Monoclonal Immunoglobulin Deposition Research Articles

Monoclonal gammopathy of renal significance: Spectrum of diseases and approach to a case.

The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic multiple myeloma is increasingly recognized. When the kidney is involved, the monoclonal etiology of these diseases results in clinical and laboratory features distinct from those of other disease, necessitating the nomenclature monoclonal gammopathy of renal significance (MGRS). The detection of these monoclonal diseases involving the kidney is important since they are poorly responsive to conventional immunosuppression and instead require clone-directed therapy. The new International Kidney and Monoclonal research group consensus definition of MGRS includes all proliferative conditions of B cells and/or plasma cells. Renal lesions due to monoclonal immunoglobulins are quite capable of progression with resulting end-stage renal disease development. Hence, these lesions require therapeutic intervention even if they do not satisfy myeloma criteria or the presence of any myeloma defining event. The spectrum of renal lesions that can be observed in a case of MGRS is wide and mirrors the list that may be seen in a case of any plasma cell neoplasm. This includes Ig light chain, heavy chain, and heavy and light chain amyloidosis; immunotactoid glomerulonephritis (GN); monoclonal immunoglobulin deposition disease including light chain, heavy chain, or heavy and light chain disease; light chain proximal tubulopathy; crystal-storing histiocytosis; proliferative GN with monoclonal immunoglobulin deposits; C3 glomerulopathy with monoclonal gammopathy and cast nephropathy. The initial approach after histological assessment is based on presence or absence of monoclonal immunoglobulin deposits. If monoclonality is evident, it is important to distinguish between conditions with deposition of intact immunoglobulin molecule or light chains only. The treatment of MGRS is directed at the underlying neoplastic B-cell or plasma cell clones.

Complement activation and cryoglobulinemia are common in monoclonal gammopathy of renal significance: Data from a case series.

Monoclonal gammopathy of renal significance (MGRS) denotes kidney diseases caused by monoclonal immunoglobulins in patients who do not have an overt hematological malignancy. Treatment is primarily directed against the underlying clone. Complement activation and cryoglobulinemia are known factors that can contribute to tissue damage, however, the full extent of their involvement is not clear. This was a retrospective study including all patients with MGRS referred for consultation to our hospital over a 3-year period. We identified 17 patients, of which 12 had proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Treatment with anti-clonal or immunosuppressive therapy was successful in 60% of patients with PGNMID, and treatment success was more common in patients with λ chain (100%) compared to κ chain deposits (20%). Serum markers of complement involvement were identified in 41% of all patients (88% of tested samples), most commonly high serum C5b-9 values or anti-factor H autoantibodies (both 24%). Patients with complement involvement did not respond well to treatment, which was unsuccessful in all treated patients with anti-factor H autoantibodies and 75% of patients with high serum C5b-9 values. Cryoglobulinemia was identified in 29% of all patients (71% tested samples) and was monoclonal in 40% of positive cases and mixed in 60%. None of the patients with cryoglobulinemia had organized deposits, however, there was a trend toward more common intramembranous deposits. In patients with monoclonal cryoglobulinemia both anti-clonal and immunosuppressive treatment were unsuccessful. All patients with mixed cryoglobulinemia were treated successfully with immunosuppressive therapy. Treatment of patients with PGNMID was successful in most cases. Complement involvement as well as monoclonal and mixed cryoglobulinemia were relatively common in our cohort, with the first two generally associated with unsuccessful treatment and the latter with successful treatment.

