Sequential Liver,Kidney, and Autologous Stem Cell Transplant for AL Amyloidosis: A Case Report

AL type amyloidosis is a systemic disease characterized by the accumulation of amyloid fibrils that can affect many organs such as the skin, gastrointestinal tract, heart, lungs, liver, and kidney. The most frequently involved organ in amyloidosis is the kidney, but cardiac amyloidosis with the poor prognosis is amyloid organ involvement. In this study, we present the treatment of a 40-year-old female patient with acute Budd-Chiari syndrome and very severe proteinuria with sequential liver, kidney, and autologous stem cell transplant after the diagnosis of systemic amyloidosis. To reduce the effects of massive proteinuria and very severe hypoalbuminemia, bilateral renal artery embolization was performed first. After the evaluation of the patient, she underwent liver transplant from a deceased donor, and then kidney transplant was performed from her son 1 month later. Afterward, the patient was discharged without any problems and underwent chemotherapy and stem cell transplant for primary AL amyloidosis. She was followed up without any problem in terms of liver, kidney, and stem cell at the 24th postoperative month. This case shows that autologous stem cell transplant after kidney and liver transplant may be a good treatment option in a selected patient with stem cell involvement diagnosed as having AL amyloidosis.     

Delayed autologous stem cell transplantation following cardiac transplantation experience in patients with cardiac amyloidosis

This study sought to retrospectively investigate the outcomes of patients with light‐chain amyloidosis (AL) with advanced cardiac involvement who were treated with a strategy of heart transplantation (HT) followed by delayed autologous stem cell transplantation (ASCT) at 1‐year posttransplant. Patients with AL amyloidosis with substantial cardiac involvement have traditionally had very poor survival (eg, several months). A few select centers have reported their outcomes for HT followed by a strategy of early ASCT (ie, 6 months) for CA. The outcomes of patients undergoing a delayed strategy have not been reported. All patients with AL amyloidosis at a single institution undergoing evaluation for HT from 2004‐2018 were included. Retrospective analyses were performed. Sixteen patients underwent HT (including two combined heart‐kidney transplant) for AL amyloidosis. ASCT was performed in a total of nine patients to date at a median 13.5 months (12.8‐32.9 months) post‐HT. Survival was 87.5% at 1 year and 76.6% at 5 years, comparable to institutional outcomes for nonamyloid HT recipients. In addition to these 16 patients, two patients underwent combined heart‐lung transplantation. A strategy of delayed ASCT 1‐year post‐HT for patients with AL amyloidosis is feasible, safe, and associated with comparable outcomes to those undergoing an earlier ASCT strategy.     

Successful Long-Term Outcome of the First Combined Heart and Kidney Transplant in a Patient with Systemic AL Amyloidosis

Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. During the follow-up period (36 months), plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission.     

High-dose intravenous melphalan with autologous stem cell transplantation in AL amyloidosis-associated end-stage renal disease

BACKGROUND: The development of end-stage renal disease (ESRD) is common among patients with amyloid light-chain AL amyloidosis-associated renal disease and survival of these patients is poor. High-dose intravenous melphalan and autologous stem cell transplantation induce remission of the plasma cell dyscrasia in a significant proportion of patients with AL amyloidosis. The efficacy and tolerability of such treatment for patients with AL amyloidosis-associated ESRD are unknown. METHODS: Between June 1994 and June 2000, 15 patients with AL amyloidosis-associated ESRD were treated with intravenous melphalan (70 to 200 mg/m2) and autologous peripheral blood stem cell transplantation. Clinical and laboratory data were prospectively collected prior to treatment, during the peritransplant period, and at 3 months, 12 months, and annually thereafter. Treatment outcomes and toxicities were compared with 180 non-ESRD patients treated during the study period. RESULTS: Eight of 15 patients (53%) had a hematologic complete response following treatment. Two patients (13%) died during the peritransplant period. Transfusion requirements were greater and there was a trend toward increased severity of mucositis in the ESRD patients compared with the non-ESRD patients. Median survival for the ESRD patients with a hematologic complete response was 4.5 years. Five patients with hematologic complete response have either undergone or are awaiting renal transplantation. CONCLUSION: High-dose intravenous melphalan with stem cell transplantation is an effective treatment in selected patients with AL amyloidosis-associated ESRD. Although the toxicity profile is greater in ESRD patients, the treatment offers the possibility of successful renal transplantation if hematologic remission is achieved. This treatment should be considered for patients with AL amyloidosis-associated ESRD.     

