Kidney Transplantation After Hematopoietic Cell Transplantation in Plasma Cell Dyscrasias: Case Reports.

The plasma cell dyscrasias (PCDs) include a number of entities such as multiple myeloma, primary amyloidosis, and monoclonal immunoglobulin deposition disease. Hematopoietic cell transplant (HCT) is the only cure for a variety of hematologic and oncologic diseases. Clinically significant renal impairment is a common feature in plasma cell myeloma, affecting 20% to 55% of patients at initial diagnosis; 2% to 3% of patients present with failure sufficiently severe to require hemodialysis. This circumstance is associated with a high early mortality. The necessity for immunosuppression after HCT could complicate its management and may precipitate the development of complications. In some patients an effective alternative could be kidney transplant (KT); however, the presence of 2 transplants will require optimal adjustment of immunosuppression and management of complications. At present, there are few published cases of KT after HCT, and the experience of managing 2 transplants is limited. We would like to describe our experience with 4 patients who had a PCD and initially received HCT and received subsequent KT. In our experience the progress and outcome of KT after HCT were optimal. We would like to address that a higher incidence of cytopenia associated with the combination of immunosuppression (lenalidomide, tacrolimus, mycophenolate, etc.) and other drugs (ie, valganciclovir) should be considered together with an increased risk of opportunistic infections and PCD relapse.

Paraproteinemic Keratopathy: The Expanding Diversity of Clinical and Pathologic Manifestations.

PURPOSE: To describe 7 patients with paraproteinemic keratopathy and to highlight the clinical and pathologic diversity of this rare entity and the importance of timely, systemic evaluation. DESIGN: Retrospective, multicenter collaborative case series. PARTICIPANTS: Seven patients with paraproteinemic keratopathy. METHODS: Clinical and pathologic records were reviewed to identify patients with well-documented corneal immunoglobulin deposits. Detailed ophthalmologic and medical histories were assembled. In 6 patients, corneal tissue was evaluated histochemically and immunohistochemically; in selected cases, corneal tissue was evaluated by in situ hybridization and ultrastructurally. MAIN OUTCOME MEASURES: Visual acuity and anterior segment examination at presentation and follow-up; local therapy; systemic diagnosis and management; and histopathologic, immunohistochemical, in situ hybridization, and ultrastructural findings. RESULTS: Seven patients were identified with corneal immunoglobulin deposition. In addition to previously reported crystalline, nummular, patch-like, and lattice-like corneal opacities, prominent corneal vascularization was present in 2 patients mimicking interstitial keratitis and limbal stem cell deficiency. All patients had evidence of paraproteinemia in a setting of monoclonal gammopathy of undetermined significance, smoldering plasma cell myeloma, or Waldenström macroglobulinemia. Corneal findings were the first manifestation of systemic disease in 4 patients, and the diagnosis was not suspected in 3 of these patients. Pathologic evaluation of biopsied corneal and conjunctival tissues demonstrated immunoglobulin deposits. Previously unreported ultrastructural patterns in the cornea were noted: large scroll-like immunotactoid deposits, immune complex-like deposits, and randomly arranged fibrils morphologically intermediate between amyloid and immunotactoid deposits. Surgical intervention to improve vision was performed in 4 patients, with recurrence of deposits in 3 patients. Three patients underwent systemic therapy with diminution of the deposits and improvement in vision in 1 patient. CONCLUSIONS: The clinical and pathologic expressions of corneal immunoglobulin deposits are protean and present a diagnostic challenge. Early recognition of this rare entity is important to address the potentially serious associated systemic disease.

Isolated intracerebral light chain deposition disease: novel imaging and pathologic findings.

Light chain deposition disease (LCDD) is a rare clinicopathologic entity first described in 1976 and is characterized by a monoclonal gammopathy resulting in nonamyloid immunoglobulin light chain tissue deposition. Only four cases of intracerebral LCDD have been previously reported, all in the setting of a known plasma cell dyscrasia or in the presence of local mature plasma cells. We present the first case of intracranial LCDD in the absence of a known plasma cell dyscrasia or local mature plasma cells.

Value of whole body MRI and dynamic contrast enhanced MRI in the diagnosis, follow-up and evaluation of disease activity and extent in multiple myeloma.