Monoclonal gammopathy of renal significance; experience of a tertiary care hospital in India

Introduction: Monoclonal gammopathy of renal significance (MGRS) disorders are indolent B-cell or plasma cell lymphoproliferative neoplasms which do not meet the hematological criteria for malignancy, however they cause renal dysfunction as a result of production of nephrotoxic monoclonal immunoglobulin (MIg). Objectives: To study the clinical presentation, laboratory features, light microscopy and immunofluorescence (IF) characteristics of all cases of MGRS diagnosed at our hospital over a period of five years. Patients and Methods: A record of all renal biopsies performed at our hospital between 2014-2019 was accessed from the database. Out of 1356 kidney biopsies, 68 had evidence of MIg deposition on immunofluorescence. Only six cases met the criteria of MGRS. Histopathological and immunofluorescence characteristics were studied to classify the lesions as per International Kidney and Monoclonal Gammopathy (IKMG) Research Group classification. Results: All six cases presented with deranged renal function. Four had sub-nephrotic and one had nephrotic range proteinuria. MIg was identified in only one case on serum protein electrophoresis and free light chain assay. Using a conjunction of histomorphology of renal lesions, special stains and immunofluorescence all six cases of MGRS were categorized as per IKMG classification into monoclonal immunoglobulin deposition disease (two cases), AL amyloidosis, light chain cast nephropathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain proximal tubulopathy (LCPT). Conclusion: MGRS presents as renal failure and proteinuria. MIg may not be detected on protein electrophoresis due to low-secretion in serum. A kidney biopsy is essential to study the morphology of renal lesions and identify MIg deposition.

Clinical and morphological spectrum and long-term outcome in monoclonal gammopathy of renal significance: one center study

INTRODUCTION AND AIM . Monoclonal gammopathy of renal significance (MGRS), heterogeneous nosological entity, is caused by monoclonal immunoglobulin (IG) produced by a "small" B-cell lineage clone. The analysis of long-term renal prognosis in various clinical and morphological types of disease and in different degrees of hematological response (HR) in the Russian patient cohort became the goal of this study. PATIENTS AND METHODS . Patients met the criteria of MGRS (morphologically verified monoclonal IG related kidney damage, an aberrant clone in the bone marrow and/or the level of serum/urine paraprotein not met the oncohematological criteria for treatment initiation) were enrolled in this one-center prospective study from 01.01.2011 till 01.03.2020. The morphological spectrum of MGRS, types of therapy, hematological and renal responses (RR) were analyzed. HR was assessed depending on the type of monoclonal IG according to the accepted criteria. The presence of RR was considered as a decrease in daily proteinuria> 30 % from the initial level or less than 0.5 g in the absence of a decrease in eGFR> 25 % at the time of the end of follow-up. The progression of renal dysfunction was documented with a decrease in eGFR> 25 % from baseline. Renal outcome (initiation of renal replacement therapy or eGFR <15 ml/min/1.73m2 at the end of follow-up) and death were determined. Long-term renal survival was assessed by the Kaplan-Meier method. The median follow-up period was 18 (4; 38) months. RESULTS . The incidence of MGRS was 4.9 % (n = 102) of all performed kidney biopsies (n = 2042), the majority of cases represented with AL amyloidosis (AL, n = 73; 71.6 %). In cases of non-amyloid variant of MGRS (non-AL MGRS, n=29, 28.4 %) the most common types of renal injury were light chain deposition disease (27,6 %) and proliferative glomerulonephritis with deposition of monoclonal IG (27.6 %). The majority of patients (80.4 %) was treated with clone-specific agents, autologous bone marrow transplantation was performed in 13 cases. HR was achieved in 74 % and 80 % of the treated patients with AL and non-AL MGRS, respectively. RR was obtained in 42 % of patients with AL and in 62 % of patients with non-AL MGRS. The five-year cumulative renal survival did not differ significantly between the groups: 66 % in AL and 44 % in non-AL MGRS ( р =0,78). Cumulative renal survival in patients who did not achieve HR was significantly lower (42 %) than in cases with complete HR (86 %), p =0.0014. CONCLUSION . MGRS is a clinically and morphologically heterogeneous nosological entity characterized by a poor renal prognosis, especially in the absence of clone-specific therapy. Treatment in MGRS should be carried out in a timely manner with the participation of a hematologist and nephrologist in order to prevent loss of kidney function and increase life expectancy.