No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement.

BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.     

Successful treatment of primary AL amyloidosis by VAD therapy, high-dose melphalan, and autologous peripheral stem cell transplantation

We report a 58-year-old Japanese man with primary systemic AL amyloidosis who achieved disappearance of proteinuria including Bence-Jones protein (λ-type) after two courses of VAD therapy (vincristine, doxorubicin, and dexamethasone) and subsequent high-dose melphalan, followed by autologous peripheral blood stem cell transplantation. Because this patient did not have any apparent amyloidosis-related heart or liver damage and met all of the eligibility criteria for this therapy, this treatment was performed. Both proteinuria and M-protein disappeared completely, and he is doing well clinically at 19 months after treatment. However, amyloid deposits were still found in the kidneys, including the glomeruli and tubulointerstitium, when renal biopsy was done at 8 months after treatment. In the future, we may reach a time when clinical remission corresponds to histological remission.     

Late onset renal failure and nephrotic syndrome after autologous stem cell transplant for Al amyloidosis

We present a patient with AL amyloidosis who had an autologous stem cell transplant (ASCT) over 9 years ago. She has since then developed slowly progressive renal insufficiency and the nephrotic syndrome. Hematologic evaluation has failed to identify recurrent disease and a renal biopsy demonstrated extensive amyloid deposition and substantial glomerulosclerosis. We suggest that the patient has chronic glomerulosclerosis as a consequence of renal damage associated with her disease process and her treatment.     

Late Onset Renal Failure and Nephrotic Syndrome after Autologous Stem Cell Transplant for AL Amyloidosis

We present a patient with AL amyloidosis who had an autologous stem cell transplant (ASCT) over 9 years ago. She has since then developed slowly progressive renal insufficiency and the nephrotic syndrome. Hematologic evaluation has failed to identify recurrent disease and a renal biopsy demonstrated extensive amyloid deposition and substantial glomerulosclerosis. We suggest that the patient has chronic glomerulosclerosis as a consequence of renal damage associated with her disease process and her treatment.     

Renal involvement in systemic amyloidosis: an Italian collaborative study on survival and renal outcome.

BACKGROUND: Few data are available from large population-based studies on survival and renal outcome of patients with renal involvement and different types of systemic amyloidosis. METHODS: Two hundred and ninety of over 373 patients affected from systemic amyloidosis with renal involvement diagnosed in Italy between January 1995 and December 2000 were followed from diagnosis to death or until the last available clinical control. Eighty-three patients were excluded from analysis either because the amyloid type remained undetermined or they were lost at follow-up. Clinical and laboratory information was collected according to the different types of amyloidosis using a specific form which included renal function with 24 h proteinuria at diagnosis and at the end of follow-up, the type and the date of onset of dialysis and the kind of treatment they underwent. RESULTS: The median time of follow-up was 24 months in primary (AL) amyloidosis (range: 1-88 months), 16 months in AL with associated multiple myeloma (MM + AL: range 1-76 months), 30 months in reactive (AA) amyloidosis (range: 1-99 months) and 52 months in patients with familial forms (AF: range 14-82 months). Patients with AL showed a significantly shorter survival than AA. Despite no significant differences of renal outcome or survival on dialysis being observed between the two groups, a lower renal survival with a higher number of patients who progressed to end-stage renal disease (ESRD) was observed in patients with AA. Overall survival was markedly improved in patients with AL who underwent a specific therapy (conventional chemotherapy or autologous stem cell transplantation (ASCT)) even in the absence of a positive kidney response. Multivariate analysis showed cardiac involvement and specific therapy to significantly influence survival in AL whereas age, serum creatinine (sCr) and heart involvement significantly affected survival in AA. In both groups, sCr and heart involvement were the most relevant predictors for renal outcome, together with urinary protein excretion, in patients with AA. CONCLUSIONS: Our results show a worse survival in AL due to the higher prevalence of heart involvement in this group and emphasize that a specific therapy significantly prolongs survival and slows the progression of renal disease in patients with AL. We suggest that a late nephrological referral is likely the cause of the higher sCr found at presentation in patients with AA and probably accounts for the lower renal survival observed in the short term in these patients. At the time being, renal transplantation and ASCT are still rare therapeutic options for renal patients affected from systemic amyloidosis.     

