Vincent Javaugue

Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.

Long-term Kidney Disease Outcomes in Fibrillary Glomerulonephritis: A Case Series of 27 Patients

BACKGROUND Fibrillary glomerulonephritis (GN) is a rare disorder with poor renal prognosis. Therapeutic strategies, particularly the use of immunosuppressive drugs, are debated. STUDY DESIGN Case series. SETTING & PARTICIPANTS 27 adults with fibrillary GN referred to 15 nephrology departments in France between 1990 and 2011 were included. All patients were given renin-angiotensin system blockers and 13 received immunosuppressive therapy, including rituximab (7 patients) and cyclophosphamide (3 patients). OUTCOMES & MEASUREMENTS Clinical and histologic features of patients and kidney disease outcome. Renal response was defined as a >50% decrease in 24-hour proteinuria with <15% decline in estimated glomerular filtration rate (eGFR). RESULTS All patients presented with proteinuria, associated with nephrotic syndrome (41%), hematuria (73%), and hypertension (70%). Baseline median eGFR was 49 mL/min/1.73 m(2). Eight patients had a history of autoimmune disease and none had evidence of hematologic malignancy during follow-up. Light microscopic studies showed mesangial GN (70%), predominant pattern of membranous GN (19%), or membranoproliferative GN (11%). By immunofluorescence, immunoglobulin G (IgG) deposits (IgG4, 15/15; IgG1, 9/15) were polyclonal in 25 cases. Serum IgG subclass distribution was normal in the 6 patients tested. After a median 46-month follow-up, renal response occurred in 6 of 13 patients who received immunosuppressive therapy with rituximab (5 patients) or cyclophosphamide (1 patient). Of these, 5 had a mesangial or membranous light microscopic pattern, and median eGFR before therapy was 76 mL/min/1.73 m(2). In contrast, chronic kidney disease progressed in 12 of 14 patients who were not given immunosuppressive therapy, 10 of whom reached end-stage renal disease. LIMITATIONS Number of patients, retrospective study, use of multiple immunosuppressive regimens. CONCLUSIONS The therapeutic approach in fibrillary GN remains challenging. The place of immunosuppressive therapy, particularly anti-B-cell agents, needs to be assessed in larger collaborative studies.

Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy–associated C3 glomerulopathy

The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; P = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.

Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients

BACKGROUND Light chain myeloma cast nephropathy (MCN) is the major cause of renal failure in multiple myeloma and strongly impacts patient survival. The role of kidney biopsy in the management of MCN is unclear. METHODS Renal pathological findings were retrospectively studied in 70 patients with multiple myeloma and MCN. Patients were categorized according to the achievement or not of renal response, as defined by estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m(2) and/or dialysis independence at 3 months. RESULTS Thirty-two patients (46%) achieved a renal response. In the whole study population, the following parameters differed significantly between patients with and without renal response, respectively: baseline median eGFR (13.3 versus 9.3 mL/min/1.73 m(2), P = 0.017), Acute Kidney Injury Network Stage 3 (68.8 versus 92.1%, P = 0.019), haematological response rate (94 versus 34%, P < 0.0001), median percentage of free light chain (FLC) reduction at Day 21 (92 versus 24%, P = 0.006) and median number of casts/10 fields (14 versus 25, P = 0.005). The extent of interstitial fibrosis and tubular atrophy was similar. In multivariate analysis, only FLC reduction at Day 21 was significantly associated with renal response. However, when considering only the subgroup of haematological responders, both median number of casts [odds ratio (OR) = 0.93, 95% confidence interval (95% CI): 0.88-0.98, P = 0.01] and extent of tubular atrophy (OR = 0.03, 95% CI: 0.00-0.52, P = 0.02) were independent predictors of renal response. CONCLUSIONS In MCN, the presence of numerous casts and diffuse tubular atrophy is associated with poor renal prognosis. These data suggest that additional strategies to reduce FLC burden should be considered in patients with extensive cast formation.

A mouse model recapitulating human monoclonal heavy chain deposition disease evidences the relevance of proteasome inhibitor therapy.

Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin κ locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomib-based treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology.

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS.

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m2, respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient (ClinicalTrials.gov number: 980654).

Animal models of monoclonal immunoglobulin-related renal diseases

The renal deposition of monoclonal immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique immunoglobulin can contribute to the abnormal propensity of monoclonal immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without immunoglobulin involvement that have similar pathogenic mechanisms.

Carfilzomib Weekly 20/56mg/m2, Lenalidomide and Dexamethasone for Early Relapsed Refractory Multiple Myeloma

tion at 12 months was 10% (90% CI 2-17) with deferasirox DT, and 19% (90% CI 12-25) with deferasirox FCT. It is important to note that mean actual deferasirox dose remained stable throughout the 6-month study with both DT (27.1-28.2 mg/kg/day) and FCT (20.1-21.6 mg/kg/day). According to the predicted results from the proposed model, and with a similar exposure to deferasirox, patients treated with FCT would have had a greater reduction in serum ferritin at 12 months than patients treated with DT. Although it cannot be excluded that other factors might have influenced the trajectories of this model, such as the higher baseline serum ferritin values in the FCT group, this greater serum ferritin reduction with deferasirox FCT could be attributed to better treatment adherence. Previous analyses have indicated that improved patient-reported outcomes, especially increased adherence, are significant mediators of the association between treatment with deferasirox DT vs FCT, and the reduction from baseline in serum ferritin achieved over 6 months of treatment. Further exploration of long-term efficacy outcomes and their associated factors is needed to confirm improved efficacy with deferasirox FCT.

Analysis of a Compartmental Model of Endogenous Immunoglobulin G Metabolism with Application to Multiple Myeloma

Immunoglobulin G (IgG) metabolism has received much attention in the literature for two reasons: (i) IgG homeostasis is regulated by the neonatal Fc receptor (FcRn), by a pH-dependent and saturable recycling process, which presents an interesting biological system; (ii) the IgG-FcRn interaction may be exploitable as a means for extending the plasma half-life of therapeutic monoclonal antibodies, which are primarily IgG-based. A less-studied problem is the importance of endogenous IgG metabolism in IgG multiple myeloma. In multiple myeloma, quantification of serum monoclonal immunoglobulin plays an important role in diagnosis, monitoring and response assessment. In order to investigate the dynamics of IgG in this setting, a mathematical model characterizing the metabolism of endogenous IgG in humans is required. A number of authors have proposed a two-compartment nonlinear model of IgG metabolism in which saturable recycling is described using Michaelis–Menten kinetics; however it may be difficult to estimate the model parameters from the limited experimental data that are available. The purpose of this study is to analyse the model alongside the available data from experiments in humans and estimate the model parameters. In order to achieve this aim we linearize the model and use several methods of model and parameter validation: stability analysis, structural identifiability analysis, and sensitivity analysis based on traditional sensitivity functions and generalized sensitivity functions. We find that all model parameters are identifiable, structurally and taking into account parameter correlations, when several types of model output are used for parameter estimation. Based on these analyses we estimate parameter values from the limited available data and compare them with previously published parameter values. Finally we show how the model can be applied in future studies of treatment effectiveness in IgG multiple myeloma with simulations of serum monoclonal IgG responses during treatment.