PURPOSE: To evaluate the significance of dynamic contrast enhanced MRI (DCE-MRI) and whole body MRI (WB-MRI) in the diagnosis, prognosis and assessment of therapy for patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). MATERIALS AND METHODS: The retrospective study includes 219 patients providing 463 WB-MRI and DCE-MRI investigations for the subgroups MGUS (n=70), MM active disease (n=126; this includes 70 patients with new diagnosis of MM, according to the International Staging System (ISS): 41.4% ISS stage I, 20.0% ISS stage II, 7.1% ISS stage III, 31.4% insufficient for staging; and 56 patients with '(re-)active disease': 16.07% relapse, 32.14% progressive disease and 51.79% stable disease) and MM remission (n=23; 60.87% complete remission, 17.39% very good partial remission and 21.74% partial remission). Investigations of patients with hereditary multiple exostoses (n=5), neurofibromatosis (n=7) and healthy persons (n=9) were added as control subjects (n=21). WB-MRI evaluation was done by evaluating thirteen skeletal regions, providing a 'skeletal score'. DCE-MRI images of the spine, were analyzed with regions-of-interest and time-intensity-curves (TIC). RESULTS: All TIC parameters can significantly differentiate between the predefined subgroups (p<0.001). One hundred days after autologous stem cell transplantation a 75% decrease of the slope wash-in value (p<0.001) can be seen. A cubic regression trend between 'skeletal score' and slope wash-in (adj.R(2)=0.412) could demonstrate a significant increase bone marrow perfusion if MM affects more than 10 skeletal regions (p<0.001), associated with a poorer prognosis (p<0.001). CONCLUSION: DCE-MRI evaluation of the spine is useful for diagnosis of MM, follow-up after stem cell transplantation and evaluation of disease activity. A combined evaluation with WB-MRI and DCE-MRI provides additional micro-vascular information on the morphologic lesions and could help categorize patients with MM in two different groups to offer useful therapeutic and prognostic advise.

Defining the role of renal transplantation in the modern management of multiple myeloma and other plasma cell dyscrasias.

Plasma cell dyscrasias (PCD) are due to an abnormal proliferation of a single clone of plasma or lymphoplasmacytic cells leading to secretion of immunoglobulin (Ig) or an Ig fragment, causing the dysfunction of multiple organs. Median survival of these patients has significantly improved over the last decade due to availability of treatment options such as high-dose melphalan with autologous stem cell transplantation and novel anti-myeloma agents. Renal transplantation has not traditionally been considered in these patients due to the previously limited prognosis, along with concerns relating to disease recurrence affecting the renal allograft and increased infection susceptibility following renal transplant due to immunosuppression and the PCD itself. However, with the increasing range of effective treatment options, renal transplantation could now be considered, especially in young patients with good performance status. It is therefore timely to reappraise the potential role of renal transplantation in end-stage renal disease due to multiple myeloma and other PCD. This review summarizes the literature relating to renal transplantation in PCD, including multiple myeloma, monoclonal Ig deposition disease and systemic AL amyloidosis, to attempt to identify patients who may benefit most from this approach and to explore areas for further development.

Effect of stem cell transplantation for B-cell malignancies on disease course of associated polyneuropathy.

B cell dyscrasias are often refractory to medical treatments, and hematological stem cell therapy (SCT) may be warranted. It is not clear whether an associated polyneuropathy may also profit from SCT. In exceptional cases SCT has been tried in patients with monoclonal gammopathy and progressive polyneuropathy refractory to medical treatments. In a cohort of 225 patients with monoclonal gammopathy and polyneuropathy, we selected the six patients who underwent SCT and retrospectively examined the effects of SCT on the disease course of the associated polyneuropathy. In all patients except one, the indication for SCT was hemato-oncological (multiple myeloma in 4 patients and primary AL amyloidosis in 1). The remaining patient had an IgG monoclonal gammopathy of undetermined significance and a progressive and painful polyneuropathy for which she was treated with SCT. SCT led to improvement of motor scores and autonomic symptoms in one patient; three patients experienced improvement of neuropathic pain or sensory deficits but showed further progression of weakness. One patient showed no improvement at all. One patient died within 100 days after SCT. In conclusion, SCT as a treatment of refractory hematological malignancy may occasionally have a positive effect on the associated progressive polyneuropathy, although the benefits are very limited and the treatment-related mortality is high.

Recurrence of monoclonal gammopathy associated with donor-derived myelodysplastic syndrome after cord blood stem cell transplantation.

Myelodysplastic syndrome (MDS) is known to be associated with functional abnormalities of B cells, including hypergammaglobulinemia and monoclonal gammopathy (MG). However, the pathogenesis of these immunological disorders has not been clarified. We report a patient who developed donor-derived MDS followed by leukemic transformation after cord blood transplantation for MDS with MG. Interestingly, MG reappeared before development of donor-derived MDS. We analyzed the immunoglobulin allotype gene polymorphisms to determine whether the MG after cord blood transplantation was of recipient origin or donor origin. Results of genetic analysis and enzyme-linked immunosorbent assay of IgG1 allotype revealed that the MG after cord blood transplantation was of donor origin. Although the mechanism of donor-derived MG remains unclear, the persistent presence of recipient's antigen presenting cells might have induced the abnormal immunoglobulin production.