N-glycosylated IgG in patients with kidney transplants increases calcium/calmodulin kinase IV in podocytes and causes injury.

Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.

Clinicopathologic Assessment of Monoclonal Immunoglobulin-associated Renal Disease in the Kidney Allograft: A Retrospective Study and Review of the Literature.

Monoclonal immunoglobulin (MIg)-associated renal disease (MIgARD) comprises a group of disorders caused by direct deposition of paraproteins in the kidney. Allograft MIgARD is infrequently encountered and poorly characterized. First, we assessed our allograft biopsies diagnosed with MIgARD between 2007 and 2018. The cohort included the following 26 patients: proliferative glomerulonephritis with MIg deposits (PGNMID) (n = 13), AL amyloidosis (n = 5), light chain deposition disease (n = 5), light chain proximal tubulopathy (n = 2), and light chain cast nephropathy (n = 1). Second, we conducted a literature review to evaluate the rare non-PGNMID entities. We identified 20 studies describing 29 patients that were added to our cohort (total n = 42). Part 1: Patients' median age was 55 years; 31% were women, and 19% were blacks. Twelve patients (46%) lost their grafts at a median of 8 months after diagnosis. Compared to non-PGNMID, PGNMID patients had lower frequency of detectable paraproteins (31% versus 92%, P = 0.004) and hematologic neoplasms (23% versus 77%, P = 0.02). Within PGNMID group, 6 patients changed their apparent immunofluorescence phenotype between monotypic and polytypic, while all 3 patients with hematologic neoplasms had substructure on electron microscopy. Part 2: Whereas light chain cast nephropathy occurred the earliest and had the worst graft survival, AL amyloidosis occurred the latest and had the best graft survival. MIgARD in the kidney allograft is associated with poor prognosis. While posttransplant PGNMID can change its apparent clonality by immunofluorescence supporting oligoclonal immune responses, the presence of deposit substructure is an important indicator of underlying hematologic neoplasm. Non-PGNMID are often associated with hematologic neoplasms and varied prognosis.

P0415MONOCLONAL GAMMOPATHY-RELATED RENAL DISEASES: NEW CLINICAL AND HISTOLOGICAL PATTERNS

Abstract Background and Aims In the last few years new clinical-histopathological forms of paraproteinemia associated kidney disease have emerged: light chain proximal tubulopathies, proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and C3-glomerulopathy. It is now widely recognized that the pathogenic role of the monoclonal protein depends on the free light chain chemical-physical features, even in the case of “dangerous small B cell clones”. Thus MGRS (monoclonal gammopathy of renal significance) associated disease is now considered a different entity from monoclonal gammopathy of undetermined significance (MGUS). Method We retrospectively evaluated the clinical-histopathological features of the biopsies performed in our Nephrological Unit on patients with MGUS in 2008-2018, in order to re-classify them in accordance with the recent scientific literature. Results Nine patients (7 M/2 F; age 46-77 y) were analyzed: five of them suffering from CKD stage 2, four of them with AKI or rapidly progressive CKD, 7 with proteinuria > 1 g/day, 2 with physiological proteinuria. Bone marrow biopsy: 7 patients with MGUS, 2 with smoldering multiple myeloma. Renal biopsy: 4 glomerulopathies (monoclonal fibrillary glomerulonephritis, cryoglobulinaemic (type I) glomerulonephritis, C3 glomerulonephritis, PGNMID), 5 proximal tubulopathies (2 LCPT with Fanconi syndrome, 1 LCPT without cytoplasmic inclusions and with interstitial inflammatory reaction, 2 LCPT with acute tubular necrosis) Table 1, Table 2, Light microscopy and IF of PGNMID. Conclusion MGRS is responsible for the pathogenesis of new histopathological renal lesions, based on new pathogenetic pathways. The clinical and histological features of the different disease states are dependent on the structure of FLCs. Our retrospective analysis of MGRS biopsies confirms how difficult and complex the diagnostic challenge of monoclonal renal injury really is. The differentiation between MGUS and MGRS is based on renal biopsy and demonstration of monoclonality on kidney tissue even if serum/urine immunofixation is negative. Early biomarkers of the pathogenetic role of monoclonal FLC should be identified both for diagnosis and therapeutical monitoring.

