Light Chain Tubulopathy Research Articles

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

Treatment of Non-Amyloid Monoclonal Gammopathies of Renal Significance (MGRS) with Clone Directed Therapies-Single Center Experience

Background: MGRS is a group of heterogeneous disorders characterized by renal dysfunction related to monoclonal immunoglobulin deposition where the underlying plasma cell or B cell clone does not cause tumor complications or meets current hematological criteria for specific therapy (1). The diagnosis of these disorders is established by renal biopsy demonstrating glomerular or tubulointerstitial monoclonal protein deposition. The glomerular disorders include proliferative glomerulonephritis with monoclonal Ig deposition (PGNMID), paraprotein associated C3 glomerulopathy, immunotactoid glomerulopathy, and paraprotein associated fibrillary glomerulonephritis and Type 1 cryoglobulinemic glomerulonephritis. The tubulointerstitial disorders include fanconi syndrome and proximal light chain tubulopathy (2). Given the pathogenesis of the disorders, therapies targeting the underlying plasma cell and/or B cell clone have been used in the past but standard therapy has not been established. Given the rarity of MGRS as defined above, we report our single center experience for therapy of such disorders. Methods: We retrospectively reviewed the charts of patients treated for MGRS at Columbia University Medical Center and collected information on the renal pathologic diagnosis, presence or absence of monoclonal gammopathy and therapy and response. The diagnosis of MGUS and MGRS was based on standard criteria (3). For the assessment of renal response, we used criteria for renal organ response for AL amyloidosis (4). Results: A total of 8 patients were treated at our center for MGRS between 3/2015 and 1/2019. The type of MGRS diagnosis was PGNMID in 5 patients, C3 glomerulopathy in 1 patient, immunotactoid GN in 1 patient and MGUS associated dense deposit disease (DDD) in 1 patient. Monoclonal Ig deposit was IgG kappa type in 3, IgG Lambda in 2, IgM lambda in 1 patient and only Complement deposits C3 glomerulopathy and DDD. All pts had proteinuria at diagnosis with median proteinuria 4g/24hr (range 2.8-11.7g/24hr). Impaired renal function was present 5/8 pts with median serum creatinine 1.4mg/dl (range 1-4.6). None of the patients with PGNMID (N=5) had a concurrent monoclonal gammopathy by standard testing but the rest 3 patients had MGUS with positive SPEP and bone marrow involvement by a clonal plasma cells. First line treatment regimens included use of Bortezomib based regimen (Bortezomib, cyclophosphamide, dexamethasone) in 3 patients, Rituximab based regimens (Rituximab, Prednisone and Rituximab, cyclophosphamide, prednisone) in 4 patients and Daratumumab in one patient. Second line Daratumumab based therapy was used in 2 patients who did not respond to the first line therapy and lead to response in one patient. Improvement in proteinuria was seen in 6/8 patients with >30% decrease in proteinuria (range 50-90% reduction). The median time to response was 2 months (range 1-4 months). Improvement in eGFR was seen in 1/8 patients but majority of patients continuing to have stable eGFR and 1/8 patient progressed to ESRD. The responses were durable and after a median follow-up of 11.8 months only one patient had recurrent disease. Conclusion: Currently there is no standard of care therapy for treatment of patients diagnosed with MGRS disorders. Clone directed therapies including Bortezomib, Daratumumab and Rituximab based regimens aimed at suppressing the production of the involved immunoglobulin are effective for treatment of these disorders both in the presence and absence of a concurrent MGUS. These therapies should be explored further in a larger prospective multi-center trial for MGRS disorders.

Long Term Outcomes in Monoclonal Gammopathy of Renal Significance (MGRS)

