Objectives: Monoclonal gammopathies represent a spectrum of clinical and biological abnormalities characterized by monoclonal immunoglobulin production from plasma cell clones. In kidney transplant recipients, monoclonal gammopathies and their identification constitute a complex and multifactorial phenomenon involving immunological alterations and underlying pathologies such as multiple myeloma or lymphoproliferative diseases.
Materials and Methods: We retrospectively studied patients who underwent kidney transplant at the Nephrology Department of Sahloul University Hospital from November 1, 2007, to December 31, 2024, and who had detection of monoclonal gammopathies during follow-up.
Results: Among 332 kidney transplant recipients, 10 (3.0%) developed monoclonal gammopathies. Mean age was 42.4 years (range, 27-58 years), with male predominance (70%). Hypertension was the most frequent comorbidity (50%). Only 1 patient had preexisting monoclonal gammopathies before transplant. Chronic interstitial nephropathy was the most common initial nephropathy (62.5%). Mean time to diagnosis of monoclonal gammopathies posttransplant was 58.9 months. Serum protein electrophoresis revealed monoclonal peaks in the gamma-globulin region (70%), beta-1 globulin (20%), and beta-2 globulin (10%). Immunofixation showed immunoglobulin G lambda (40%), immunoglobulin G kappa, immunoglobulin A lambda and kappa, and isolated light chains. Proteinuria was present in 60% and anemia in 70% of cases. Evolution included return to hemodialysis in 3 patients, infectious complications in 4 patients, and 1 death.
Conclusions: The effect of monoclonal gammopathies on kidney transplant recipients remains an evolving research domain where diagnostic and therapeutic advances play a key role in improving management of these vulnerable patients.

Key words : Immunosuppression, MGUS, Multiple myeloma, Renal transplant, Transplant outcomes

Introduction
Kidney transplantation represents the optimal treatment for end-stage renal disease, offering superior survival and quality of life compared with dialysis.¹ However, long-term immunosuppression and altered immune homeostasis in transplant recipients create a unique milieu that predisposes to various complications, including malignancies and paraproteinemias.^2,3 Monoclonal gammopathies (MG) encompass a heterogeneous group of disorders characterized by the clonal proliferation of plasma cells producing monoclonal immunoglobulins (M-proteins).⁴ The spectrum ranges from monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition, to overt multiple myeloma.⁵ In the general population, MGUS prevalence increases with age, affecting approximately 3% to 4% of individuals aged >50 years and 5% to 7% of those aged >70 years.^6,7 The immunological landscape following kidney transplant is markedly different from the general population. Chronic immunosuppression, particularly with calcineurin inhibitors and antimetabolites, disrupts normal immune surveillance mechanisms.⁸ Furthermore, chronic antigenic stimulation from the allograft, viral infections (particularly cytomegalovirus and Epstein-Barr virus), and preexisting renal disease may contribute to aberrant B-cell and plasma cell proliferation.^9,10 The clinical significance of MG in kidney transplant recipients extends beyond oncological concerns. M-proteins can directly injure the kidney allograft through various mechanisms, including cast nephropathy, light-chain deposition disease, amyloidosis, and immunoglobulin-related glomerulopathies.^11,12 Despite the potential clinical impact, data on MG in kidney transplant recipients remain limited, particularly in North African populations. Understanding the incidence, clinical characteristics, and outcomes of MG in this population is crucial for developing appropriate surveillance strategies and management protocols. In this study, our objectives were to (1) determine the incidence of MG in kidney transplant recipients at our center, (2) characterize the clinical and biological features of affected patients, (3) evaluate outcomes, including graft survival and patient mortality, and (4) identify potential risk factors for MG development posttransplant.

Materials and Methods

Study design and population
We conducted a retrospective descriptive study of all patients who underwent kidney transplantation between November 1, 2007, and December 31, 2024, at the Nephrology Department of Sahloul University Hospital, Sousse, Tunisia, and who had MG. Included patients had MG detected during routine follow-up or clinical investigation. All patient data were handled confidentially, and no identifiable personal information was accessed or disclosed. Inclusion criteria were detection of monoclonal protein on serum protein electrophoresis (SPE) and/or immunofixation during posttransplant surveillance and having complete medical records spanning at least 6 months posttransplant. Patients who had incomplete medical records or were lost to follow-up within 6 months posttransplant were excluded.