P0307KIDNEY-HEMOPATHY CONSULTATION: A SINGLE-CENTER EXPERIENCE

Abstract Background and Aims Renal involvement in plasma cell dyscrasia has been widely described, including Monoclonal Gammopathy of Renal significance (MGRS). Chronic kidney disease (CKD) in hematological disorders carries major implications for management, prognosis and the potential for progressive renal injury and ESRD. Specific monthly Kidney-Hemopathy Consultation has been created in 2017 in the department of Nephrology. The aimed of this was to describe the clinical, biological and histological characteristics of patients with hematological disorders and CKD. Method From 01/05/2017 to 31/12/2019 adults with hematological disorders and CKD (eGFR<60ml/min and/or proteinuria or hematuria) were prospectively included. Results Fifty-six patients (27 men) were enrolled: Multiple Myeloma (n=30), MGUS (n=11), Lymphoma (n=5), Acute Leukemia (n=4), LMC (n=2), 1 LLC (n=2), Cryoglobulinemia (n=1), Refractory Anemia with Excess blasts (n=1), Bone marrow aplasia (n=1). This nephrology consultation was the first for 22 patients (39%), referred by a hematologist in 38 cases (68%). Renal injury was confirmed after the hematologic diagnosis in 34 patients (61%) and precedes the diagnosis of plasma cell dyscrasia for 8 patients (14%). The median eGFR was 54.1ml/min/1.73m (128-4): CKD stage II (n=16), stage III (n=28), stage IV (n=7) and stage V (n=2). Proteinuria was >0.5g/day for 22 (39.3%) patients including a Bence-Jones proteinuria for 15 patients (27%). Acute Kidney Injury (AKI) was confirmed in 34 patients (63%) and 8 (24%) requiring acute dialysis. Histologic diagnostic of kidney injury was confirmed for 21 patients (38%): 16 kidney biopsies and 5 AL renal amyloidosis confirmed by salivary glands or abdominal fat biopsy. MGRS was confirmed in 34 patients (61%): Cast nephropathy (n=10;29%), AL amyloidosis (n=7;20%); C3 nephropathy (n=3; 9%), Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits (n=3), Light Chain Proximal Tubulopathy (n=3), Randall-type monoclonal immunoglobulin deposition disease (n=2, 6%), 1 Minimal Change Disease (n=1; 3%), Glomerulonephritis with Organized Microtubular Monoclonal Ig Deposits (n=1) and exclusive tumoral renal infiltration (n=1). Associated tumoral infiltration or crystalline podocytopathy was confirmed in 2 and 1 biopsy respectively. Glomerular MGRS was highly suspected for 2 patients, even if no biopsy was performed. MGRS was excluded for 22 patients (39%): AKI due to antibiotics or sepsis (n=8; 36%), hypovolemia (n=4; 18%) or hypercalcemia (n=3; 14%); 2 renal artery stenosis due to tyrosine kinase inhibitors (n=2; 9%), nephroangiosclerosis (n=1), lithiasis (n=1), CKD post- nephrectomy CKD (n=1), and immunoallergic nephritis (n=1). Hematological treatment was initiated in 54 patients (96%). All patients with MGRS were treated, whom 17 (50%) completely or partially in the Nephrology department. Proteasome inhibitors, alkylant agents and IMIDs were the main molecule used in first line therapy (56%, 23% and 12% respectively). Eleven patients (20%) had stem cell transplantation. After a median follow up of 16 months (38-0), complete or very good partial hematologic response was obtained in 48 patients (89%); whom 30 with MGRS (88%). Median eGFR was 45ml/min/1.73m (142-4): CKD stage II (n=18), stage III (n=23) and stage IV (n=9). Only 1/3 CKD stade V patient needed chronic replacement therapy. Eight patients died (14%): 4 uncontrolled hematologic disease (50%) and 3 septic complications (38%). Conclusion Very closed collaboration between Nephrology and Hematology Department in our Center contributes to improve early management of patients with hematological disorders associated with CKD, and probably their survey. Hemato-Nephrology is a viable and emergent specialty.