Abstract Background: MGRS is a heterogeneous group of pathologic renal conditions attributed to a clonal plasma cell disorder, without classical features of myeloma. However, there is a need to distinguish MGRS from MGUS and unrelated renal abnormality as the clonal protein in MGRS plays a direct role in kidney damage and requires treatment of the underlying clone. Outcomes in patients with diagnosis of cast nephropathy and renal amyloidosis have been previously reported. But long-term outcomes of MGRS patients with other renal histologies remain unclear. Also data on whether the level of tumour burden in the marrow and type of treatment for MGRS influence long-term outcomes is lacking. This analysis was conducted to study long term outcomes in renal biopsy proven (non cast nephropathy & AL Amyloid) MGRS patients. Aims: This multi-centre retrospective study was set up to analyse clinical outcomes in renal biopsy proven MGRS patients. Long-term haematological and renal outcomes were analysed. Correlation between tumour burden, type of treatment applied and level of response obtained was also analysed. Methods: Thirty-seven MGRS patients were retrospectively audited across 3 centres in the United Kingdom and 1 centre in the Republic of Ireland between 2004 and 2016. Patients were eligible for inclusion if they had a confirmed diagnosis of MGRS by renal biopsy. Patients with cast nephropathy and renal AL Amyloidosis were excluded. Renal survival was defined as the time until renal replacement therapy was required or failure to come off the renal replacement therapy commenced at diagnosis. Overall survival (OS) was calculated from the time of MGRS diagnosis until death from any cause. Results: Median age at diagnosis was 68 years and median follow-up was 33.5 months (range, 0.7-141.7 months). There were 29 male patients and 8 female patients. 20/25 patients had hypertension at the time of diagnosis (records unavailable for 12 patients). Majority of patients were kappa light chain restricted 85% vs 15% lambda LC restricted. Renal histology showed: 65% Light Chain Deposition Disease, 8% Mixed Heavy and Light Chain Deposition Disease, 1 % Proliferative Glomerulonephritis with monoclonal IgG, 11% Light Chain Tubulopathy, 6% Cryoglobulunemia, 3% Immunotactoid Glomerulonephritis. Renal survival for the whole cohort was 74% and overall survival was 84%. At the time of renal biopsy, 43% of patients had >10% plasma cells versus 46% of patients with 10% plasma cells versus 70 % in 10% plasma cells, not statistically significant (P = 0.14). Chemotherapy treatment was administered in 24 patients (65%) for their MGRS versus 13 patients (35%) who had no treatment for their PC clone. Of the 24 patients who had treatment: 20 had Bortezomib-based therapy (VEL), 6 had Thalidomide-based therapy, 4 had Lenalidomide and 4 had stem cell transplant. Patients who received VEL treatment for PC clone had a renal survival of 84 % versus 63% in patients who did not have VEL treatment (P = 0.45). OS in patients who received VEL was 95 % versus 72 % in patients who did not receive VEL treatment (P= 0.1). Good haematological response (≥VGPR) in 11/37 patients achieved and renal survival in these patients was significantly better at 90 % versus 61 % in patients who had Conclusion: We report long-term outcomes in a large cohort of MGRS patients: 74% renal survival and 84% overall survival at a median of 33 months follow up. For the first time, we show treatment for the PC clone shows better outcomes; with patients treated with VEL therapy significantly improved renal survival. Patients with higher tumour burden have a non-significant reduction in overall survival. Overall, the results of this study show better OS in MGRS patients when compared with outcomes previously reported in cast nephropathy and renal AL amyloid. Download : Download high-res image (110KB) Download : Download full-size image Disclosures Ramasamy: Celgene: Honoraria, Research Funding.

Long Term Outcomes in Monoclonal Gammopathy of Renal Significance (MGRS)