Data collection
We extracted retrospective data from institutional electronic medical records (DMI system) and paper charts using a standardized form, with rigorous cross-checking for accuracy. Key variables encompassed demographic/baseline characteristics (age, sex, comorbidities, end-stage renal disease etiology, pretransplant dialysis/malignancy), transplant details (donor type, HLA matching, immunosuppression, rejection, delayed graft function), MG features (timing, SPE/immunofixation, M-protein quantification, proteinuria, blood counts, biochemistry, bone marrow/imaging/biopsy findings), and outcomes (graft function, progression to myeloma, treatments, graft loss, infections, mortality, follow-up duration).

Statistical analyses
We compared 2 groups of patients: those with MG (MG subgroup) and those without MG (non-MG subgroup). We presented continuous variables as means ± SD and categorical variables as numbers and percentages. For statistical comparisons between groups, we used the t test for the continuous variables and the χ2 test or the Fisher exact test for the categorical variables. P < .⁰⁵ was considered statistically significant. We used IBM SPSS statistics (version 25) for all analysis.

Results

Study population and monoclonal gammopathy incidence
During the 17-year study period (November 2007 to December 2024), 332 kidney transplant procedures were performed at our center. Monoclonal gammopathy was detected in 10 patients, yielding an overall incidence of 3%. The MG subgroup exhibited a mean age at transplant of 42.4 ± 12.8 years (range, 27-58 years), which was significantly higher than the mean age of 32.4 ± 13.1 years observed in the non-MG subgroup (P = .⁰¹⁹). The MG subgroup had a higher male proportion than the non-MG subgroup (70% vs 64.8%); distributions were not significant and aligned with typical male predominance in renal transplant cohorts (P = .³⁰²). Demographic and clinical characteristics of the 10 patients diagnosed with MG are summarized in Table 1. In the MG subgroup, hypertension was the most prevalent comorbidity at 70%, exceeding the 63.23% rate in the non-MG subgroup (P < .⁰⁰¹). Diabetes mellitus affected 30% of MG patients, which was higher (P = .⁰⁰¹) than the 5% prevalence in the non-MG subgroup, suggesting a notable enrichment in this subgroup. Mean body mass index (calculated as weight in kilograms divided by height in meters squared) was 24.15 ± 5.1 in the MG subgroup and 22.6 in non-MG subgroup, indicating no significant difference of adiposity average (P = .³⁷⁰). Chronic interstitial nephropathy was the most common cause of end-stage renal disease, affecting 50% (5 patients) in the MG subgroup versus 37.2% in the non-MG subgroup. In the MG subgroup, 8 patients (80%) required pretransplant hemodialysis, closely mirroring the 78.7% rate in the overall transplant cohort. The MG subgroup had a shorter mean dialysis duration than the non-MG subgroup of 27 ± 36.2 months (range, 3-96 mo) versus 37.7 ± 46.9 months (range, 0-240 mo), suggesting potentially earlier access to transplantation among MG patients despite similar modality predominance (P = .⁵⁸²). Most kidney transplants in the MG subgroup were from living donors (9/10, 90%), mirroring the 92.5% rate in the overall transplant population. Mean donor age in the MG subgroup was 39.8 ± 9.8 years (range, 23-56 years), comparable to 40.4 ± 12.3 years in the general cohort, with an overall indication of a young donor pool for Tunisian programs (P = .⁸⁸⁴). The MG subgroup showed moderate HLA incompatibility, with a mean of 3.3 ± 0.7 mismatches (range, 3–5) versus 2.94 ± 1.76 in the general population. This level aligns with living donor transplants in resource-limited settings, where full matching is uncommon due to familial relations (P = .⁴¹⁰). In the MG subgroup, induction immunosuppression consisted of thymoglobulin (anti-thymocyte globulin) and methylprednisolone in 9 of 10 patients (90%) compared with 64% in the non-MG subgroup. This significantly higher use (P = 0.013) suggested preference for intensified lymphocyte depletion in the MG subgroup, potentially due to perceived higher immunological risk (P < .⁰⁰¹).