P0463KIDNEY INVOLVEMENT IN PARAPROTEINEMIC DISEASES - ANALYSIS OF THE SINGLE CENTER REGISTER OF KIDNEY BIOPSIES

Abstract Background and Aims Kidneys are often damaged in paraproteinemic conditions. Paraproteins are monoclonal immunoglobulins or immunoglobulin fractions that are produced by a clonal population of B- or plasma cell lineage and can cause a variety of histological patterns of kidney injury, such as light chain (AL) amyloidosis or light chain cast nephropathy (LCCN). Monoclonal gammopathy of renal significance (MGRS) represents a group of disorders in which a monoclonal immunoglobulin secreted by B- or plasma cell clone causes renal damage. By definition, these disorders do not meet diagnostic criteria for overt, symptomatic multiple myeloma or a lymphoproliferative disorder, but in contrast to monoclonal gammopathy of undetermined significance (MGUS) there is evidence of end-organ damage that can warrant therapy. Method All patients with paraproteinemic kidney disease were identified by retrospective review of the Hospital Register of kidney biopsies done at Department of Nephrology and Dialysis, in Dubrava University Hospital, Zagreb, from 2009 until 2018. Every kidney biopsy was analyzed by light, immunofluorescent and electron microscopy. Laboratory findings, including serum protein electrophoresis, serum free light chain level and immunofixation of serum proteins, were done for every patient. Clinical and histologic features of patients and features of underlying hematological conditions were analyzed. Results We identified 47 patients (3,28% of all biopsies that were done in that period) with kidney disease with clear hematological background. The mean patients' age at the time of the biopsy was 63 years and 27 of them were females. Two patients had signs of direct infiltration of kidneys with malignant lymphomic cells (non-Hodgkin lymphoma) and were excluded from the analysis. Clinical presentation of the patients at the time of biopsy were: proteinuria in 85% of patients, full nephrotic syndrome in 55%, azotemia in 66% of patients (80% had acute kidney injury of unclear etiology) and hematuria in 12,7%. Most common histologic patterns of kidney injury were AL amyloidosis (45%) and LCCN (30%) but additionally 7 different histological patterns were found: light chain depostion disease, light chain proxymal tubulopathy, fibrillary and imunotactoid glomerulopathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposition, crioglobulinemic glomerulopathy type I and tubulointerstitial damage caused by immunoglobulin deposition. Figure 1 shows main features of patients with AL amyloidosis and cast LCCN. Conclusion Kidney disease can be initial presentation of an underlying paraproteinemia and, as our data showed, can clinicaly present with acute kidney injury, nephrotic or subnephrotic range proteinuria or full nephrotic syndrome. Variety of histologic patterns of kidney injury were described and AL amyloidosis and LCCN were the most common histological findings. Detailed hematologic workup should follow kidney biopsy in order to determine the exact nature and extension of the disease and therefore the most appropriate therapy.