Multicentric Castleman disease with secondary AA renal amyloidosis, nephrotic syndrome and chronic renal failure, remission after high-dose melphalan and autologous stem cell transplantation

Multicentric Castleman disease is a systemic lymphoproliferative disease with incomplete understood etiology. The various renal complications of this disease may include minimal change disease, mesangial proliferative glomerulonephritis, membranous glomerulonephritis and nephrotic syndrome, caused by secondary amyloidosis. In several reported cases of localized Castleman disease associated with renal amyloidosis and nephrotic syndrome, resection of organs involved by lymphoid proliferation resulted in complete remission. However, therapy of multicentric Castleman disease with renal amyloidosis is not well-established. We treated a case of a 39-year-old woman with multicentric Castleman disease complicated by nephrotic syndrome caused by secondary AA amyloidosis. The patient underwent autologous peripheral blood stem cell transplantation (auto-PBSCT), achieving complete remission. Autologous stem cell transplantation may be an attractive choice in therapy for refractory multicentric Castleman disease.     

Living Donor Kidney and Autologous Stem Cell Transplantation for Primary Systemic Amyloidosis (AL) with Predominant Renal Involvement

Primary systemic amyloidosis (AL) is characterized by multiorgan deposition of monoclonal immunoglobulin light chain. Renal involvement is common and impaired kidney function is associated with reduced median survival. Autologous stem cell transplantation (SCT) for AL achieves superior response rates compared to chemotherapy alone but patients with end-stage renal disease (ESRD) may be excluded from consideration. A treatment approach consisting of living donor kidney transplantation (LDKTx) followed by autologous SCT was developed for AL with ESRD. Eight patients underwent LDKTx with immediate graft function. Two suffered unanticipated complications post-KTx and died 10 and 3 months later. Two cases of subclinical acute cellular rejection (ACR) and one case of clinical ACR occurred--all reversible with corticosteroid. Six patients had successful stem cell harvests performed and five of these underwent SCT with satisfactory trilineage engraftment. Renal function remained stable following SCT in four and was reduced in one due to infectious and bleeding complications. One patient, who has thus far elected not to undergo SCT, has proteinuria and histologic evidence of recurrent renal amyloidosis. This experience supports the feasibility of sequential living donor KTx and autologous SCT for carefully selected patients with ESRD due to AL.     

High-Dose Melphalan and Autologous Hematopoietic Stem Cell Transplantation in Primary Amyloidosis: Single-Center Results

Background

Systemic immunoglobulin light-chain amyloidosis (AL) is a plasma cell dyscrasia resulting in multisystem organ failure and death. Autologous hematopoietic stem-cell transplantation (ASCT) has been widely used to treat patients with AL. However, treatment-related mortality remains high and reported series are subject to selection bias.

Methods

To define the role of patient selection in stem cell transplantation, we evaluated 24 consecutive AL patients transplanted at our center.

Results

Complete hematologic response was achieved in all 20 patients surviving >100 days posttransplantation. The 1-year overall survival (OS) rate after ASCT was 78.5%. The 5- and 10-year progression-free and OS rates were 57% and 47%, respectively. Treatment-related deaths owing to cardiovascular problems occurred in 16% of cases.

Conclusion

ASCT for AL amyloidosis can be safely performed in experienced transplantation centers, and increased risk is associated mainly with cardiovascular system involvement.     

AL amyloidosis with renal involvement

Primary (AL amyloidosis) is a systemic disease characterized by an amyloid deposition process in many organs, with unsatisfactory survival of patients. The monoclonal light chains form the fibrils that deposit and accumulate in tissues. Renal involvement is very frequent in AL amyloidosis and could lead to development of nephrotic syndrome followed by the renal failure in many cases. Classic therapeutic combination melphalan and prednisone has been supplemented with drugs with different mechanisms of action in this group of patients: high-dose dexamethasone, high-dose dexamethasone with melphalan, combination of vincristine, doxorubicin, and dexamethasone or newly high-dose melphalan supported by peripheral blood stem cell transplantation. This progressive therapy leads to the better survival and prognosis in the majority of patients. Alternative therapeutic approaches include thalidomide (alone or in combination with cyclophosphamide), lenalidomide, iododoxorubicin, etanercept and rituximab. The development of immunotherapy is expected in the near future.     