​ Maintenance immunosuppression included mycophenolate mofetil and prednisone associated with tacrolimus in 5 patients (50%) in the MG subgroup versus 56.7% in the non-MG subgroup. Four patients (40%) in the MG subgroup received cyclosporine (vs 30.7% of those in the non-MG subgroup), and 1 patient (10%) was switched to sirolimus due to tacrolimus toxicity 1 month posttransplant compared with 12.6% with sirolimus use in the non-MG subgroup. These distributions indicate broadly similar maintenance strategies across groups, with modest variations possibly reflecting individual tolerability or clinical adjustments. Mean time from kidney transplant to MG diagnosis was 8.3 ± 5.5 years (range, 0-20 years). The Kaplan-Meier cumulative risk function for time to MG diagnosis posttransplant showed a 30% risk by 6 years, with stepwise increases at 3 and 6 years, followed by stabilization up to 12 years (Figure 1). One patient (10%) had preexisting MG diagnosed before transplant, characterized by an immunoglobulin A (IgA) kappa monoclonal protein peak and negative proteinuria. This patient received a renal graft from a deceased donor despite the preexisting condition, likely due to the absence of high-risk features (eg, no symptomatic myeloma or severe renal infiltration by gammopathy), as supported by standard guidelines permitting transplant in stable MGUS without contraindications.​ Posttransplant evolution showed persistence of MG without progression. A bone marrow examination revealed 3% plasma cells, consistent with a low-burden clone. No specific anti-MG treatment was administered, reflecting a watchful waiting approach given the indolent course and lack of clinical complications. Serum protein electrophoresis results showed a monoclonal peak in gamma-globulin region in 7 patients (70%), a monoclonal peak in beta-1 globulin region in 2 patients (20%) and a monoclonal peak in beta-2 globulin region in 1 patient (10%) (Figure 2). Immunoglobulin G (IgG) lambda was the most frequently observed subtype, identified in 4 patients (40%), followed by IgG kappa and IgA kappa, each detected in 2 patients (20%). One patient showed IgA lambda, and 1 patient showed isolated kappa light chains. Overall, IgG-associated MGs predominated in this cohort. Proteinuria was detected in 6 patients (60%), with a mean average at 1.17 ± 1.4 g/day (range, 0.005-4.8 g/day). Anemia affected 7 patients (70%), with a mean hemoglobin of 10.21 ± 2.7 g/dL (range, 5.3-14 g/dL). Thrombocytopenia occurred in 1 patient (10%) and leukopenia in 2 patients (20%). Mean baseline creatinine level was 86 ± 18.5 µmol/L (range, 65-119 µmol/L), and mean creatinine level at the time of diagnosis was 176.1 ± 120.1 µmol/L (range, 64-460 µmol/L). No hypercalcemia was noted in the MG subgroup. Bone marrow aspiration and biopsy were performed in 5 of 10 patients in the MG group. In 4 of these patients, multiple myeloma was excluded, but 1 patient showed 11% plasma cells. The remaining 5 patients, who did not undergo the procedure, remained clinically stable with no active signs of myeloma. Only the patient with confirmed multiple myeloma underwent body scans, which revealed no lytic lesions. Three patients in the MG group had kidney allograft biopsies, prompted by specific indications, including rising creatinine, new-onset proteinuria, and high proteinuria levels. Histopathological findings revealed no abnormalities in 1 graft, membranoproliferative glomerulonephritis with negative immunofluorescence and immunohistochemistry revealing lambda light chain deposits in 1 graft (Figure 3), and diabetic nephropathy in the third graft. Based on integrated clinical, laboratory, imaging, and bone marrow findings, patients were classified as follows: MGUS in 8 patients (80%), smoldering multiple myeloma in 1 patient (10%), no symptomatic multiple myeloma, and monoclonal gammopathy of renal significance (MGRS) in 1 patient (10%). Patients diagnosed with MGUS underwent active surveillance. Two patients received anti-myeloma chemotherapy (patient with confirmed myeloma and patient with MGRS), which included bortezomib-thalidomide-dexamethasone for 4 cycles, as recommended in International Myeloma Working Group/European Hematology Association-European Myeloma Network guidelines. Among the 10 patients in the MG subgroup, 3 returned to hemodialysis during the follow-up period. The other 7 patients had stable creatinine levels. Regarding infectious complications, 4 patients developed infectious complication (2 cases of pneumonia, 1 case of kerato-uveitis, and 1 case of Staphylococcus aureus cellulitis). One patient (10%) died during the follow-up period. The interval from kidney transplant to death was 13 years, and the interval from MG diagnosis to death was 4 years. Primary cause of death was COVID-19 pneumonia necessitating intensive care admission, with immunosuppression identified as a major contributory factor.