P0204PREVALENCE AND PREDICTIVE FACTORS OF BIOPSY-PROVEN NEPHROPATHY RELATED TO MONOCLONAL GAMMOPATHY

Abstract Background and Aims The prevalence of monoclonal gammopathy (MG) and kidney disease increases with age. When a patient present with both conditions, it is often necessary to perform a kidney biopsy in order to rule out a Monoclonal Immunoglobulin-Related Nephropathy (MIRN) that may require a specific therapy that targets either an overt hematological malignancy or a MG or Renal Significance (MGRS). The aim of our study was to identify factors that predict the presence of MIRN in this setting. Method This retrospective monocentric study included all patients who underwent a kidney biopsy between 2007 and 2018 with concurrent presence of GM, as defined by positive serum immuno-electrophoresis and/or Bence-Jones proteinuria. Results 328 patients were included, representing 11.8% of all kidney biopsies performed in our center during this period. Indication of biopsy was renal failure (eGFR <60ml/min/1.73m) in 77.4% of cases and/or proteinuria (urine protein-to-creatinine ratio >0.5g/g) in 75.9% of them. Median (IQR) serum creatinine was 155 μmol/L (111-233), eGFR 37.5 (22-56) ml/min/1.73m, serum albumin 29.5 (24-35) g/l. Median age was 67 (57/75), the M/F ratio was 198/130, diabetes mellitus was present in 21.3% of cases, hypertension in 53.1%. Kidney biopsy revealed that nephropathy was related to MG in 91/328 patients (27.7%). Myeloma cast nephropathy and AL amyloidosis were the most common histopathological subtypes (36 and 34% respectively), followed by monoclonal immunoglobulin deposition disease (15%) and cryoglobulinemic glomerulonephritis (8%). Patients with MIRN had more severe renal function impairment with median (IQR) serum creatinine of 176 (119-307) vs 149 (108-216) μmol/l (p=0.003) and heavier proteinuria, 3.9 (2.2-8.2) vs 2.0 (0.9-5.2) g/g (p< 0.001), when compared to non-MIRN patients. Hematological malignancy was diagnosed in 83 cases (25,3%) (Multiple Myeloma in 62, non-Hodgkin Lymphoma in 6, Waldenström Macroglobulinemia in 6, Chronic Lymphoid Leukemia in 6, Plasmocytoma in 3). Among them, MIRN was diagnosed in 51 (61%) cases but tumoral lympho-plasmocytic infiltration was observed in 9 (11%) cases. In this subgroup of patients, no laboratory test could predict the presence of a specific nephropathy. Among patients with no hematological malignancy (n=245), MIRN was diagnosed in 40 cases (16%) to confirm MGRS diagnosis. The markers that were most commonly associated with the presence of MGRS were positive Bence-Jones proteinuria (OR 4.7; 95%CI 2.2-10.3; p< 0.001), abnormal serum Free Light Chain (FLC) ratio (OR 4.2; 95%CI 1.7-10.7; p< 0.001), and serum electrophoresis spike >1.5 g/l (OR 5.9; 95%CI 2.6-13.5; p< 0.001). However, none of those markers had sufficient power to formally predict the result of the biopsy, as positive (PPV) or negative (NPV) predictive values were 36/41/45 % and 89/86/88 % respectively. Conclusion Almost one-third of patients with MG and kidney disease referred to our Department have biopsy-proven related nephropathy. Although negativity of Bence-Jones proteinuria and a normal serum FLC ratio are frequently associated with the absence of MGRS, kidney biopsy, beyond its diagnostic and prognostic interest, remains the most discriminating test.

Clone-directed therapy for proliferative glomerulonephritis with monoclonal immunoglobulin depositions: is it always necessary?

Monoclonal gammopathy of renal significance (MGRS) encompasses a group of disorders in which a monoclonal immunoglobulin (M-protein) secreted by a B-cell or plasma cell clone causes renal disease. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a form of MGRS where M-protein is deposited in the glomerulus. Although evidence is limited, the current consensus is that therapy for PGNMID should be directed against the underlying clone. However, it is conceivable that there is heterogeneity in the renal prognosis of PGNMID and that not all patients have need for clone-directed therapy. Here, we report two cases of PGNMID with IgM-kappa gammopathy. In one case of a 53-year-old woman the glomerulonephritis resolved without clone-directed therapy. In the other case of a 34-year-old woman clone-directed therapy was discontinued due to adverse effects. Although no hematological response was achieved, the PGNMID resolved. In both cases there are no signs of a recurrent glomerulonephritis in over 3 years of follow-up. Here, we review the literature and suggest that some PGNMID patients have a favorable renal prognosis in whom clone-directed therapy can be withheld or postponed. Further research is warranted to yield predictors to identify these patients and to better understand the disease course of PGNMID.

