Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance : Transplantation

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Review

Kidney Transplantation in Patients With Monoclonal Gammopathy of Renal Significance

Sprangers, Ben MD, PhD1,2; Hegenbart, Ute MD, PhD3; Wetzels, Jack F.M. MD, PhD4

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Transplantation ():10.1097/TP.0000000000004443, December 19, 2022. | DOI: 10.1097/TP.0000000000004443
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Abstract

INTRODUCTION

Small amounts of monoclonal immunoglobulins or their fragments can cause injury to various organs including the kidney. The term monoclonal gammopathy of renal significance (MGRS) was coined to define disorders characterized by kidney injury caused by a monoclonal immunoglobulin, for which the underlying B cell or plasma cell clone alone does not meet hematological criteria for therapy.1-3 The most common forms of MGRS are listed in Table 1.

TABLE 1. - Subtypes of MGRS
Monoclonal immunoglobulin-associated amyloidosis (amyloidosis caused by fragments of an amyloidogenic light and/or heavy chain)
Monoclonal immunoglobulin deposition disease
Light chain proximal tubulopathy
Immunotactoid glomerulopathy
(Proliferative) glomerulonephritis with monoclonal immune deposits
C3-glomerulopathy (monoclonal Ig associated)
Cryoglobulinemic vasculitis a
Fibrillary glomerulopathy with monoclonal immune deposits a
Crystalglobulin-induced nephropathy b
Crystal storing histiocytosis b
Thrombotic microangiopathy c
Adapted from references.2,3
aRare, discussed in the supplementary appendix (SDC, https://links.lww.com/TP/C637).
bVery rare, no data, not discussed.
cThere is an association between TMA and the presence of a monoclonal immunoglobulin, but mechanistic prove is lacking, and there are no data on kidney transplantation in patients with TMA associated with a monoclonal immunoglobulin.
Ig, immunoglobulin; MGRS, monoclonal gammopathy of renal significance; TMA, thrombotic microangiopathy.

Although the introduction of very effective hematological therapy has increased the response rate and improved outcome in MGRS, many patients will develop end-stage kidney disease, and may request kidney transplantation. The prospects of kidney transplantation for patients with MGRS are not well defined. A recent review discussed kidney transplantation in patients with all plasma cell dyscrasias.4 The authors briefly touch upon kidney transplantation in patients with MGRS and state that “MGRS has a high rate of recurrence with allograft injury following kidney transplantation… Kidney transplant candidates with a diagnosis of MGRS should be evaluated carefully and ideally treated for their underlying plasma cell dyscrasia in remission for at least 2 y before kidney transplantation to achieve optimal outcomes.”4 However, in this review only a few paragraphs are devoted to MGRS, no details per MGRS subgroup are given, and only 4 manuscripts are referenced.4 Leung et al3 also provide a general recommendation of pretransplant hematological treatment and attainment of at least very good partial response (VGPR).

With respect to kidney transplantation in patients with AL-amyloidosis, experts are more balanced. Stern and Havasi recommend that patients with AL-amyloidosis should achieve complete or VGPR that is durable for 9–12 mo before kidney transplantation.5 Still they admit that the optimal timing of kidney transplantation requires further studies. Leung et al suggest that patients with AL-amyloidosis might be an exception to the rule, in view of the notion that in AL-amyloidosis outcome was similar whether patients received clone-directed therapy before or after kidney transplantation.3 A recent commentary also pointed to positive outcomes of kidney transplantation in patients with AL-amyloidosis and a suboptimal hematological response, and even in treatment naïve patients. The authors conclude that “these observations imply that renal transplantation should not be precluded ‘a priori’ in such settings” and that more evidence is needed to identify the best strategies.6 The relatively good outcome after kidney transplantation in treatment naive patients with AL-amyloidosis is attributed to the relatively low risk and slow rate of recurrence.3

We suggest that a “one size fits all” strategy is also not appropriate for nonamyloid MGRS. In fact, most reviews do not take into account the high risks of hematological treatment in patients with kidney failure, the variable effects of MGRS recurrence on graft outcome, and the overall benefits of kidney transplantation. The evaluation of and decision-making in patients with MGRS who are kidney transplant candidates is an elaborate process. There are some similarities in decision-making in kidney transplant candidates with a history of a malignancy. A recent review provided expert opinion recommendations and discussed the relevant factors such as the expected risks of recurrent malignancy, and ensuing death and graft failure, ethical considerations such as the fair distribution of a scarce resource (ie, a donor kidney), and the role of living kidney donor transplantation.7 Importantly, the annual mortality rate on dialysis should be accounted for. Based on a large survey, most physicians favored acceptance of a patient as candidate for kidney transplantation if expected 5-y patient survival exceeded 80%.7

Patients with MGRS, which is not a malignant condition, do not have a life-threatening condition. As such, patient survival is not a major issue, unless there are severe extrarenal (cardiac) manifestations. Still, kidney transplantation can be considered futile in patients with MGRS who develop recurrent disease which leads to early graft loss. Thus, in patients with MGRS, there are many relevant factors that need to be considered when considering kidney transplantation. These are listed and commented on in Table 2. Some of these are general and include patient characteristics such as age, comorbidity, the availability of a suitable living donor, expected waiting time, previous hematological therapy, hematological response, and current levels of M-protein and free light chains (FLCs). Others are subtype-specific and include the likelihood of severe extrarenal disease, the recurrence rate (in treated and untreated patients), the effect of recurrent disease on graft function, and the efficacy of hematological “rescue” therapy on graft survival. Ethical considerations, including the use of scarce donor kidneys, are also relevant and may vary between countries or regions. In this review, we summarize the current knowledge of kidney transplantation in patients with MGRS-associated kidney diseases, provide information that can be used in clinical practice, and suggest possible decision algorithms (Table 2; Figures 1–3).