Background: MGRS is a heterogeneous group of pathologic renal conditions attributed to a clonal plasma cell disorder, without classical features of myeloma. However, there is a need to distinguish MGRS from MGUS and unrelated renal abnormality as the clonal protein in MGRS plays a direct role in kidney damage and requires treatment of the underlying clone. Outcomes in patients with diagnosis of cast nephropathy and renal amyloidosis have been previously reported. But long-term outcomes of MGRS patients with other renal histologies remain unclear. Also data on whether the level of tumour burden in the marrow and type of treatment for MGRS influence long-term outcomes is lacking. This analysis was conducted to study long term outcomes in renal biopsy proven (non cast nephropathy & AL Amyloid) MGRS patients.Aims: This multi-centre retrospective study was set up to analyse clinical outcomes in renal biopsy proven MGRS patients. Long-term haematological and renal outcomes were analysed. Correlation between tumour burden, type of treatment applied and level of response obtained was also analysed.Methods: Thirty-seven MGRS patients were retrospectively audited across 3 centres in the United Kingdom and 1 centre in the Republic of Ireland between 2004 and 2016. Patients were eligible for inclusion if they had a confirmed diagnosis of MGRS by renal biopsy. Patients with cast nephropathy and renal AL Amyloidosis were excluded. Renal survival was defined as the time until renal replacement therapy was required or failure to come off the renal replacement therapy commenced at diagnosis. Overall survival (OS) was calculated from the time of MGRS diagnosis until death from any cause.Results: Median age at diagnosis was 68 years and median follow-up was 33.5 months (range, 0.7-141.7 months). There were 29 male patients and 8 female patients. 20/25 patients had hypertension at the time of diagnosis (records unavailable for 12 patients). Majority of patients were kappa light chain restricted 85% vs 15% lambda LC restricted. Renal histology showed: 65% Light Chain Deposition Disease, 8% Mixed Heavy and Light Chain Deposition Disease, 1 % Proliferative Glomerulonephritis with monoclonal IgG, 11% Light Chain Tubulopathy, 6% Cryoglobulunemia, 3% Immunotactoid Glomerulonephritis. Renal survival for the whole cohort was 74% and overall survival was 84%. At the time of renal biopsy, 43% of patients had >10% plasma cells versus 46% of patients with <10% plasma cells. Renal survival was comparable between these cohorts with 74% renal survival in patients with >10% plasma cells versus 70 % in <10% plasma cells (P = 0.87). OS was better in patients with <10% plasma cells 94 % versus 75% in patients with >10% plasma cells, not statistically significant (P = 0.14).Chemotherapy treatment was administered in 24 patients (65%) for their MGRS versus 13 patients (35%) who had no treatment for their PC clone. Of the 24 patients who had treatment: 20 had Bortezomib-based therapy (VEL), 6 had Thalidomide-based therapy, 4 had Lenalidomide and 4 had stem cell transplant. Patients who received VEL treatment for PC clone had a renal survival of 84 % versus 63% in patients who did not have VEL treatment (P = 0.45). OS in patients who received VEL was 95 % versus 72 % in patients who did not receive VEL treatment (P= 0.1). Good haematological response (≥VGPR) in 11/37 patients achieved and renal survival in these patients was significantly better at 90 % versus 61 % in patients who had <VGPR (P = 0.05) Figure 1. ). OS was also improved at 91 % versus 82 % in patients who had <VGPR (P = 0.53). Two out of four patients were able to come off renal replacement therapy after being treated with Bortezomib and achieving a complete haematological response.Conclusion: We report long-term outcomes in a large cohort of MGRS patients: 74% renal survival and 84% overall survival at a median of 33 months follow up. For the first time, we show treatment for the PC clone shows better outcomes; with patients treated with VEL therapy significantly improved renal survival. Patients with higher tumour burden have a non-significant reduction in overall survival. Overall, the results of this study show better OS in MGRS patients when compared with outcomes previously reported in cast nephropathy and renal AL amyloid. [Display omitted] DisclosuresRamasamy:Celgene: Honoraria, Research Funding.

Two cases of multiple myeloma, presenting with light-chain tubulopathy

Two cases of multiple myeloma, presenting with light-chain tubulopathy

Successful Treatment of Dialysis Dependant AKI Due to Light Chain Tubulopathy in an HIV Treatment Naïve Patient With the Combination of Plasma Exchange, HAART, and Chemotherapy

Successful Treatment of Dialysis Dependant AKI Due to Light Chain Tubulopathy in an HIV Treatment Naïve Patient With the Combination of Plasma Exchange, HAART, and Chemotherapy

A Case of Pseudohyperphosphatemia in a Patient with Multiple Myeloma

ì €ìžë“¤ì€ IgG, kappa ë‹¤ë°œê³¨ìˆ˜ì¢ í™˜ìžì—ì„œ ì„¤ëª ë˜ì§€ 않는 ê³ ì¸ì‚°í˜ˆì¦ì´ 있어 ê°€ì„±ê³ ì¸ì‚°í˜ˆì¦ì„ ì˜ì‹¬í•˜ê³ sulfosalicylic acid를 이용하여 환자의 혈청에서 단백질을 ì œê±° 후 다시 인을 ì¸¡ì •í•˜ì—¬ ì •ìƒ 인 수치를 보인 1예를 경험하였으므로 ë¬¸í—Œê³ ì°°ê³¼ 함께 ë³´ê³ í•˜ëŠ” 바이다. 중심 단어: ë‹¤ë°œê³¨ìˆ˜ì¢ ; ê³ ì¸ì‚°í˜ˆì¦

Acute light chain tubulopathy in myeloma

Acute light chain tubulopathy in myeloma

Proximal Tubule Cytoplasmic Fibrillary Inclusions Following Kidney Transplantation in a Patient With a Paraproteinemia

Proximal Tubule Cytoplasmic Fibrillary Inclusions Following Kidney Transplantation in a Patient With a Paraproteinemia

Light chain tubulopathy without Fanconi syndrome

Light chain tubulopathy without Fanconi syndrome