Discussion
Among kidney transplant recipients at our center over a 17-year period, our retrospective study showed an incidence of 3% for MG. This finding adds to the limited literature on MG in transplant populations and provides novel data from a North African cohort. Our incidence falls within the range of reported prevalence rates. A French cohort reported a prevalence of 3.7%, but higher rates were observed in an Italian cohort (8.1%) and a German cohort (10.7%), highlighting substantial interstudy and geographical variability in MG occurrence after kidney transplant.^13-15 The variability in reported incidence across studies reflects differences in screening practices, follow-up duration, patient demographics, immunosuppression protocols, and geographic/ethnic variations.¹⁶ The mean age of 43 years at transplant in our MG cohort was relatively young compared with typical MGUS populations in the general population, where prevalence reaches 4.9% in individuals aged 40 and older and substantially higher rates in those over 70 years.^17,18 Several mechanisms may account for this accelerated phenotype. Chronic immunosuppression fundamentally alters immune surveillance mechanisms that normally suppress aberrant plasma cell clones, and the persistent antigenic stimulation from the allograft, combined with recurrent viral infections (particularly Epstein-Barr virus and cytomegalovirus), creates a proinflammatory milieu that may drive B-cell and plasma cell proliferation.¹⁹ Patients with end-stage renal disease may also have preexisting immune dysfunction characterized by chronic inflammation, altered cytokine profiles, and immune senescence, which are factors that may predispose to earlier clonal plasma cell emergence.²⁰ The male predominance (70%) observed in our study is consistent with the general epidemiology of MGUS and multiple myeloma, which shows a higher incidence in males across most populations; interestingly, however, once MGUS is present, progression rates to multiple myeloma do not differ significantly in male versus female patients.²¹ One patient in our MG subgroup (10%) had preexisting MG before transplant. The decision to proceed with transplant in patients with known MGUS or smoldering myeloma remains controversial. It has been suggested that well-selected patients with stable, low-risk MGUS should not be categorically excluded from transplant, given the substantial mortality associated with remaining on dialysis.²² These patients requires intensive posttransplant monitoring with serial SPE, serum free light chains, complete blood counts, calcium, and renal function testing at 3- to 6-month intervals, with lower thresholds for bone marrow examination and imaging if progression is suspected.⁵ Immunosuppression in patients with MG pathogenesis is complex and multifactorial.²³ Thymoglobulin (rabbit anti-thymocyte globulin) induction therapy can cause profound, prolonged T-cell depletion, and thymoglobulin and other T-cell depleting agents are associated with increased risk of posttransplant lymphoproliferative disease, particularly Epstein-Barr virus-driven B-cell lymphoproliferative disorders.¹⁰ Although direct evidence linking thymoglobulin to monoclonal gammopathy is scare, the biological rationale is compelling. Tacrolimus and cyclosporine, cornerstone immunosuppressants in kidney transplant, primarily inhibit T-cell activation by blocking calcineurin-dependent interleukin 2 transcription. Although their primary target is T cells, calcineurin inhibitors have complex effects on B-cell and plasma cell biology. Suppression of T-cell function includes cytotoxic and regulatory T cells that normally limit aberrant B-cell and plasma cell proliferation. This loss of immune surveillance may permit clonal plasma cell escape.^24,25 Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, thereby blocking purine synthesis and suppressing lymphocyte proliferation. Mycophenolate mofetil affects both T cells and B cells. Although mycophenolate mofetil suppresses B-cell proliferation, its effects on plasma cell biology are complex. Mature, long-lived plasma cells are relatively resistant to antiproliferative agents because they are nondividing cells.²⁶ Consequently, mycophenolate mofetil may suppress normal B-cell responses while having limited effect on established clonal plasma cells, potentially creating a competitive advantage for malignant clones. The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth, proliferation, and survival, and mTOR inhibitors have demonstrated anti-tumor effects in various malignancies, including multiple myeloma in preclinical models.^27,28 However, mTOR inhibitors also have immunomodulatory effects that could theoretically influence plasma cell clone dynamics.²⁹ The mean time to MG diagnosis was 8.3 years posttransplant, indicating that MG is predominantly a late complication. The literature on timing of MG development posttransplant is limited. However, our mean time was consistent with MG being a late complication, similar to other posttransplant malignancies such as solid-organ cancers, which typically emerge after several years of cumulative immunosuppression.³⁰ The late emergence of MG has important implications for surveillance strategies. Screening protocols must extend throughout the life of the graft and the patient, not just the early posttransplant period. Given the relatively slow evolution of MGUS (with ~1% annual progression risk in the general population³¹), annual or biannual SPE screening may be reasonable, with more frequent testing in high-risk subgroups. Results of M-protein characteristics in the MG subgroup showed predominance of IgG-type M-proteins (40% based on IgG lambda), which mirrors the general pattern in MGUS, where IgG accounts for approximately 60% of cases.