TABLE 2. - Factors contributing to decision-making in patients with MGRS who would like to pursue kidney transplantation and their relevance
Factor Relevance
Diagnosis of kidney disease Review disease history and kidney biopsy and perform ancillary studies if necessary to ascertain a diagnosis of MGRS and its subtype
Hematological evaluation Exclude hematological malignancy; evaluate M-protein and free light chains: presence of M-protein and or high levels of culprit light chain define treatment response (in treated patients) or risk of progression (in untreated patients)
Hematological treatment Review hematological therapy and classify response (see Table 4). Patients with good hematological response (CR/VGPR) can be accepted for kidney transplantation. In patients with a limited response or no response, a personalized approach is necessary.
Donor type A living kidney donor will allow short waiting time for kidney transplantation, with a reduced risk of delayed graft function posttransplant. Availability of a living donor kidney does not add to shortage of organs.
Waiting time A long waiting time necessitates pretransplant hematological therapy
Extrarenal disease The presence of extrarenal disease argues against pursuing kidney transplantation without initial hematological therapy.
Recipient CKD stage A recipient with CKD stage IV/V not on dialysis benefits from preemptive kidney transplantation, and has an increased risk of side effects of hematological therapy (specifically HDM-ASCT).
Recurrence rate and time to recurrence A high risk of early recurrence argues against preemptive kidney transplantation without prior hematological therapy (for example, C3-glomerulopathy)
dFLC A high dFLC in untreated patients argues against pursuing kidney transplantation without prior hematological therapy
Recurrent disease: clinical risks and response to therapy MGRS subtypes characterized by recurrence causing severe AKI are less likely to show good renal response to therapy. Risks of hematological therapy in kidney transplant patients are less well studied, although Bortezomob-based therapies and HDM-ASCT have been used successfully. Expecting future data on daratumumab
Age and comorbidity Usual risk factors for kidney transplantation. High age would favor early, preemptive kidney transplantation
Kidney shortage From a societal perspective, a deceased donor kidney should be used in a patient with a priori acceptable graft survival
AKI, acute kidney injury ; CKD, chronic kidney disease; CR, complete response; dFLC, difference between the concentration of the involved and not-involved light chain; HDM-ASCT, high-dose melphalan-autologous stem cell transplant; VGPR, very good partial response.

F1
FIGURE 1.:
Algorithms of management of patients with AL-amyloidosis, who are considered for kidney transplantation. Pretransplant evaluation includes assessment of extrarenal disease, measurement of free light chains and calculation of the difference between the concentration of the involved and not-involved light chain (dFLC), eGFR (in patients not treated with dialysis), and the prospect of a living kidney donor. A, Algorithm for patients treated with dialysis, who are waitlisted for a deceased donor kidney. Hematological therapy is advised. HDM-ASCT can be considered in patients with insufficient response to chemotherapy. B, Algorithm for patients not on dialysis. When a living kidney donor is available, preemptive kidney transplantation without prior hematological therapy can be considered. AKI, acute kidney injury; Bor, Bortezomib; CAPD, continuous ambulatory peritoneal dialysis; CKD, chronic kidney disease; CR, complete response; Dara, Daratumumab; Dex, dexamethasone; eGFR, estimated glomerular filtration rate; HDM-ASCT, high-dose melphalan-autologous stem cell transplant; NR, no response; PR, partial response; SAE, serious adverse event; Tx, transplantation; VGPR, very good partial response.
F2
FIGURE 2.:
Pretransplant evaluation of patients with MGRS.** Pretransplant evaluation includes a thorough assessment of the initial diagnosis, often necessitating review of the original kidney biopsy with additional studies as needed. In patients with a diagnosis of C3GN, a search for hereditary or acquired (not monoclonal immunoglobulin associated) dysregulation of complement is advised. #In patients with hematological malignancy, treat and evaluate according to hematological guidelines. *Includes C3GN; polyclonal ITG; undefined native kidney disease diagnosis in a patient with MGUS. **For AL-amyloidosis and MIDD (see Figure 1). C3GN, complement C3 glomerulonephritis; CR, complete response; EM, electron microscopy; FGN, fibrillary glomerulonephritis; IF, immunofluorescence; IHC, immunohistochemistry; ITG, immunotactoid glomerulopathy; LCPT, light chain proximal tubulopathy; LM, light microscopy; MGRS, monoclonal gammopathy of renal significance; MIDD, monoclonal immunoglobulin deposition disease; Nef, nephritic factors; NR, no response; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin deposits; PR, partial response; VGPR, very good partial response.
F3
FIGURE 3.:
Approach to accepting a patient with MGRS for kidney transplantation and posttransplant follow-up in patients with MGRS.** Patients with MGRS can be accepted for kidney transplantation, even if hematological CR/VGPR criteria are not met. There are exceptions: patients with C3GN can develop very rapid recurrence leading to early graft loss, and in these patients, pretransplant hematological therapy is advised. Although not based on high-level evidence, we suggest to consider pretransplant hematological therapy in patients with MGRS and high FLC load, or patients with a rapid deterioration (RPGN-like) of kidney function in their native kidneys, attributed to the MGRS. **For AL-amyloidosis and MIDD, see Figure 1. C3GN, complement C3 glomerulonephritis; CR, complete response; FGN, fibrillary glomerulonephritis; ITG, immunotactoid glomerulopathy; LCPT, light chain proximal tubulopathy; LMW, low molecular weight protein; MGRS, monoclonal gammopathy of renal significance; MIDD, monoclonal immunoglobulin deposition disease; NR, no response; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin deposits; PR, partial response; UPCR, urine protein creatinine ratio; VGPR, very good partial response.