我国2004年至2009年自体干细胞移植治疗糖尿病足文献计量分析

目的 用文献计量法总结我国2004年至2009年自体干细胞移植(ASCT)治疗糖尿病足的文献,介绍其发展、术式,预测发展趋势等.方法 以"糖尿病足"为检索词,从中文生物医学期刊文献数据库和中国生物医学文献数据库获取题录,再获取原文,按作者、手术方式、刊文期刊、发文机构、地区等行计量分析.结果 共检获104篇,主要发文期刊、发文机构、作者、地区发文数量及术式分别是中国组织工程研究与临床康复杂志(6篇),北京首都医科大学(10篇),谷涌泉(9篇),北京(17篇),手术方式以外周血干细胞移植(ABMSCT)和骨髓干细胞移植(APBSCT)为主.结论 概括性介绍我国发表的ASCT治疗糖尿病足的文献,为深入研究提供了可靠资料.阐述此课题的研究现状并预测主要发展趋势:在严格量化适应证前,ABMSCT及APBSCT为ASCT的主要手术方式;量化ASCT的适应证,与其他药物联用使ASCT更好地发挥作用必将是这一课题的研究热点.     

Fatal disseminated aspergillosis following sequential heart and stem cell transplantation for systemic amyloidosis.

Infectious complications are a major cause of morbidity and mortality in transplant recipients. We describe a case of fatal disseminated aspergillosis immediately following autologous peripheral stem cell reconstitution in a patient who had undergone orthotopic heart transplantation for systemic amyloidosis. The case described suggests that the infectious risks in patients undergoing these sequential procedures may be distinct from those occurring in patients undergoing either procedure independently. Potential prophylactic and therapeutic interventions are discussed. Since this experimental and evolving approach for the management of systemic amyloidosis is potentially applicable to a limited number of patients, multicenter collaboration may be needed to further define the infectious risks in this unique subset of transplant recipients.     

How to treat patients with systemic amyloid light chain amyloidosis? Comparison of high-dose melphalan, low-dose chemotherapy and no chemotherapy in patients with or without cardiac amyloidosis

Background

High-dose melphalan and autologous stem cell transplantation (HDM) is an effective treatment for systemic amyloid light chain (AL) amyloidosis but the eligibility criteria exclude many patients with this disorder. The aim of this study was to determine appropriate treatment strategies for systemic AL amyloidosis according to each patient??s clinical condition in Japan.

Methods

Historical cohort study. Fifty-three patients with systemic AL amyloidosis (those with malignancies were excluded) were treated in our hospital with HDM (15 patients), melphalan + prednisolone (MP) (17 patients), vincristine + adriamycin + dexamethasone (VAD) (11 patients), or supportive treatment (no chemotherapy, 10 patients). We compared the survival rates among these treatment groups.

Results

Mean survival was significantly longer in the HDM group than in the other three groups (P?P?Conclusions HDM should be considered the treatment of choice in eligible patients with systemic AL amyloidosis even in the presence of cardiac amyloidosis. If HDM is not eligible, indications for VAD therapy should be carefully evaluated in patients with cardiac amyloidosis.     

Hyperkalemia: An adaptive response in chronic renal insufficiency

Immunoglobulin light chain amyloidosis and the kidney. Amyloidosis (AL) is a common cause of nephrotic syndrome in nondiabetic, nonhypertensive adults. All adult patients with nephrotic syndrome should have immunofixation of serum and urine as a screen. The finding of a monoclonal protein, particularly of lambda type, should lead to a subcutaneous fat aspirate or bone marrow biopsy to search for amyloid deposits. When the result of either test is positive, a kidney biopsy is unnecessary. The prognosis of patients who have renal amyloidosis depends on the concentration of serum creatinine at presentation and whether an echocardiographic evaluation demonstrates infiltrative cardiomyopathy. Most therapies are directed against the plasma cell dyscrasia present in all patients with AL and can include melphalan and prednisone, high-dose dexamethasone, and, most recently, peripheral blood stem cell transplantation.     

