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.     

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.     

Metachronous development of nonamyloidogenic [lambda] light chain deposition disease and IgG heavy chain amyloidosis in the same patient

We report a highly unusual case of monoclonal immunoglobulin deposition disease-associated nephrotic syndrome in which a patient developed both lambda light chain deposition disease and 6 years afterward IgG-heavy chain amyloidosis. The patient initially underwent autologous peripheral blood stem cell transplantation as treatment of the underlying plasma cell dyscrasia causing the light chain deposition disease-related nephrotic syndrome. After 6 years of clinical remission, recurrence of the nephrotic syndrome led to a renal biopsy demonstrating IgG-heavy chain amyloidosis. Interestingly, much of the characteristic nodular glomerular sclerosis seen in light chain deposition disease regressed between the time of the first biopsy and the second. Given the length of time between the development of the two diseases and the apparent success of stem cell transplantation in treating the first, we think that the patient produced two distinctly different abnormal plasma cell clones. To our knowledge, this is the first report of two different monoclonal immunoglobulin deposition diseases occurring in the same patient.     

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.     

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.     

Successful treatment of nephrotic syndrome due to systemic AL amyloidosis after autologous stem cell transplantation: renal response is an important therapeutic end point

Primary systemic (AL) amyloidosis involves vital organs from the early phase of illness, resulting in poor prognosis. Today, high-dose melphalan followed by autologous peripheral blood stem cell transplantation is an effective treatment for systemic AL amyloidosis. We report a patient with nephrotic syndrome due to systemic AL amyloidosis, who was successfully treated with autologous peripheral blood stem cell transplantation. At follow-up 36 months from ASCT, the patient showed a significant improvement in the signs of peripheral neuropathy and reduction in proteinuria without further organ involvement. Due to poor prognosis with conventional therapy, autologous stem cell transplantation should be considered for treatment in patients with systemic AL amyloidosis, and favorable outcome is ensured with achievement of renal response after ASCT.     

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.     

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.     

Longterm complete remission of AL-amyloid-related nephrotic syndrome

We describe a 59-year-old man with nephrotic syndrome that was diagnosed as suspected minimal change nephrotic syndrome by the routine examination of renal tissues at first biopsy, because renal histology showed segmental mild mesangial expansion with argyrophilic staining and partial foot process fusion without any deposition. Prednisolone therapy induced complete remission of nephrotic syndrome. Relapse occurred after 4 years of complete remission, and the second renal biopsy revealed amyloid light-chain (AL)-amyloidosis. Re-examination of the first biopsy tissues by Congo red staining confirmed a small amount of amyloid deposition in the mesangial areas although the mesangial areas showed argyrophilic staining, which is atypical for amyloid deposition. This case raises a caution that even when renal histology is not suggestive of amyloidosis and prednisolone therapy is very effective, when a renal histology diagnosis is not confirmed, the clinician should suspect amyloidosis and should, at least, undertake Congo red staining to definitively rule out amyloidosis.     

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.     

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.     

Primary amyloidosis--involving principally intrarenal blood vessels

We analysed renal biopsies from 34 nephrotic patients with renalamyloidosis, seven with primary form kappa chain (AL amyloidosis)and 27 with secondary amyloidosis associated with the otherchronic diseases. Renal biopsy specimens were analysed usingoptical and immunofluorescence microscopy. The extent of amyloiddeposits was graded from 0 to + + + +. Intrarenal blood vesseldeposits were more prominent than intraglomerular in five ofseven patients with AL amyloidosis, while they were identicalin one, and in one, intraglomerular amyloid deposits were dominant.The results were different in the group of patients with secondaryamyloidosis: a lower degree of intrarenal blood vessels depositionthan glomerular was noted in 22 of 27 cases, the degree of depositionwas identical in 4 of 27 cases and more expressed blood vesseldeposition was present in only one case. Granular or combineddeposits (granular + linear) were found on immunofluorescencemicroscopy in primary form, but the dominant form of depositionwas amorphous in secondary amyloid.     

Resolution of mesangial light chain deposits 3 years after high-dose melphalan with autologous peripheral blood stem cell transplantation

A 52-year-old woman was admitted to our hospital for treatment of nephrotic syndrome. Funduscopic findings showed fundal hemorrhage and soft exudates, and serologic analysis showed a monoclonal serum component that was identified as Bence Jones protein-k type. A bone marrow biopsy showed diffuse proliferation of atypical plasma cells, while a renal biopsy showed diffuse and nodular mesangial proliferation. Immunohistochemical staining confirmed the presence of k chains along the glomerular basement membrane and in mesangial areas. The patient was diagnosed as multiple myeloma (Bence Jones k type) with light chain deposition disease (LCDD). After high-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT), the multiple myeloma and nephrotic syndrome were in complete remission; her renal function was improved, but a renal biopsy performed 6 months after PBSCT showed the persistence of diffuse and nodular lesions. By contrast, a renal biopsy performed 3 years later showed complete resolution of the diffuse and nodular mesangial proliferation.     

