Bone marrow aspirate and biopsy were performed in 6 patients with MGUS. In 5 of 6 cases, clonal bone marrow plasma cells were less than 10%. Whereas in 1 case, MM was diagnosed.
In patients with MGUS flow cytometry analysis of bone marrow cells showed the absence of any significant alteration. During follow-up, no patients had bone marrow biopsy or laboratory characteristics suggestive for smoldering myeloma. One patient developed a posttransplant lymphoproliferative disorder (specifically, low-grade non-Hodgkin lymphoma) after the diagnosis of MGUS.
Serum-free light chain dosing was available only in a minority of patients and therefore was not included in the analysis.
Clinical Outcomes: Matched Case-Control Analysis
We compared the 39 KT patients with stable MGUS with 79 matched KT recipients who did not develop MGUS. As expressed in Table 3A, there were no significant differences in age, sex, and mean duration of follow-up between the 2 groups. Types of immunosuppressive regimens and number of HLA mismatches were also similar, as was the prevalence of main viral infections.
As reported in Table 3B, the incidences of hematological and solid neoplasms (including skin malignancies) were similar in both groups. On the other hand, the MUGS group presented a significantly higher prevalence of MBL, an asymptomatic premalignant condition characterized by the expansion of a clonal B cell population.14
Of note, patients with MGUS were tested significantly more frequently with peripheral blood flow cytometry compared with controls (77% vs 19%; P = <0.0001).
The rate of serious infectious events was slightly higher in the MGUS group, although the difference was not statistically significant. There was no difference in the overall incidence of biopsy-proven rejection between the 2 groups. Furthermore, it is worth to note that the 10 (91%) cases of rejection preceded the diagnosis of MGUS by a mean age of 5 years. KT patients with MGUS had a slightly higher risk of developing CKD stage IV, but the difference with the control group was not significant. Graft and overall survival after KT were not significantly different among patients with MGUS and controls, as exemplified by the Kaplan-Meier curves in Figure 1 and Figure 2. In the univariate logistic regression, reported in Table 4, the only factor potentially associated with the development of MGUS after KT was a positive history for inflammatory kidney disease (glomerulonephritis or acute interstitial nephritis) before KT.
Prevalence of MGUS after KT is unclear and mainly based on small single-center descriptions. Exposure to immunosuppressive treatment could theoretically contribute to a higher prevalence of MGUS in KT recipients, as already noted7; nevertheless, few studies conducted in recent years reported opposite findings.8,9 Moreover, risk factors for MGUS development have not been clearly identified, and the prognosis of this condition after solid organ transplantation remains elusive. Although some authors suggest a benign course for this condition,15 there are few reports about its potential association with hematologic malignancies,8,10,16 and a recent study performed in liver transplant recipients described a higher incidence of medical complications in patients with MGUS.11
As previously noted, serum monoclonal proteins can frequently be transient after transplantation,7,8 much more than what was reported for the general population. A consistent number of our patients had a MGUS that spontaneously disappeared during the follow-up; although it was not possible to trace all changes made to pharmacologic treatments, modulations in the immunosuppressive therapy dose may account for this phenomenon. Assuming that a transient condition should not bear substantial clinical implications, we focused our attention on the group of patients diagnosed with stable MGUS after KT.
The overall prevalence of patients with stable MGUS after KT in the present study was 8.1%, much higher than what was reported in the general population. The age-specific analysis demonstrated a nonsignificant difference in MGUS prevalence between age classes in our group (Table S1, SDC,http://links.lww.com/TP/B468), contrasting again with reports on the common clinical course of the condition in nontransplanted subjects. It is relevant to note that 9 (23%) patients were younger than 50 years, differing strikingly from general population, where the condition is fairly uncommon before 50 years of age.2,4 Our findings are in line with a previous report from Braun et al,17 describing a high prevalence of monoclonal gammopathy in relatively young (mean age, 53.4 years) KT recipients with a functioning graft for more than 30 years. The distribution of MGUS after KT was not gender specific, whereas population-based studies reported the condition to be more prevalent in men.2,4 Thus, KT seems to act as a predisposing factor for the development of MGUS, irrespective of age and sex. We speculate that the reduced immunologic surveillance due to the immunosuppressive treatment may possibly favor the proliferation of a plasma cell clone in susceptible KT recipients.
The median time from KT to the diagnosis of MGUS was 5.2 years, in contrast with a previous study,7 where a shorter time interval was reported; this difference is likely related to the more aggressive induction treatments used in the early transplantation era there analyzed.