⁶ Our cohort showed a higher proportion of IgA (40% vs 12% typical) and light chain only (10% vs 3% typical),³¹ although small sample size limited definitive conclusions. Bone marrow examination was performed in only 50% of patients in our MG subgroup. Our practice aligned with the current International Myeloma Working Group guidelines for the most part, although we acknowledge that some patients with M-protein of 1.0 to 1.5 g/dL and abnormal free light chain ratios might have benefited from bone marrow examination for more precise risk stratification.⁵ Kidney allograft biopsy was performed in 3 of 10 patients in our MG subgroup. The literature on biopsy thresholds in transplant recipients with MG is limited to expert opinion and case series. General principles include the following.^12,32 (1) Nephrotic-range proteinuria is an absolute indication for biopsy in the presence of MG. (2) Light-chain disease should prompt early biopsy even with lesser degrees of proteinuria (>1 g/day). (3) Declining graft function unexplained by other causes warrants biopsy. Finally, (4) serial monitoring may be appropriate for stable patients with low-level proteinuria and low-risk M-proteins. The concept of MGRS has gained recognition in recent years^11,33 but remains underreported in the literature. Monoclonal gammopathy of renal significance encompasses conditions where a monoclonal protein causes kidney damage despite not meeting criteria for multiple myeloma or other malignant plasma cell disorders. In our cohort, 1 patient had biopsy-proven membranoproliferative glomerulonephritis, consistent with MGRS. After multidisciplinary discussion involving nephrology, hematology, and pathology, clone-directed therapy was initiated in this patient. However, the patient ultimately progressed to end-stage kidney disease, requiring return to hemodialysis, and subsequently developed an infectious complication leading to death after intensive care admission. Published case series have suggested that MGRS in allografts carries important risk of graft loss if untreated. However, clone-directed therapy can achieve hematologic and renal responses, potentially preserving graft function.^33,34 The recognition of MGRS is crucial because MGRS represents a treatment indication even in the absence of systemic myeloma.³⁵ In fact, clone-directed therapy is indicated when a monoclonal protein causes organ damage (MGRS) or when criteria for symptomatic multiple myeloma are met.¹² The literature on MGRS treatment in transplant recipients is limited to case reports and small series. Key principles include the following.^12,33 (1) Observation or symptomatic management alone is inadequate; clone eradication or suppression is necessary to halt kidney injury. (2) Bortezomib-based regimens are first-line: proteasome inhibitors have proven efficacy in MGRS and are relatively safe in renal impairment. (3) Novel agents show promise, with daratumumab (anti-CD38) demonstrating efficacy in MGRS case reports, including in transplant recipients.³⁶ Finally, (4) immunomodulatory drugs (lenalidomide) are controversial, with concern on potential for triggering rejection, although case reports describe successful use.³⁷ For patients with MGUS, active surveillance is the standard of care.³⁸ Our monitoring includes annual SPE, complete blood count at every visit to detect cytopenia, serum calcium at every visit to detect hypercalcemia, serum creatinine/estimated glomerular filtration rate at every visit to monitor graft function, and urine protein quantification at every visit. Graft loss occurred in 3 of 10 of patients in our MG subgroup. In fact, MGRS carries high risk of graft loss if untreated: Case series have reported 50% to 70% graft loss rates in untreated MGRS.³⁸ For MGUS, no data have specifically addressed graft survival in transplant recipients. Our study had several strengths. First was the long follow-up period (17 years), encompassing a substantial transplant cohort. Second, we provided detailed characterization of M-protein types and clinical outcomes, in addition to histopathological data from kidney biopsies. Our study also had several limitations, including the retrospective nature, which limited causal inference and may have introduce selection bias. We also had a small sample of only 10 MG cases; thus, statistical power for comparative analyses and risk factor identification were limited. Because this was a single-center study, our findings may not be generalizable to other populations with different demographics, immunosuppression protocols, or health care systems. Finally, we had some incomplete investigations, with not all patients having comprehensive evaluation including bone marrow examination, advanced imaging, serum free light-chain assays, or kidney biopsies.

Conclusions
Our study reported a 3.0% incidence of MG in kidney transplant recipients at our center, predominantly as late-onset complication, leading to graft loss (30%), infections (40%), and mortality (10%). Routine surveillance, multidisciplinary evaluation, and introduction of clone-directed therapies when needed are crucial, and further research is needed to clarify mechanisms and optimize management in this high-risk population.