Isolated mediastinal amyloidosis mimicking a neoplastic lesion

Isolated mediastinal amyloidosis is a rare condition. We report an unusual case of amyloid presented as an isolated mass, entirely confined within anterior mediastinum and FDG-avid, mimicking a neoplastic lesion. Because the differential diagnosis included several diseases as lymphoma, a biopsy via mediastinotomy was attended to avoid unnecessary sternotomy. The pathological results diagnosed to be an amyloidosis. The patient was asymptomatic and biopsy allowed an exact diagnosis, thus we decided against the complete excision. No monoclonal gammopathy and/or amyloid deposition were found. Thus, other treatments as high-dose melphalan and/or autologous stem cell transplantation were not indicated.     

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.     

Kidney and liver involvement in monoclonal light chain disorders

Monoclonal light chains (LCs) are responsible for a wide spectrum of renal and hepatic diseases, that above all include amyloid light-chain (AL) amyloidosis and light chain deposition disease (LCDD). Amyloid deposits stain for Congo red on light microscopy and have fibrillar aspect on electron microscopy, whereas deposits in LCDD are positive using monotypic LCs on immunofluorescence and have a granular aspect on electron microscopy. Sometimes fibrillar and granular deposits are observed in the same organ or in different organs of the same patient. Kidney and liver involvement is a frequent finding, both in primary amyloidosis (AL amyloidosis) or in LCDD. Renal manifestations include proteinuria, nephrotic syndrome, and progressive renal failure. End-stage renal disease requiring dialysis is observed in about 20% of patients with AL amyloidosis and in 70% of patients with LCDD. The mean survival time is about 12 to 18 months in AL amyloidosis and 34 months in LCDD. The most important prognostic factor is severe cardiac involvement, which reduces the mean survival to only 6 months. Hepatic manifestations include hepatomegaly, portal hypertension, ascites, intrahepatic cholostatic jaundice, and hepatic insufficiency. The mean survival of patients with liver damage is 14 months, but it is reduced to 5 months in patients with cholostatic jaundice. Contemporary kidney and liver involvement is usually observed on histologic examination, less frequently as clinical manifestation. No specific treatment exists for AL amyloidosis and LCDD, and the prognosis remains severe. The aim of treatment is to suppress proliferation of the abnormal clone of plasma cells and remove tissue deposits. The regimens, including melphalan-prednisone (MP) or vincristine-doxorubicin-dexamethasone (VAD), are used both in AL amyloidosis or in LCDD with some effectiveness. New approaches, especially the use of 4'-iodo-4'deoxydoxorubicin, could achieve better results. Dialysis seems to not worsen the outcome in both diseases because survival of patients on dialysis is not different from that of patients not reaching uremia. Also, kidney and liver transplantation is effective, though amyloidosis or LCDD may occur in transplanted organs. The most interesting therapeutic approach is autologous-blood stem-cell transplantation, which may produce a complete remission of the plasma-cell dyscrasia and a substantial improvement of clinical manifestations related to LC deposits.     

Marked improvement by high-dose chemotherapy and autologous stem cell transplantation in a case of light chain deposition disease

A 55-year-old woman presented with heavy proteinuria (6.2 g/day) in April 2007. Because monoclonal IgG-k was detected in serum and urine samples, bone marrow aspiration and renal biopsy were performed. She was diagnosed with plasma cell dyscrasia because a bone marrow aspiration specimen showed plasma cells at 6.1%. Renal tissues revealed the formation of nodular glomerulosclerosis which was negative for Congo-red staining. Renal immunohistochemistry showed positive staining for kappa light chains in the nodular lesions, proximal tubules and part of Bowman's capsules. Her renal involvement was diagnosed as light chain deposition disease. Proteinuria disappeared and renal function stabilized after high-dose chemotherapy and autologous stem cell transplantation. It appears that an early initiation of active therapy such as high-dose chemotherapy and autologous stem cell transplantation may be beneficial for patients with light chain deposition disease.     

Strong transthyretin immunostaining: potential pitfall in cardiac amyloid typing

Although systemic amyloidosis commonly presents with renal disease, cardiac involvement usually determines the patient's prognosis. Cardiac involvement is seen in light chain amyloid and transthyretin amyloidosis. Distinguishing between these two is critical because prognosis and treatment differ. Our study demonstrates the unreliability of transthyretin immunostaining in subtyping cardiac amyloid. Between January 2003 and August 2010, we retrieved 229 native endomyocardial biopsies, of which 24 had amyloid. Immunohistochemistry for κ, λ, transthyretin, and serum amyloid A protein was performed on formalin-fixed, paraffin-embedded sections. Staining was graded as weak (trace to 1+) or strong (2 to 3+). Mass spectrometry (MS)-based proteomic typing of microdissected amyloid material was performed on selected cases. Fifteen patients had monoclonal gammopathy/plasma cell dyscrasia with cardiac amyloid. Eight of them (53%) showed strong transthyretin staining in the cardiac amyloid deposits. MS was performed in 5 of these 8 biopsies, and all 5 biopsies revealed light chain amyloid-type amyloid. Two of these 5 light chain amyloid biopsies did not even have concomitant strong staining for the appropriate light chain. Among the 15 cases with plasma cell dyscrasia, only 7 biopsies showed strong staining for the corresponding monoclonal light chain. Strong, false-positive immunostaining for transthyretin in cardiac amyloid is a potential pitfall, augmented by the frequent lack of staining for immunoglobulin light chains. Therefore, the presence of amyloid in the cardiac biopsy should prompt a search for plasma cell dyscrasia irrespective of transthyretin staining. Confirmation with MS should be sought, particularly if there is any discrepancy between κ/λ staining and serum immunofixation results.