Distribution of the immunoglobulin isotypes in our group was similar to what was reported for the general population, with a definite prevalence for the IgG class (see Table 2); nevertheless, we unexpectedly encountered a very high incidence of substantially differing from data available in normal subjects, where they account for 3% of all monoclonal proteins.2
Although few studies identified EBV18,19 and CMV19 infections as potential risk factors for the development of MGUS in transplanted patients, we are not able to confirm these associations. In our study, in the rate of infections for EBV, CMV did not differ significantly between patients with MGUS after KT and matched KT recipients, as expressed in Table 3A. In addition, we report no differences in the rate of infection of BK and JC polyomavirus between MGUS patients and controls.
We encountered no differences between the group of patients with stable MGUS and a matched cohort of KT recipients with respect to strong outcomes, such as mortality and graft failure (as depicted in Figure 1 and Figure 2). The rate of development of “de novo” malignancies, both hematological and solid cancers, was similar between the 2 groups (as reported in Table 3B), in accordance with data previously reported in liver transplant recipients.11 Of note, only 1 patient developed fatal MM after 1.5 years from transplant and 1 month from MGUS diagnosis.
On the other hand, MUGS group presented a higher rate of MBL, a premalignant condition which can predispose to the development of chronic lymphocytic leukemia and other lymphoproliferative malignancies14,20,21; nevertheless, the strength of this association is dampened by the fact that MGUS patients were tested more often with peripheral blood flow cytometry than controls. Based on our experience, we believe that these findings should prompt regular hematological follow-up in KT recipients with MGUS. Monitoring of the monoclonal protein blood levels and performance of flow cytometry for early detection of B lymphocytic clones should be advised; clinicians should maintain a high degree of suspicion for malignancy during follow-up of these patients.
Similar to what was reported by Galioto et al,11 who described an increased rate of infections in liver transplant recipients with MGUS, our patients in the MGUS group had a slightly higher, although not significant, incidence of serious infectious events (see Table 3B). In a large epidemiologic study performed in Sweden, normal subjects with MGUS were reported to be at increased risk for bacterial infections irrespective of serum monoclonal protein level, supporting the hypothesis of an underlying state of immunodeficiency in this condition.22 This predisposition, combined with the detrimental effects of immunosuppressive therapy in transplanted patients may further worsen their immunologic competence.
Considering the incidence of biopsy-proven rejection, the groups did not differ significantly; it was interesting to note that in the MGUS group, 91% of rejection episodes preceded the diagnosis of MGUS, suggesting that the incremented immunosuppression imposed by the biopsy findings might have played a role in the development of the monoclonal gammopathy.
The only predictive factor for the development of MGUS after KT in the univariate analysis was a pretransplant history of inflammatory kidney diseases (glomerulonephritis or acute interstitial nephritis). We speculate that previous exposure to immunosuppressive agents commonly used to treat these conditions, although difficult to quantify, may contribute to the development of a monoclonal plasma cell clone after KT. Moreover, autoimmune connective tissue disorders, frequently a cause of immune-related renal diseases, and inflammatory disorder, including glomerulonephritis, have been associated with an increased risk of MGUS development in population-based studies.23,24 On the other hand, more plausible risk factors, such as previous viral infections and different immunosuppressive protocols, already identified in previous studies,7,18,19 were not associated with development of MGUS after KT in our patients, as reported in Table 4.
Our study has some limitations that should be acknowledged: shortness of follow-up, relatively small number of cases, and retrospective design of our analysis must be taken into account before considering these results as conclusive.
In conclusion, we report a high incidence of stable MGUS after KT (8.1%). Different from the general population, the occurrence of MGUS was not influenced by age and sex, with a considerable number of cases developing in young subjects. The burden of immunosuppressive treatment posttransplantation and history of inflammatory kidney disease may cause immune dysregulation and favor the development of a plasma cell clone. The presence of MGUS did not impact graft survival, overall survival, and incidence of malignancies; there was a slight, although nonsignificant, increase in the cumulative incidence of serious infections. Although MGUS did not show a very aggressive course in terms of frank progression to MM, we found a significant increase in the incidence of MBL, a premalignant condition which warrants a strict hematological follow-up in KT patients. Further studies are needed to elucidate the complex epidemiologic characteristics of MGUS developed after KT and to confirm its association with MBL.
The authors gratefully thank Teresa Carbone, Monica Pecorari and William Gennari for their assistance in data collection.
The study was approved by the Ethics Committee of Policlinico of Modena (Prot. no 1476/C.E.) and written informed consent was obtained from all participants before any study procedures.
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