclonal gammopathy after liver transplantation: a risk factor for long-term medical complications other than malignancies.Transpl Int20122525–33
30. Chakalarovski C, Lang P, Buisson C, et al. Monoclonal immunoglobulins in patients with renal transplants: characterization, evolution and risk factors.Transpl Int19925Suppl 1S23–S25
31. Ginevri F, Nocera A, Bonato L, et al. Cytomegalovirus infection is a trigger for monoclonal immunoglobulins in paediatric kidney transplant recipients.Transplant Proc1998302079–2082
32. Acuna SA, Huang JW, Scott AL, et al. Cancer screening recommendations for solid organ transplant recipients: a systematic review of clinical practice guidelines.Am J Transplant201717103–114
© 2019 The Authors. Published by Wolters Kluwer Health, Inc.
33. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work GroupKDIGO clinical practice guideline for the care of kidney transplant recipients.Am J Transplant20099Suppl 3S1–155