MATERIALS AND METHODS

We have searched the literature, selecting studies published in English after 2002, using the following search strategy: ((((kidney[Title]) OR (renal[Title])) AND ((transplantation[Title]) OR (allograft[Title]))) NOT (stem cell[Title])) AND ((amyloidosis[Title]) OR (Monoclonal[Title]) OR (light chain[Title]) OR (PGNMID[Title]) OR (MIDD[Title]) OR (LCDD[Title]) OR (LCPT[Title]) OR (Complement C3[Title]) OR (immunotactoid[Title]) OR (fibrillary[Title])) NOT ((antibodies[Title]) OR (antibody[Title]) OR (autologous[Title]) OR (transthyretin[Title]) OR (liver[Title])).

We excluded cases of “de novo” MGRS after kidney transplantation, cases with non–AL-amyloidosis, and cases with uncertain diagnosis. For the MGRS subtypes AL-amyloidosis, larger cohort studies were available, and we excluded single case reports. Some centers have updated their cohorts, and we included the latest article. Because most MGRS are rare diseases and kidney transplantation is not often considered, we often had to draw conclusions from small case series or even case reports. For immunotactoid nephropathy, there were almost no recent literature data, therefore we accepted references from older date.

In this article, we summarize data for monoclonal immunoglobulin-associated amyloidosis, monoclonal immunoglobulin deposition disease, light chain proximal tubulopathy, immunotactoid glomerulopathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, and C3-glomerulopathy, the most common subtypes of MGRS. Information on monoclonal fibrillary glomerulopathy and cryoglobulinemic vasculitis is given in the supplementary appendix (SDC, https://links.lww.com/TP/C637). We end the article with information on hematological treatment in patients with CKD stage IV/V and hematological response criteria.

Kidney Transplantation in Monoclonal Immunoglobulin-associated Amyloidosis

Monoclonal immunoglobulin-associated amyloidosis is characterized by deposits of fibrils that originate from fragments of light and/or heavy chains.2,3,8,9 Patients with monoclonal immunoglobulin-amyloidosis and kidney involvement typically present with nephrotic syndrome. Monoclonal immunoglobulin-associated amyloidosis is a multiorgan disease, with involvement of the heart being the most severe manifestation. Hematological treatment has improved outcome, median survival increasing from 18 mo in the 20th century to 51 mo in patients diagnosed in the period 2011–2015.10 Still, such treatment may not prevent kidney failure in patients who present with severe kidney injury. Thus, 5 yr renal survival is only 30% in patients who present with an estimated glomerular filtration rate (eGFR) <50 mL/min/1.73m2 and proteinuria >5 g/d.11 With improvement in therapy and increased patient survival kidney transplantation is considered feasible in patients with AL-amyloidosis. Detailed data of recent studies of kidney transplantation in AL-amyloidosis are given in Table S1, SDC,https://links.lww.com/TP/C637.12-18 Obviously, there is bias in the selection of patients for kidney transplantation, with exclusion of many patients based on age, severe cardiac involvement, low-performance status, and pulmonary dysfunction.14 In the United Kingdom, only 10.8% of patients diagnosed between 1978–2011 with kidney failure due to AL-amyloidosis received a kidney transplant.14 The single-center studies included 190 patients, 120 males and 70 females. Most patients had received 1 or more lines of hematological treatment. More than half (57%) of patients had been treated with high-dose melphalan followed by autologous stem cell transplantation (HDM-ASCT) before kidney transplantation, mainly driven by the US centers. The majority of patients had achieved complete remission (CR) (53%) or VGPR (14%). Average follow-up ranged from 4.6 to 8.9 y. The overall outcome was good, with median overall patient survival ranging from 9.0 to 10.5 y.12-18 Renal recurrence of amyloidosis was observed in 12.5%–35% of patients, and overall (including hematological and extrarenal) recurrence occurred in 22%–40% of patients. The difference in recurrence rate is partly explained by center-specific management, such as the use of protocol transplant biopsies. Importantly, graft failure was attributed to recurrent amyloidosis in only 5 patients, whereas at least 16 patients died due to recurrent hematological disease or recurrent (extrarenal) amyloidosis.12-18 Overall, outcome was better and recurrence rate lower in patients who had achieved CR or VGPR. In 1 study, renal recurrence occurred in 6 of 27 patients with CR/VGPR (22%) and in 8 of 16 patients with partial response (PR)/no response (NR) (50%).12 Another study noted that renal recurrence developed earlier in patients with PR or NR (all ≤60 mo), whereas median time to recurrence was 121 mo and beyond in patients with VGPR and CR, respectively.19 Still, although CR was associated with improved survival, VGPR was not always associated with better outcome compared to PR/NR.13,17 In the latter study, renal recurrence occurred independently of hematological response at time of transplantation: renal recurrence in patients with CR was 3 of 25, in patients with VGPR 2 of 11, and in patients with PR/NR 2 of 14 (Law S personal communication).

