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.     

Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation as a late complication of chronic graft-versus-host disease

BACKGROUND: This study aims to determine the incidence and outcome of nephrotic syndrome in patients who underwent allogeneic stem cell transplantation in a single center. METHODS: Records of 279 adult patients with hematological diseases who underwent allogeneic hematopoietic stem cell transplantation were analyzed to evaluate the incidence and outcome of nephrotic syndrome. The diagnosis of chronic graft-versus-host disease was based on clinical evidence with histological confirmation whenever possible. RESULTS: Of the 279 patients, 105 with a minimum follow-up of 100 days developed chronic graft-versus-host disease: six of these had nephrotic syndrome. The cumulative incidence of nephrotic syndrome was 8% at day +1,681. Patients grafted with peripheral blood stem cells had a higher probability of developing nephrotic syndrome than did those grafted with bone marrow: 24% and 3%, respectively. The pathological diagnosis was membranous glomerulonephritis in four patients, and minimal change disease in one; the diagnosis could not be histologically confirmed in the sixth patient. All patients had extensive chronic graft-versus-host disease and were receiving treatment with cyclosporine A and steroids (four patients). Response to immunosuppressive therapy with cyclosporine A and steroids was achieved in all patients at a median time of 12 weeks after transplantation. CONCLUSION: Patients with chronic graft-versus-host disease may be considered to be at risk of nephrotic syndrome: careful monitoring of renal function is advisable, particularly in patients receiving allogeneic peripheral stem cell grafts.     

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.     

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.     

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.     

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.     

Complications rénales au décours de la greffe de cellules souches hématopoïétiques

Hematopoietic stem cell transplantation is a widely used therapeutic modality for many, mainly malignant, diseases. Toxicities of this procedure include acute and chronic renal dysfunction. Acute renal failure, generally reversible is due to acute tubular necrosis (tumor lysis syndrome, marrow-infusion toxicity, sepsis, nephrotoxins), hepatic veno-occlusive disease or acute graft-versus-host disease. Chronic renal failure is often multifactorial, caused by conditioning-associated endothelial cell toxicity (bone marrow transplant nephropathy) and calcineurin inhibitors toxicity. Renal pathologic findings are somewhat similar to thrombotic microangiopathy, with sometimes systemic disease. Rare cases of nephrotic syndrome have been described after hematopoietic stem cell transplantation, mainly membranous nephropathy, associated with graft-versus-host disease. Therapeutic options for renal dysfunction after hematopoietic stem cell transplantation are limited but kidney transplantation is possible in case of end-stage renal disease.     

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.     

A boy with membranous nephropathy after allogeneic bone marrow transplantation

A 6-year-old boy developed bronchiolitis obliterans organizing pneumonia and nephrotic syndrome 5 months after allogeneic bone marrow transplantation from an unrelated donor for acute lymphoblastic leukemia. His renal biopsy showed membranous nephropathy. He was treated with prednisolone and cyclosporine A. Proteinuria disappeared 3 months after the onset of nephrotic syndrome. To our knowledge, this patient is the youngest case with nephrotic syndrome due to membranous nephropathy after hematopoietic stem cell transplantation.     

Permanent Improvement of Renal Dysfunction and Proteinuria with Colchicine in a Patient with Tumoral Amyloidosis and Basal Cell Carcinoma

Basal cell carcinoma and amyloid deposition was reported not uncommonly, but renal failure and nephrotic syndrome were rare. Here in, we reported a 72 years old male patient with nephrotic syndrome, renal failure and relatively small basal cell carcinoma. In this patient toumoral excision caused temporary improvement. When the proteinuria reappeared, due to amyloid deposition in toumoral tissue, colchicine was began. With colchicine therapy permanent improvement of nephrotic syndrome was achieved in follow-up 18 months.     

Permanent improvement of renal dysfunction and proteinuria with colchicine in a patient with tumoral amyloidosis and basal cell carcinoma

Basal cell carcinoma and amyloid deposition was reported not uncommonly, but renal failure and nephrotic syndrome were rare. Here in, we reported a 72 years old male patient with nephrotic syndrome, renal failure and relatively small basal cell carcinoma. In this patient toumoral excision caused temporary improvement. When the proteinuria reappeared, due to amyloid deposition in toumoral tissue, colchicine was began. With colchicine therapy permanent improvement of nephrotic syndrome was achieved in follow-up 18 months.     

Cardiac and intestinal amyloidosis in a renal transplant recipient with familial Mediterranean fever.

In Turkey, familial Mediterranean fever (FMF) is an important cause of nephrotic syndrome and endstage renal disease due to renal deposition of AA type amyloid. We report a case of living-related donor renal transplant recipient with FMF and renal AA type amyloidosis, who died of progressive heart failure due to cardiac involvement. The patient also had intractable diarrhea caused by biopsy-proven intestinal amyloidosis. The patient was on 1 mg/day colchicine. Although he was attack-free throughout the post-transplant period, intestinal and clinically significant cardiac amyloidosis, which implied the presence of sustained inflammation and continuing amyloid deposition, appeared three years after renal transplantation. Cardiac deposition of AA amyloid may cause clinically significant heart disease, leading to cardiovascular mortality after renal transplantation for end-stage renal disease in FMF patients.     