AL amyloidosis with IgD-lambda monoclonal gammopathy and lambda-type Bence-Jones protein: successful treatment by autologous stem cell transplantation.

A 45-year-old Japanese woman had been diagnosed with monoclonal gammopathy of undetermined significance (MGUS) featuring urinary Bence-Jones protein of the lambda type (BJP-lambda) for 11 years. She then developed eyelid purpura, dyspnea, and flank pain. Abdominal CT scans revealed renal infarction. Biopsy of the kidney, heart, jejunum, and skin demonstrated amyloid deposits in the vessel walls, but not in the glomeruli. She was diagnosed as having AL amyloidosis with IgD-lambda monoclonal gammopathy and BJP-lambda. Autologous stem cell transplantation (SCT) was done after chemotherapy with vincristine, daunorubicin, dexamethasone (VAD), and high-dose melphalan (HDM). This reduced the IgD level from 156 to 0.1 mg/dL, along with the disappearance of BJP, despite cerebral infarction during chemotherapy. We recommend SCT for patients with IgD-associated AL amyloidosis.

Intracellular extraocular muscle light- and heavy-chain deposition disease contributing to compressive optic neuropathy in a patient with preexisting Graves' orbitopathy.

PURPOSE: Light- and heavy-chain deposition disease (LHCDD) is a rare form of nonamyloidal monoclonal immunoglobulin deposition disease (MIDD) in which light- and heavy-chain immunoglobulin fragments accumulate systemically, typically leading to end organ dysfunction. Herein we describe the case of a 64-year-old female with a history of Graves' orbitopathy and multiple myeloma who presented with bilateral asymmetric compressive optic neuropathies. PROCEDURE: A biopsy of the right medial rectus muscle was taken during orbital decompression surgery. RESULTS: Light and electron microscopy of the biopsy specimen led to a diagnosis of intracellular skeletal muscle LHCDD. CONCLUSION: This is the first published report to describe the findings of: (1) intracellular deposition of nonamyloidal MIDD; (2) orbital involvement of nonamyloidal MIDD, and (3) compressive optic neuropathy resulting from any form of MIDD.

Light chains: heavy burden in kidney transplantation.

Plasma cell dyscrasias are frequently encountered malignancies which are often associated with kidney disease through the production of monoclonal immunoglobulin (Ig). Recent advances in the field include the availability of an assay for free light chains, the introduction of new agents which more effectively target malignant plasma cells, and refinements in the application of stem-cell transplantation. Well-selected patients with plasma cell dyscrasias whose monoclonal Ig is well controlled may be candidates for kidney transplantation. Kidney transplant patients with allograft dysfunction from recurrent or de novo monoclonal Ig deposition can be successfully identified and treated with these new approaches.

Primary cystic lung light chain deposition disease: a clinicopathologic entity derived from unmutated B cells with a stereotyped IGHV4-34/IGKV1 receptor.

We have recently described a new form of light chain deposition disease (LCDD) presenting as a severe cystic lung disorder requiring lung transplantation. There was no bone marrow plasma cell proliferation. Because of the absence of disease recurrence after bilateral lung transplantation and of serum-free light chain ratio normalization after the procedure, we hypothesized that monoclonal light chain synthesis occurred within the lung. The aim of this study was to look for the monoclonal B-cell component in 3 patients with cystic lung LCDD. Histologic examination of the explanted lungs showed diffuse nonamyloid kappa light chain deposits associated with a mild lymphoid infiltrate composed of aggregates of small CD20(+), CD5(-), CD10(-) B lymphocytes reminiscent of bronchus-associated lymphoid tissue. Using polymerase chain reaction (PCR), we identified a dominant B-cell clone in the lung in the 3 studied patients. The clonal expansion of each patient shared an unmutated antigen receptor variable region sequence characterized by the use of IGHV4-34 and IGKV1 subgroups with heavy and light chain CDR3 sequences of more than 80% amino acid identity, a feature evocative of an antigen-driven process. Combined with clinical and biologic data, our results strongly argue for a new antigen-driven primary pulmonary lymphoproliferative disorder.

Differential epitope mapping of antibodies to PDC-E2 in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation and primary biliary cirrhosis.