Outcome was good in patients who developed CR/VGPR independent of the type of induction treatment, arguing against routine use of HDM-ASCT. Notably, the need for hematological treatment before kidney transplantation in all patients with AL-amyloidosis can be questioned. In AL-amyloidosis renal recurrences occur relatively late and only rarely cause graft failure (5/40). Obviously, many patients were treated with chemotherapy or HDM-ASCT either preemptive after kidney transplantation or because of relapse. Treatment often resulted in remission. As a result, there were no differences in survival between patients with or without relapse. Importantly, 2 studies provided details of 13 patients who were not treated before transplantation.12,15 It is likely that these patients were selected, had no (clinically relevant) extrarenal amyloidosis, a low difference between the affected and unaffected FLC, and often were planned for chemotherapy and/or HDM-ASCT after successful kidney transplantation. Although most patients were transplanted in the period before 1999, their clinical course is notable. Ten patients were indeed treated with HDM-ASCT after kidney transplantation, however the time to ASCT ranged from 2 mo to 21 y. Most achieved a CR, and had good survival. Overall 5-y graft survival in the study of Heybeli et al was 78% in the treatment-naive patients, as compared to 35% in the NR/PR group.15 In a recent study, the aggregated results of kidney transplantation in 237 patients with AL-amyloidosis were reported.18 Of note, this study included data from 175 already reported patients and the data were not different from those mentioned above. The authors conclude that patients with CR and VGPR should be considered for kidney transplantation.18 However, this conclusion is debatable: in fact, the data show that overall survival and graft survival are similar in patients with VGPR compared to less than VGPR (respectively 6.7 and 6 y versus 6.8 and 5.7 y). Moreover, outcomes in patients with less than VGPR at the time of kidney transplantation are encouraging. In this study, 50 patients experienced amyloid recurrence in the graft and treatment effectively prevented graft loss in 87% of these.18 As this study included patients who underwent kidney transplantation between 1987 and 2020, we are convinced that currently—with the availability of daratumumab—these outcomes could even be improved further.18

Thus, kidney transplantation in untreated patients and even in patients with NR/PR may be considered, provided the patients are considered candidates for hematological treatment posttransplantation. In this respect, it is noteworthy that in patients with cardiac amyloidosis good outcome is achieved with a strategy that involves preemptive cardiac transplantation, followed by hematological therapy.20 An algorithm to assist in decision-making is provided in Figure 1A and B.

Kidney Transplantation in Monoclonal Immunoglobulin Deposition Disease

Monoclonal immunoglobulin deposition disease (MIDD) is defined by the presence of nonorganized deposits of light chain deposition disease (LCDD), heavy chain deposition disease, or both (light/heavy chain deposition disease), along the basement membranes of various organs.2,3,8 Although kidney injury is the most common clinical presentation, extrarenal manifestations in the heart or liver can occur. The clinical presentation of patients with MIDD is variable. Most patients present with renal insufficiency, hematuria, and moderate proteinuria. Some patients may present with low eGFR in the absence of proteinuria, whereas less than one-third present with nephrotic syndrome. Although in MIDD renal response is associated with hematological response, effective hematological therapy does not always prevent kidney failure. Kourelis et al reported a renal response in 57% of patients with CR/VGPR.21 Renal survival is dependent on eGFR at presentation: dialysis-free survival was 9 y in patients who presented in CKD stage 2 of 3, and 2.7 y in patients who presented in stage 4 of 5.22

For a long time, kidney transplantation was not considered an option for patients with MIDD. This notion was mainly based on the bad outcome of kidney transplantation in patients with LCDD reported in 2004.23 This report described 7 patients with LCDD, diagnosed in the period 1972–1999, who had received a kidney transplant without prior effective hematological therapy. A recurrence of LCDD in the graft was observed in 5 of 7 patients, and occurred after median of 33 mo (3–46 mo). Patients with recurrence developed kidney failure (N = 2) or died (N = 3). In this study, only 1 patient survived without recurrence. Notably, several patients had an hematological malignancy, which likely contributed to high mortality.23

It is evident that outcome after kidney transplantation is favorable in patients with MIDD who have achieved a good hematological response. Detailed data of 5 studies, including 37 patients, who had received hematological therapy before transplantation, and achieved hematological response (mainly CR and VGPR, rarely PR), are provided in Table S2, SDC,https://links.lww.com/TP/C637.19,22,24-26 Recurrent disease in the allograft was observed in 9 patients, and median time to recurrence was 48 mo (32–108 mo). Chemotherapy was effective in maintaining graft function in some but not all patients.

Recurrence rate in patients with MIDD who received kidney transplantation without prior treatment is difficult to ascertain (details in Table S2, SDC,https://links.lww.com/TP/C637).19,22,24-26 Still, the limited data suggest that recurrence rate in untreated MIDD is very high (>85%). Recurrences also occur relatively early, approximately a median of 22 mo (range 5–106 mo) after kidney transplantation.27-37 However, case reports suggested good response to rescue therapy in some patients with posttransplant MIDD, with graft survival exceeding 9 y.37 The cohort studies included 22 previously untreated patients with a diagnosis of (likely recurrent) MIDD in the kidney allograft. Overall outcome was poor, with graft loss occurring in 14 patients. However, many patients were untreated or treated in an era without proteasome inhibitor therapy. Graft loss occurred in 4 of 11 patients treated with chemotherapy. Some patients who received aggressive therapy, including ASCT, developed CR, and had well-maintained graft function for 5–10 y.19,22,24-26 Although recurrence rate is high, we suggest that in view of the relatively late onset of recurrence, and the relative good outcome with effective rescue therapy decisions regarding kidney transplantation in patients with MIDD can follow the algorithm provided for AL-amyloidosis (Figure 1A and B).