Diagnosis and treatment of AL amyloidosis

AL (amyloid light-chain) amyloidosis is a plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure. Virtually all patients with AL amyloidosis have a monoclonal protein in the serum or urine or a monoclonal population of plasma cells in the bone marrow. The most common target organ is the kidney and renal amyloidosis manifests as proteinuria or nephrotic syndrome in 3/4 of the patients. The median survival is one to two years. It is important to recognize that the amyloidosis is a dynamic process, and chemotherapy induced reduction of the activity of the plasma cell clone reduces the supply of the amyloid precursor protein and can result in a major regression of the deposits. Amyloid-related nephrotic syndrome and renal failure are potentially reversible. Conventional-dose melphalan as standard treatment can prolong the median duration of survival about 10 months, but the clinical response rates with improvement of impaired organ function are low with a slow response. Upfront high-dose chemotherapy with autologous peripheral blood stem cell transplantation is much more effective and can result in a major improvement of the patient's clinical condition, but the treatment-related toxicity can be relevant due to impaired organ function. The initial use of a conventional-dose chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD) to achieve a remission and subsequent high-dose chemotherapy is the concept of a German trial. The improvement of the condition of the patient by this approach may increase the tolerability of high-dose chemotherapy and reduce transplantation-related problems.     

De novo AL Amyloidosis in the Kidney Allograft

We report four cases of de novo amyloidosis occurring after 16, 18, 28 and 31 years following kidney transplantation. These patients presented with proteinuria and progressive allograft dysfunction. Kidney biopsy showed AL amyloidosis in all compartments of the allograft kidney. Serum immunofixation studies revealed monoclonal lambda light chains in all four cases. Bone marrow examination showed 10% plasma cells in one case, 5–10% in two cases and less than 5% in one case. Two patients died unexpectedly within 3 months and 1 year of the diagnosis of allograft AL amyloidosis. Of the remaining two, one underwent autologous stem cell transplant that resulted in complete hematologic remission. However, the patient relapsed within 2 years and also developed progressive kidney allograft failure. The patient received a second autologous stem cell transplant with complete hematologic response, followed by a second kidney transplant, which showed no evidence of amyloid at 1‐year posttransplant. The remaining case was treated with prednisone and bortezomib, which has stabilized kidney function in the short term. In conclusion, this study shows that AL amyloidosis is an uncommon but important cause of late onset proteinuria in the kidney allograft that results in kidney allograft failure.     

Treatment options for severe cardiac amyloidosis: heart transplantation combined with chemotherapy and stem cell transplantation for patients with AL-amyloidosis and heart and liver transplantation for patients with ATTR-amyloidosis.

OBJECTIVE: Cardiac amyloidosis (CA) is associated with a poor prognosis and a survival rate of less than 30% 2 years after clinical manifestation. Considered as a semi-malignant disease, CA is often a contraindication for HTx; however, depending on the type of CA, there are excellent treatment regimes that can be combined with HTx. In AL-amyloidosis, chemotherapy and stem cell transplantation are necessary and in TTR-amyloidosis, where the liver is the source of the pathologic protein, liver transplantation is recommended after HTx. METHODS AND RESULTS: More than 60 patients with AL-amyloidosis and more than 25 patients with ATTR-amyloidosis have been investigated at our centre. Eighteen patients showed signs of end-stage heart failure. Four patients died within 1 month after listing for HTx. Seven patients with AL (mean age 41.8 years) and five patients with ATTR-amyloidosis (mean age 42.6 years) were successfully transplanted with an actual survival rate of 91.6%. One patient died 8 months after HTx due to infection. Five AL patients received chemotherapy and SCT and one ATTR patient was liver transplanted. Three AL patients showed complete remission of amyloidosis. CONCLUSIONS: Cardiac amyloidosis is a potentially curative disease after HTx when combined with either chemotherapy and SCT or LiverTx depending on the type of the amyloidosis. Due to the natural course of the disease, urgent HTx after cardiac manifestation is mandatory. With this approach, excellent survival rates and even remission of the underlying disease is possible.