Nephrotic syndrome in patients after successful myeloablative allogeneic hematopoietic stem cell transplantation: clinical findings obtained from four transplanted patients

We experienced four patients who suffered from nephrotic syndrome after a successful allogeneic hematopoietic stem cell transplantation (HSCT). These cases were seen in the nineteen-year period from September, 1986 to June, 2005. Our data showed that the incidence of nephrotic syndrome was 0.51% (3 out of 585 HSCT patients) in our hospital. Pathological findings of their renal biopsy specimens revealed that 3 patients had membranous nephropathy and that one patient had minimal change disease. Three patients were positive for anti nuclear antibody. Administration of prednisolone or cyclosporine improved the nephrotic syndrome, leading all patients to a complete or almost complete remission. The nephrotic syndrome occurred at 17 to 25 months after HSCT and accompanied the relapse of chronic graft-versus-host disease (GVHD), possibly due to the termination or a decrease of immunosuppressant administration in all patients. This suggests that immunological abnormality associated with chronic GVHD may be partly involved.     

Focal glomerulosclerosis: natural history and treatment. A report of 70 cases

70 cases of focal glomerulosclerosis (FGS) followed for periods ranging from 1 to 24 years are reported. 39 patients had a nephrotic syndrome. 31 patients had asymptomatic proteinuria. 97 renal biopsies were performed. At least one biopsy specimen from every patient showed focal and segmental involvement of glomeruli, but no lesions were observed on the first biopsy in 6 patients. 26 of the 35 patients with a nephrotic syndrome were treated with steroids alone and/or chemotherapy and/or indomethacin. Resistance to treatment was encountered in 21 patients. Complete remission was observed in 6 cases, despite persistence or accentuation of histological lesions on serial biopsies in 3 cases. Actuarial renal survival rate at 10 years was 45% in the group with a nephrotic syndrome versus 91% in patients with proteinuria. FGS with a persistent nephrotic syndrome represents the 'malignant' form of the disease. Recurrence of the disease was observed after transplantation in 2 cases and was absent in 1.     

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.     

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 complications of high-dose chemotherapy and peripheral blood stem cell transplantation

Following bone marrow transplantation, acute renal failure and proteinuria are common complications with a high mortality, particularly in patients requiring hemodialysis. Incidence, potential predisposing factors, and outcome of acute renal complications in patients with hematological malignancies receiving autologous peripheral blood stem cell transplantation were prospectively studied in 53 patients. Eight patients developed acute renal failure. Three of them required hemodialysis. Of all patients with acute renal failure, only those requiring hemodialysis died, due to nonrenal causes. Only 1 of the 45 patients without renal failure died. Mild proteinuria of predominantly tubular origin occurred in 16 patients, in 3 with and in 13 without acute renal failure. As predisposing factors for acute renal failure were identified: renal hypoperfusion due to systemic inflammatory response syndrome, sepsis or septic shock, and combined administration of nephrotoxic drugs. Especially those patients receiving high numbers of nephrotoxic drugs in combination with renal hypoperfusion were likely to develop acute renal failure. These results suggest that patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation have a low risk of developing acute renal failure and proteinuria.     

High dose chemotherapy in light chain or light and heavy chain deposition disease

BACKGROUND: Conventional chemotherapy for myeloma yield unsatisfactory results in light and/or heavy chain deposition disease [(H)CDD] Because of the well-established dose-response effect of high dose melphalan in multiple myeloma, aiming to dramatically reduce the pathogenic monoclonal immunoglobulin (MIg) level, high dose therapy is a tempting alternative approach. METHODS: We treated 11 young patients with L(H)CDD by high dose therapy with the support of autologous blood stem cell transplantation. All had renal symptoms, including four who required dialysis and seven who had various, mainly cardiac, extrarenal manifestations. RESULTS: No toxic deaths occurred. A decrease in the MIg level was observed in eight patients, with complete disappearance from serum and urine in six cases. Improvement in manifestations related to MIg deposits were observed in six patients, including renal, cardiac, and hepatic responses in 4/11, 4/4, and 2/2 cases, respectively. Histologic regression of MIg deposits was documented in cardiac, hepatic, and skin biopsies. In contrast, examination of the kidney still showed light chain deposits in one patient who had renal transplantation 3 years after high dose therapy, at a time when he was in persisting remission. Within a median follow-up of 51 months, three patients were retreated because of multiple myeloma relapse, of whom one died and one required hemodialysis, and renal function secondarily deteriorated in a patient who had resistant multiple myeloma. Otherwise, no manifestations related to MIg deposits occurred or recurred in any patient. CONCLUSION: Present results of this retrospective study argue in favor of a benefit of high dose therapy with stem cell support in young patients with L(H)CDD.