Light Chain Proximal Tubulopathy

Light chain proximal tubulopathy (LCPT) is caused by storage of light chains in the proximal tubular cells, which cause proximal tubular cell damage. Patients typically present with complete or incomplete Fanconi syndrome, and its complications, for example, bone disease from phosphate loss or hypokalemia from proximal renal tubular acidosis.2,3,8 Most patients with LCPT present with severe kidney insufficiency.38 Progression rate is slow, and eGFR stabilizes with use of hematological therapy. Rarely patients will develop kidney failure. As a result, there are very few data on kidney transplantation in patients with LCPT. Reported cases with sufficient details are summarized in Table S3, SDC,https://links.lww.com/TP/C637.19,39-44 Unfortunately, many patients had an underlying hematological malignancy. The studies included 9 patients with LCPT who received a kidney transplant without prior hematological therapy. In these patients, a recurrence has been noted at a median of 12 mo (range 1–197 mo) after transplantation. A very early recurrence occurred in a patient with a high tumor load (likely multiple myeloma), and reports of kidney biopsies and the high levels of Bence Jones proteinuria suggest that kidney dysfunction in some cases was explained by associated cast-nephropathy.41,42 In some patients LCPT was diagnosed early by a protocol or per purpose (in a patient with rejection) biopsy. Hematological treatment often resulted in improvement and long-term stabilization of kidney function.39,41,43 For patients with LCPT we suggest following the algorithms provided in Figures 2 and 3. After kidney transplantation, we advise monitoring of proximal tubular function in addition to the regular monitoring of serum creatinine and proteinuria. A protocol biopsy should be considered to detect recurrence in an early phase. In patients with recurrent disease, treatment should be instituted before a major decrease in eGFR has occurred.

Kidney Transplantation in Patients With Immunotactoid Glomerulopathy

Immunotactoid glomerulonephritis is characterized by immunoglobulin-derived, organized deposits with a microtubular structure in the mesangium and glomerular capillary wall.2,3,8 Light chain restriction is observed in the majority (70%) of patients, and in patients with monoclonal immunotactoid glomerulopathy, a hematological abnormality is found more often (75% versus 26%).45,46 Patients usually present with proteinuria (and nephrotic syndrome in >50% of patients), hematuria, and mild-moderate renal insufficiency. Without therapy, most patients develop kidney failure. Treatment with rituximab or chemotherapy induces remissions in 50%–80% of patients, with kidney failure in <10% of treated patients. There are few data on kidney transplantation in patients with immunotactoid glomerulopathy. Therefore, we included older literature reports.47-49 Detailed information is provided in Table S4, SDC,https://links.lww.com/TP/C637.45-49 Admittedly, there are limitations due to the inclusion of a patient with multiple myeloma,47 and the lack of light chain staining.48,49 Reliable recurrence rates cannot be calculated, although the reports suggest that approximately 40%–50% of patients might not have recurrent disease. Interestingly, and casting doubt on the differentiation between polyclonal and monoclonal immunotactoid glomerulopathy, is the observation of 2 patients with polyclonal deposits in whom kidney biopsy of the allograft disclosed light chain restriction, for example, revealed a monotypic pattern.45 Time to recurrence was 18 mo (range 4–36 mo). However, the early recurrence was diagnosed in a kidney biopsy performed for kidney dysfunction, which showed acute rejection without glomerular abnormalities. A follow-up biopsy after 16 mo disclosed a MPGN pattern of injury. Graft failure occurred, likely due to therapeutic nihilism, because patients treated with effective hematological therapy had stable graft function.45 We advise an approach as depicted in Figures 2 and 3.

Kidney Transplantation in Patients With Proliferative Glomerulonephritis With Monoclonal Immune Deposits

Proliferative glomerulonephritis with monoclonal immune deposits (PGNMID) is defined by the presence of glomerular, nonorganized, granular deposits composed of a monoclonal immunoglobulin or a single light chain.2,3,8,50,51 PGNMID typically is a renal-limited disease. Patients present with kidney insufficiency, proteinuria, and hematuria. Renal progression is the single relevant outcome parameter. In approximately 70% of patients with PGNMID due to an intact monoclonal immunoglobulin, no hematological abnormality can be detected in serum, urine, or bone marrow. In contrast, in patients with Light chain-only PGNMID hematological abnormalities are seen more frequently (85%).51 Patients with progressive kidney disease should receive clone-directed therapy, resulting in renal response in 64%–90% of patients.52-55

Recurrence of PGNMID in the kidney allograft was first described in 2011.56 This study included 4 patients with renal failure due to PGNMID. These patients had not received effective hematological therapy.56 Recurrent PGNMID was detected at 3.8 mo (3–5 mo) after kidney transplantation. All patients had worsened kidney function, and 3 patients had proteinuria and hematuria at the time of biopsy.56 Treatment with corticosteroids and cyclophosphamide (N = 1) or rituximab (N = 3) resulted in improvement of proteinuria in all 4 patients, and an improvement of kidney function in 3. Follow-up ranged from 11 to 83 mo (mean 43 mo).56 Many case reports were published in the period 2012–2020. These cases were likely reported because of disease recurrence, introducing publication bias. Data of 25 patients (20 males and 5 females) are summarized in Table S5, SDC,https://links.lww.com/TP/C637.57-71 Details are often lacking, and we cannot always ascertain if the posttransplant disease is recurrent or de novo PGNMID. In most patients, the diagnosis of recurrent PGNMID was made based on a kidney transplant biopsy done for clinical reasons. The median interval between kidney transplantation and posttransplant PGNMID was 18 mo (range 1–204 mo). If we only included patients with a definite or very likely recurrence (n = 15), time to recurrent disease is shorter, median of 12 mo (range 1–40 mo). The data suggest that eGFR and/or proteinuria improved or remained stable in most treated patients (rituximab, bortezomib, or HDM-ASCT), whereas outcome was dismal in untreated patients.