A unique characteristic of the autoimmune liver disease primary biliary cirrhosis (PBC) is the presence of high-titer and extremely specific autoantibodies to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Autoantibodies to PDC-E2 antigen have only been detected in patients with disease or in those who subsequently develop PBC. One exception has been a subgroup of patients with multiple myeloma (MM) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) and received donor lymphocyte infusions (DLIs) after transplantation. These patients developed high-titer antibodies to a variety of myeloma-associated antigens, including PDC-E2, coincident with rejection of myeloma cells in vivo. To examine the specificity of autoantibodies to PDC in these patients, we screened sera from patients with MM, chronic leukemias, monoclonal gammopathy of unknown significance (MGUS), PBC, and healthy donors. Three of 11 patients with MM (27%) and 2 of 6 patients with chronic leukemias (33%) developed anti-PDC-E2 antibodies in association with DLI response; 2 of 12 (17%) patients in the MGUS pretreatment control population also had detectable anti-PDC responses. Interestingly, the epitope specificity of these PDC-E2 autoantibodies was distinctive, suggesting that the mechanisms leading to loss of tolerance in the transplantation patients are distinct from PBC.

Pyoderma gangrenosum complicating pacemaker implant.

A 70-year-old lady with diabetes and monoclonal gammopathy underwent pacemaker implant for 2:1 atrioventricular block. Within 7 days, a painful, infiltrating, necrotic lesion involved the implant area. Biopsy was compatible with pyoderma gangrenosum and corticosteroid treatment led to healing in 3 weeks.

Primary sclerosing cholangitis complicating plasma cell dyscrasia (PCD): remission of PCD following liver transplant.

We report the first case of primary sclerosing cholangitis (PSC) complicated with plasma cell dyscrasia (PCD) in which liver transplant resulted in unexpected therapeutic benefit of PCD. A 61-year-old man with 12 yr history of PSC presented with a monoclonal gammopathy of undetermined significance (MGUS) with an IgG level of 3400 mg/dL. It was stable initially for 3 yr but progressed to features consistent with multiple myeloma (MM): IgG rose to 5290 mg/dL along with development of terminal stage of liver failure. Liver transplant was performed in desperation. Unexpectedly, MM underwent clinical remission following transplant. At 3 and 14 months following transplant, IgG stayed below 2080 mg/dL and he was able to return to full-time employment. This case may suggest that chronic antigenic stimulation from cirrhotic liver contributed to MGUS and subsequent transformation to MM. Liver transplant eliminated chronic antigenic stimulation, apparently leading to remission of MM. Since PCD is often associated with other chronic liver diseases, similar benefit may accrue to a range of patients with chronic liver diseases complicating PCD.

Type I Gaucher disease with severe skeletal destruction, extraosseous extension, and monoclonal gammopathy.

Extraosseous extensions of Gaucher-cell deposits simulate malignant diseases. We describe a 65-year-old male with type-I Gaucher disease, confirmed by low leukocyte glucocerebrosidase activity, high plasma chitotriosidase, and N370/L444P gene-mutations, who had severe skeletal involvement, IgG-kappa monoclonal gammopathy, and a soft-tissue mass within the left iliac muscle. Bone marrow biopsy showed heavy infiltration by Gaucher cells, and histopathology of the excised extraosseous mass revealed infiltration by Gaucher cells. Thus, malignant diseases were excluded and the diagnosis of an extraosseous Gaucher-cell extension was well documented. Our case is reported because it is very interesting and unique in the literature.

Long-term outcome of renal transplantation in light-chain deposition disease.

BACKGROUND: Light-chain deposition disease (LCDD) is a monoclonal gammopathy characterized by nonamyloid deposition of light chain in various organs. A small number of kidney transplantations have been performed on LCDD patients in whom end-stage renal disease (ESRD) developed. METHODS: The authors retrospectively reviewed the clinical and histologic findings and outcome of 7 patients with LCDD who underwent kidney transplantation at our institution. RESULTS: Renal insufficiency, hypertension, and proteinuria were present in all 7 patients. Proteinuria level was greater than 3.5 g/24 h in 3 patients. Three patients had microscopic hematuria. Monoclonal protein was detected in the serum in 3 patients, urine in 5, and was undetectable in 2. Median age at presentation was 42.7 (range, 33 to 58) years. The most common renal biopsy findings were mesangial expansion, mesangial nodules, tubular basement membrane thickening, and tubular atrophy. Kappa light chain was detected in all 7 renal biopsy results. Five 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 remains on dialysis, whereas the other 4 have died. One patient died of progression of multiple myeloma 3 months after kidney transplantation without evidence of recurrence. Only 1 patient remains recurrence free after 13 years with normal renal allograft function. CONCLUSION: Although long-term benefits are occasionally seen, renal allograft survival is reduced significantly in LCDD patients. Kidney transplantation should not be an option for LCDD patients unless measures have been taken to reduce light chain production.