Renal Replacement Therapy and Kidney Transplantation in Paraproteinemias

Copyright: © 2016 Gupta S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction
Paraproteinemias are systemic disorders that affect various tissues and organs and are well known to cause renal dysfunction. • Monoclonal immunoglobulin deposition diseases (MIDD; Light-chain deposition disease [LCDD], heavy chain deposition disease, and light and heavy chain deposition disease)

Different renal manifestations include
• Light chain cast nephropathy (myeloma kidney) • Proximal tubulopathy (acquired Fanconi syndrome) • Monoclonal cryoglobulinemia • Plasma cell interstitial infiltration and/or interstitial nephritis In addition, this group of patients is at increased risk of acute and chronic kidney injury from volume depletion, hypercalcemia, hyperuricemia, hyperviscosity, direct toxic effects of medications and contrast exposure. The most frequent causes of end stage renal disease (ESRD) in this setting are myeloma cast nephropathy, light chain amyloidosis (AL) and light-chain deposition disease (LCDD). While newer chemotherapeutic agents (such as bortezomib and lenalidomide) and hematopoietic stem cell transplant offer increased survival, renal impairment continues to be associated with high morbidity and mortality [1][2][3][4][5][6][7]. Kidney transplantation can be considered in patients who have undergone successful hematopoietic cell transplantation and have achieved a complete hematologic response. The experience with renal replacement therapy and kidney transplantation in such patients with ESRD is restricted to case series and case reports. This article summarizes the trends and observations of renal replacement therapy in patients with paraproteinemia after review of literature.

Renal Replacement Therapy
Data on demographics, prognosis and survival in patients with ESRD from amyloidosis, multiple myeloma (MM), LCDD and other monoclonal proliferation disorders remains scarce. As for other causes of ESRD, patients can be treated with hemodialysis or peritoneal dialysis, though hemodialysis appears to be chosen much more frequently [8][9][10] [13,14]. In a series of 63 patients with LCDD, the median time to ESRD was 2.7 years, and patient survival was 66% at 1 year and 31% at 8 years [15]. Chain Amyloidosis on Chronic Dialysis [16]. All incident patients registered in the Renal Epidemiology and Information Network Registry between 2002 and 2011 with ESRD caused by AL amyloidosis, LCDD or myeloma cast nephropathy were included. Of 1459 patients, 265 (18%) patients had AL amyloidosis, 334 (23%) patients had LCDD, and 861 (59%) had ESRD secondary to myeloma cast nephropathy. Renal recovery was observed in only 9.1% of patients and was improved after 2006. Among 1272 patients who remained on dialysis, 67% died. Median survival on dialysis was 18.3 months. Main causes of death were malignancies (34.4%), cardiovascular diseases (18%), infections (13.3%), and cachexia (5.2%). Iggo et al. in their report of 23 patients with ESRD due to multiple myeloma, illustrated that the patients who survive the first two months, survival is approximately 45 percent at one year and 25 to 30 percent at two to three years [8]. Those who responded to chemotherapy survived significantly longer than those who did not. Korzets et al. outlined similar results with patients responding to chemotherapy with a reduction in light chain production appearing to do much better (mean survival of 47 months versus 17 months in non-responders, p value<0.05) [9]. On the other hand, Sharland et al. in their retrospective study of 140 patients with multiple myeloma, found no difference in outcomes between patients with severe renal failure, those treated with dialysis, and those with milder renal impairment (median survival, 22 months in both groups), nor was reversibility of renal failure associated with any survival advantage [17].

Kidney Transplantation
The first kidney transplantation in a patient with ESRD secondary to systemic AL amyloidosis was performed in 1967 [18]. The allograft only functioned for twelve days. Pasternack et al. studied the results of renal transplantation in 45 patients with amyloidosis receiving cadaveric kidney transplant at a single center between March 1973 and October 1981 [19]. Three-year graft survival was similar in the two groups (53 versus 49 percent) with death of patients not included in graft loss, although patient survival was lower in the amyloid group (51 versus 79 percent), predominantly due to infectious and cardiovascular complications. A retrospective study of 25 patients with AL amyloidosis who underwent kidney transplantation in the UK, revealed median graft survival was 5.8 years with a 5 and 10-year graft survival of 74% and 25% respectively [20]. Both renal and overall outcome in AL amyloidosis are best among patients achieving more than 90% suppression of the amyloidogenic monoclonal component. The median survival after renal transplantation was 89 months. Tsakiris et al. in their ERA-EDTA study, reported 35 patients with paraproteinemia receiving kidney transplants and their mean survival was 9.6 years [2]. Decourt et al. observed very low rates of kidney transplantation in patients with multiple myeloma or LCDD (2.3%) [16]. 46 of 1459 patients (3.1%) were registered on the kidney transplant waiting list after a median of 15 months. 34 (2.3%) patients received a kidney transplant after a median of 32.5 months on dialysis. Registration on the kidney transplant waiting list was more frequent in patients with AL amyloidosis (7.5%) than in patients with LCDD (4.5%) and patients with myeloma cast nephropathy (1.5%; P<0.001). Kidney transplant was also more frequent in patients with AL amyloidosis (6.4%) than in patients with LCDD (3.3%) and patients with myeloma cast nephropathy (0.7%; P<0.001). Median follow-up after kidney transplantation was 32 months. Only one patient lost allograft function after 9 months (she eventually died 8 months after resuming dialysis).
Renal allograft survival is reduced significantly in LCDD patients. Leung et al. retrospectively reviewed the outcomes of 7 patients with LCDD who underwent kidney transplantation [21]. 5 patients were on dialysis before transplantation. LCDD recurred after a median of 33.3 (range, 2 to 45) months in 5 of the 7 patients. One patient remained on dialysis, whereas the other 4 had died. One patient died of progression of multiple myeloma 3 months after kidney transplantation. Only 1 patient remained recurrence free after 13 years with normal renal allograft function.