Obviously, case reports are often biased. A large cohort study of allograft PGNMID, reported in 2018, suggested poor outcome.72 This study included 26 patients, transplanted in the period 1996–2017, with a diagnosis of IgG-associated PGNMID in the kidney allograft. Nine patients were referred from other centers, and in some patients, posttransplant PGNMID was considered de novo disease. Time to diagnosis was 5 mo (1–116 mo) in the whole group. The interval was longer in the patients with de novo disease. If we limit the analysis to patients with definite/likely recurrence 64% recurred within 6 mo, and 82% within 12 mo. Notably, an early diagnosis of recurrence was made in protocol biopsies (in 7 patients) or in biopsies done for purpose, and showing concurrent pathological lesions such as rejection or BK nephropathy. These early recurrences were characterized by mild histological lesions (predominant mesangial proliferative pattern of injury, with deposits limited to the mesangium) and a mild clinical phenotype (no or low-grade proteinuria). Follow-up averaged 87 mo (12–252 mo) after kidney transplantation. Overall, 11 patients (44%) lost their graft, attributed to PGNMID, within 36 mo after diagnosis.72 In multivariable analyses, peak proteinuria and longer time from transplant to biopsy were independent predictors of worse graft survival. Although this study argues against kidney transplantation in patients with PGNMID without hematological treatment before transplantation, we caution against such a conclusion. Patients were often diagnosed late (proteinuria at diagnosis 2.4 g/d), one-third of patients were not treated, and in other patients treatment was started relatively late (peak proteinuria 4.4 g/d).72 It is likely that outcome would have been better with earlier diagnosis, earlier start of therapy and the use of more effective therapy.

The recent study of Buxeda et al provides strong support for a “restrictive” strategy based on early diagnosis of recurrent PGNMID and use of empirical therapy.73 This single-center study included patients with a diagnosis of PGNMID in the native kidney, transplanted in the period 2003–2016. There were 20 patients and the management included protocol biopsies at 4, 12, 24, 60, and 120 mo posttransplant. Recurrent disease was treated if there were clinical manifestations (creatinine increase or proteinuria >500 mg/d) or if there were subendothelial deposits. Treatment initially consisted of cyclophosphamide (1.5 mg/kg orally for 6 wk) and in more recent years of rituximab (2 doses of 1000 mg at 2 wk interval). Since 2013, patients also received rituximab at 4 mo before transplantation.73 The data confirm the lack of sensitivity of hematological evaluation, as monoclonal immunoglobulin was detected in only 2 of 20 patients. Follow-up was 69 ± 38 mo. Overall outcome was acceptable, with death-censored graft survival of 87% at 5 y. There were 5 graft failures, attributed to recurrent PGNMID in only 3 (15%). Histological recurrence was observed in 18 patients (90%) and occurred 7 (1–65) mo after transplantation.73 Many recurrences were diagnosed in protocol biopsies, at a time when there were no clinical abnormalities. Thus, at the time of recurrence eGFR was <30 mL/min/1.73m2 in only 4 patients, proteinuria was <500 mg/d in 8 patients and hematuria was absent in 9. Five patients were not treated. Four of these had no hematuria, and proteinuria <500 mg/d. Graft function was maintained after 34–136 mo follow-up. Graft loss occurred in 1 untreated patient, who presented with proteinuria of 1.72 g/d. Thirteen patients were treated with either cyclophosphamide (N = 4) of rituximab (N = 9). The 3 patients with graft loss due to recurrent PGNMID were characterized by early recurrence (1, 3, and 3 mo), low eGFR at diagnosis (7, 14, and 57 mL/min/1.73m2), proteinuria >500 mg/d, and hematuria.73 Details of these cases are not provided, however, it is likely that in these patients graft dysfunction was caused by concurrent injury. The efficacy of rituximab in the 9 patients is supported by the initial improvement of eGFR from 32 ± 16 to 39 ± 13 mL/min/1.73m2 and reduction of proteinuria from 1280 mg/24 h to 168 mg/24 h, despite start of therapy being delayed with 5–49 mo after initial diagnosis in 5 patients.73 Only 4 patients received rituximab before kidney transplantation. Preemptive therapy did not prevent recurrences (3/4), although the authors suggest that in these patients the posttransplant course was less aggressive. Approach toward kidney transplantation in patients with PGNMID can follow the algorithms in Figures 2 and 3. Thus, kidney transplantation can be considered in patients with PGNMID without pretransplant hematological therapy. In this respect, it is important to realize that most patients with PGNMID have no detectable serum/urine abnormality. Therefore, the efficacy of chemotherapy or ASCT in inducing CR/VGPR cannot be evaluated. Pretransplant treatment with rituximab can be considered, although the evidence is very limited. Protocol biopsies should be considered to detect early recurrence, although it might be acceptable to perform a biopsy for clinical reasons only (increased serum creatinine, proteinuria >500 mg/d, hematuria). We advise routinely performing immunofluorescence and electron microscopy when per-purpose biopsies are done. Light chain restriction or positive IgG subclass staining in immunofluorescence and the presence of mesangial or subendothelial deposits in electron microscopy heralds clinical recurrence. In patients with recurrent disease and no clinical abnormalities, a wait-and-see approach is reasonable. Otherwise, early treatment with rituximab is advised, whenever proteinuria exceeds 500 mg/d, or in patients with endocapillary of mesangiocapillary patterns of injury, with subendothelial deposits, especially when paralleled by hematuria or decreasing eGFR.

Kidney Transplantation in Patients With Monoclonal Immunoglobulin-associated C3 Glomerulopathy

The C3-glomerulopathies are glomerular diseases associated with alternative complement pathway dysregulation and characterized by a dominant deposition of C3.2,3,8,74 Based on the findings on electron microscopy, C3 glomerulopathies are subdivided in C3-Glomerulonephritis and in Dense deposit disease. C3-glomerulopathy is attributed to complement dysregulation. Whereas in young patients the disease is caused by genetic and autoimmune mechanisms, in elderly patients (>50 y) C3-glomerulopathy is typically associated with a monoclonal Ig, which interferes with normal complement regulation. Monoclonal immunoglobulin-associated C3-glomerulopathy is considered a subtype of MGRS. In routine clinical practice, it is impossible to prove that the monoclonal immunoglobulin interferes with the complement cascade. Therefore, the diagnosis is made by exclusion. In the absence of genetic or autoimmune abnormalities, the presence of a monoclonal immunoglobulin is considered sufficient to make a diagnosis of monoclonal immunoglobulin-associated C3-glomerulopathy in the elderly. There is no need to search for extrarenal disease manifestations. Patients typically present with hematuria, proteinuria, and decreased eGFR. Although hematological therapy resulted in a renal response in 50%–70% of patients,74,75 these studies are biased because treatment (and thus response) was often limited to patients with an underlying hematological malignancy. Many patients with C3-glomerulopathy will develop kidney failure.

Overall recurrence rate of C3-glomerulopathy is very high, ranging from 55% to 86% (Table 3).76 Reported recurrence rate was 67% of patients with monoclonal immunoglobulin-associated C3-glomerulopathy and in 35% of nonmonoclonal immunoglobulin-associated disease.77 Time to recurrence also appeared shorter in patients with a monoclonal immunoglobulin.78 Data of patients with monoclonal immunoglobulin-associated C3-glomerulopathy and disease recurrence after kidney transplantation are summarized in Table 3.19,74,76,78,79 Recurrences can occur very rapidly after kidney transplantation, often resulting in graft loss, despite treatment with rituximab, eculizumab, and/or plasmapheresis. In incidental cases, graft function was maintained after hematological treatment which resulted in CR. Still, the outcome is dismal in patients with early recurrence, which is likely explained by the pathogenesis with kidney injury caused by complement dysregulation. Ischemia, CNI-toxicity, posttransplant infections, and rejections, all can contribute to complement activation, and contribute to the early onset of recurrent disease. Indeed, in a recent study,19 4 of 5 patients with recurrent C3-glomerulonephritis had acute rejection. The introduction of eculizumab has greatly improved outcome in patients with complement-mediated atypical hemolytic uremic syndrome. Also, in patients with C3 glomerulonephritis in native kidneys, complement therapy with the C5 inhibitor eculizumab has gained interest. Case reports have suggested efficacy of eculizumab in patients with C3 glomerulonephritis associated with a monoclonal immunoglobulin.79,80 However, In the study of Regunathan-Shenk et al, eculizumab proved effective in preventing graft loss in only 2 of 7 patients.76

TABLE 3. - Recurrent disease after kidney transplantation in patients with monoclonal immunoglobulin-associated C3 glomerulonephritis19,74,76,78,79
Author Patients with recurrence, age c /sex Time to recurrence Remarks
Chauvet (2017) 4 3–12 mo No details. One graft failure
Zand (2013) a 45, M 9 d Graft loss
34, F 4 mo HDM-ASCT, CR, stable after 10 y
39, M 48 mo This patient had 3 transplantations with recurrent disease (after 48, 54, and 2.5 mo), all graft loss. Likely untreated
Lloyd (2016) 63, M 18 mo UPCR decrease after Eculizumab, follow-up not reported, likely short follow-up
Regunathan-Shenk (2019) 43, F M 2 mo Graft loss despite Rituximab, Eculizumab, and PE
60, M 5 mo Probable recurrence, TMA in biopsy; treated with PE, Eculizumab, and tacrolimus withdrawal → no graft loss
37, F 32 mo Graft loss despite therapy with Rituximab, PE, cyclophosphamide, and steroids
Heybeli (2021) a , b 26 d Pretransplant hematological therapy, with minimal response; post-KTx therapy with ASCT, Bortezomib, and thalidomide; minimal response; graft failure 65 mo
1 138 d Pretransplant hematological therapy with minimal response; post-KTx multiple lines of therapy with CR; graft survived > 204 mo
1 75 d Diagnosis made post-KTx; graft loss after 3 mo; rejection and bleeding complications
1 75 d Eculizumab, progressive MM despite CyBorD, graft loss after 35 mo
1 126 d Progressed to MM, no follow-up
aReport from the same center. However, it is unclear which patients overlap; clinical data are different, therefore both studies are included.
bHeybeli et al provide no patient details, the study included 4M and 1F, mean age 56 (39–73) y.
cIn most studies, age at diagnosis.
ASCT, allogeneic stem cell transplantation; CR, complete response; CyBorD, cyclophosphamide, bortezomib, and dexamethasone; F, female; HDM-ASCT, high-dose melphalan-autologous stem cell transplant; KTx, kidney transplant; M, male; MM, multiple myeloma; PE, plasma exchange; TMA, thrombotic microangiopathies; UPCR, urine protein creatinine ratio.

Patients with a diagnosis of C3 glomerulonephritis and renal failure should be carefully screened for the presence of a hematological abnormality before or at the time of kidney transplant recipient evaluation. This especially holds for patients >50 y of age. Obviously, hereditary or acquired defects in the complement system must be excluded. In view of the high risk of early recurrences in patients with C3 glomerulonephritis, the high graft failure rate, and the limited efficacy of currently available anti-complement therapy, we propose that pretransplant hematological treatment targeting CR/VGPR is required in a patient with monoclonal immunoglobulin-associated C3 glomerulonephritis (Figure 3). This policy might change if future anti-complement therapies prove more successful.

Kidney Transplantation in Patients With Cryoglobulinemic Vasculitis and Monoclonal Fibrillary Glomerulopathy

In view of the paucity of data, these entities are briefly mentioned in the supplementary appendix (SDC, https://links.lww.com/TP/C637).