Hematopoietic Stem Cell Transplant
Kidney transplantation followed by autologous hematopoietic cell transplantation (AHSCT) offers increased survival in patients with end stage renal disease due to plasma cell dyscrasias [22]. Badros et al. outlined a median survival more than 51 months following AHSCT in 38 patients on hemodialysis [23]. Of note, renal failure had no impact on the quality of stem cell collections and did not affect engraftment. 43 patients with renal insufficiency but not on hemodialysis who received the same treatment had similar survival. Regression of renal damages after 4-5 months from ASCT has been also reported [24]. Several case reports and case series describing patients undergoing successful renal transplantation after hematopoietic cell transplantation can be found [25][26][27][28][29]. Time interval between the two transplants ranges 14.1 months to 4 years. Immunosuppressive therapy consisted of standard 3 drug regimens (calcineurin inhibitor, anti-metabolite and prednisone) to a couple with lenalidomide. There is little experience regarding use of lenalidomide in kidney transplant recipients, therefore, patient should be closely monitored for evidence of infection or the development of malignancy. Acute kidney rejection at 1 month from kidney transplantation was reported in one patient efficiently treated with steroids [22]. Recurrence of light chain deposition 26 months after renal transplantation was also reported [25]. During follow up complete remission and normalization of renal function was observed.

Evolution of Monoclonal Gammopathy of Undetermined Significance (Mgus) after Kidney Transplant
Bancu et al. analyzed the data for renal transplant recipients between 1996 and 2011 [30]. The subjects who presented with MGUS before or after immunosuppressive treatment were selected. Among 587 patients, MGUS was detected in 17 (2.9%) patients. 10 were men and 7 women with a mean age of 69.9 ± 10.07 years. Over a median follow-up of 6 years, all patients had a functioning graft. Nine had MGUS before transplantation. One patient had multiple myeloma, and 8 remained stable. Eight patients had development of MGUS after transplantation. Six patients remained stable, 1 showed no MGUS, and 1 displayed an increased monoclonal component in further controls. In conclusion, renal transplantation was not associated with the development of malignant processes in patients with MGUS before transplantation. The group of patients, who developed MGUS after transplantation, had a benign evolution during a 6-year follow-up in their study. Cuéllar-García et al. estimated the incidence of MGUS in kidney transplant recipients and found similar results [31]. Out of 1,016 patients who received a kidney transplant from 1992 to 2012, 16 developed MGUS. The median period of follow up was 30 months. 10 of 16 (72.5%) were more than 50 years old. Two patients developed post-transplantation lymphoproliferative disorders (PTLD). No cases of progression to multiple myeloma or amyloidosis were seen during immune suppression therapy or after. Another study by Naina et al. from Mayo Clinic USA evaluated the long-term outcomes of patients diagnosed with MGUS before or after kidney transplantation [32]. Subjects with multiple myeloma, dysproteinemia-related kidney disease or no pretransplant serum protein electrophoresis were excluded. Of 3,518 patients who underwent kidney transplantation between  [33]. Before transplantation, only 4 out of these 7 patients had protein electrophoresis studies and were diagnosed with MGUS. Median time from kidney transplantation to diagnosis of MM was 72 months (range 3-204 months). The Kidney allograft failed in four patients due to monoclonal protein-related renal disease.
De novo monoclonal immunoglobulin deposition disease is very rare in kidney transplant recipients with very few cases being reported in literature [34][35][36][37]. We also need to keep in mind that it can be difficult to assert the de novo character sometimes because serum free light chains, protein electrophoresis studies and/or kidney biopsies are not always performed before transplantation.

Conclusion
Given therapeutic advances (chemotherapy and stem cell transplant) have been made in the treatment of paraproteinemia, the renal and overall outcome have been improved in current era. Even though randomized controlled trials are lacking to assess the outcome of kidney transplantation in patients with multiple myeloma, several case reports and series showed successful kidney transplants in patients who achieved hematologic response after hematopoietic stem cell transplants. However, further studies are required to determine the optimal timing of the kidney transplant in patients with paraproteinemia.