Hematological Treatment in Patients With CKD Stage IV/V

Patients with MGRS have benefitted from major advances in hematological therapy.3,46,73,81,82 In recent years outcome after chemotherapy has improved with the introduction of new anti-plasma cell therapies.46,73,82 Current anti-plasma cell therapy includes proteasome inhibitors such as Bortezomib, immunomodulatory agents such as lenalidomide, and more recently anti-CD38 therapy with daratumumab. The introduction of these effective novel agents has challenged the use of upfront HDM-ASCT as well as the standard use of HDM-ASCT as consolidation therapy. Experts agreed that in patients who achieve complete response (CR) after 2–4 cycles of induction therapy, completing induction with chemotherapy could be considered, with ASCT delayed until the time of hematological relapse.81

When discussing pretransplant hematological therapy, it is important to consider side effects of therapy in patients with CKD stage IV/V with or without dialysis. There are no studies that specifically have evaluated side effects of chemotherapy in patients with CKD stage IV/V. Still, it is likely that patients with severe kidney failure are more likely to develop side effects, such as infections and neuropathy when exposed to Bortezomib or Lenalidomide. In a recent clinical trial with Daratumumab, patients with eGFR <20 mL/min/1.73m2 were excluded.82 The adverse events associated with HDM-ASCT are well studied. In a recent study, ASCT-related side effects were compared in 568 patients with eGFR ≥45 mL/min/1.73m2 and 87 patients with eGFR <45 mL/min/1.73m2 (all AL amyloid).83 Patients with low eGFR (note this included CKD stage 3b, IV, and V) were more likely to need hospitalization, more often progressed to dialysis, or more often died. Mortality <100 d was 14% (versus 5%) and ESRD 16% (versus 6%). Overall, up to 30% of patients could experience death or ESRD.83 These data contribute to eGFR <30 mL/min/1.73m2 being used as an exclusion criterion for performing ASCT. Consequently, in the setting of preemptive kidney transplantation, in patients with CKD IV/V not on dialysis, ASCT should not be used. The risks of ASCT are lower in patients who are treated with dialysis. Batalini et al described outcome of ASCT in 36 patients on dialysis, treated in the period 1994–2016.84 Treatment-related mortality (<100 d after ASCT) was 8% (3/36), which is reasonable, although not negligible. Notably, there were many side effects such as grade III infections, and metabolic complications. Hospitalization was needed in 33 of 36 patients, with an average duration of 16.7 ± 21.9 d.84 In weighing risks and benefits, the progress of hematological therapy in a kidney transplant recipient should be taken into account. Although there are no detailed studies, Bortezomib-based chemotherapy and HDM-ASCT have been used successfully after kidney transplantation, without excess mortality. In the coming years, we expect more data on daratumumab, which might enable more effective therapy of patients with recurrent MGRS. Importantly, the use of immunomodulatory drugs such as lenalidomide after kidney transplantation has been associated with kidney allograft rejection.85

Hematological Response Criteria in Patients With CKD Stage IV/V

Response to treatment is evaluated using serum (M-protein, the difference between involved and uninvolved FLC [dFLC], and the percentage change in dFLC) and urine (M-protein, and FLC by immunofixation) biomarkers. International guidelines developed for AL-amyloidosis define CR, VGPR, PR, and NR based on the criteria presented in Table 4.86 However, these criteria might pose problems in patients with CKD stage IV/V. It is well known that kidney dysfunction affects the renal clearance of FLC with к light chains being more GFR dependent than λ light chains.87 As a result, the absolute serum concentrations of both к and λ light chains will increase, and also the к/λ ratio will slightly increase. Therefore, in patients with CKD stage IV/V, the к/λ ratio ranges from 0.35 to 3.1 (versus 0.26–1.65 in normal population). Therefore, the authors advise to use this adapted ratio for defining CR in patients with CKD.13 Because kidney failure increases the concentration of the FLC, but also affects the difference between the involved and not-involved FLC, the definition of VGPR might even be less suitable. This likely explains the observation that disease-free survival in patients with VGPR was not different from progression-free survival in patients with PR or NR.13 Notably, some authors do not use VGPR when evaluating patients with CKD.86 Baseline dFLC is also used to predict risk of progression. It is evident that in patients with CKD this cannot be used. In fact, in the study of Cohen et al, a dFLC <10 mg/L or a concentration of involved FLC <20 mg/L was not observed during pretransplantation.13 Evaluation of urine may also pose problems. Batalini et al noted that “assessment of hematological response was difficult at times because of anuria or inability to perform immunofixation electrophoresis of urine.”84

TABLE 4. - Hematological response criteria in monoclonal immunoglobulin-associated amyloidosisb
Complete response Normal к/λ ratio absence of monoclonal protein on SPEP/IFE
Very good partial response a dFLC <40 mg/L
Partial response >50% reduction in dFLC
No response <50% decrease in dFLC
Adapted from Comenzo et al.88
aIf the initial dFLC is <50 mg/L, a dFLC <10 mg/L is considered VGPR.
bWe suggest using these criteria in all MGRS subtypes (with abnormal M-protein or light chain ratio).
dFLC, difference in mg/L between the involved and uninvolved light chain; IFE, immunofixation electrophoresis; MGRS, monoclonal gammopathy of renal significance; SPEP, serum protein electrophoresis; VGPR, very good partial response.

CONCLUSION

Decisions regarding kidney transplantation in patients with MGRS require a multidisciplinary, individualized approach. Consultation with an expert center is advised. Figures 1–3 provide information that can help in decision making.

ACKNOWLEDGMENTS

We would like to thank Albert Herelixka, University Hospitals Leuven, Belgium, for drawing the figures included in this article.

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