An update to the pathogenesis for monoclonal gammopathy of renal significance.

Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin (MIg) secreted by an otherwise asymptomatic or indolent B-cell or plasma cell clone, without hematologic criteria for treatment. The spectrum of MGRS-associated disorders is wide, including non-organized deposits or inclusions such as C3 glomerulopathy with monoclonal glomerulopathy (MIg-C3G), monoclonal immunoglobulin deposition disease, proliferative glomerulonephritis with monoclonal immunoglobulin deposits and organized deposits like immunoglobulin related amyloidosis, type I and type II cryoglobulinaemic glomerulonephritis, light chain proximal tubulopathy, and so on. Kidney biopsy should be conducted to identify the exact disease associated with MGRS. These MGRS-associated diseases can involve one or more renal compartments, including glomeruli, tubules and vessels. Hydrophobic residues replacement, N-glycosylated, increase in isoelectric point in MIg causes it to transform from soluble form to tissue deposition, causing glomerular damage. Complement deposition is found in MIg-C3G, which is caused by an abnormality of the alternative pathway and may involve multiple factors including complement component 3 nephritic factor, anti-complement factor auto-antibodies or MIg which directly cleaves C3. The effect of transforming growth factor beta and platelet-derived growth factor-β on mesangial extracellular matrix is associated with glomerular and tubular basement membrane thickening, nodular glomerulosclerosis, and interstitial fibrosis. Furthermore, inflammatory factors, growth factors and virus infection may play an important role in the development of the diseases. In this review, for the first time, we discussed current highlights in the mechanism of MGRS-related lesions.

An update to the pathogenesis for monoclonal gammopathy of renal significance.

Monoclonal gammopathy of renal significance (MGRS) is characterized by the nephrotoxic monoclonal immunoglobulin secreted by an otherwise asymptomatic or indolent B cell or plasma cell clone, without hematologic criteria for treatment. These MGRS-associated diseases can involve one or more renal compartments, including glomeruli, tubules, and vessels. Hydrophobic residue replacement, N-glycosylated, increase in isoelectric point in monoclonal immunoglobulin (MIg) causes it to transform from soluble form to tissue deposition, and consequently resulting in glomerular damage. In addition to MIg deposition, complement deposition is also found in C3 glomerulopathy with monoclonal glomerulopathy, which is caused by an abnormality of the alternative pathway and may involve multiple factors including complement component 3 nephritic factor, anti-complement factor auto-antibodies, or MIg which directly cleaves C3. Furthermore, inflammatory factors, growth factors, and virus infection may also participate in the development of the diseases. In this review, for the first time, we discussed current highlights in the mechanism of MGRS-related lesions.

Epidemiological and clinical characteristics and outcome of monoclonal gammopathy of renal significance-related lesions in Latin America.

Monoclonal gammopathy of renal significance (MGRS)-related lesions are infrequent entities. There are no publications on these disorders in Latin America (LA). The aim of this study was to describe epidemiological and clinical characteristics of these patients in LA. We performed a multicentre retrospective study. Patients with diagnosis of MGRS between 2012 and 2018 were included. Epidemiological and clinical data were collected from clinical records. Twenty-seven patients from Chile, Argentina, Ecuador and Uruguay were included. Half debuted with a nephrotic syndrome, and 32% required dialysis. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits was found in 33%, amyloidosis in 26% and monoclonal immunoglobulin deposition disease also in 26%. The immunoglobulin most frequently found in renal biopsies was IgG kappa. In 67% a paraprotein was found. Twenty patients received an anti-plasma cell regimen, and 3 a rituximab-based regimen (IgM-MGRS). Renal response (RR) was achieved in 56%. Early treatment (≤3 months) was associated with higher RR (75% vs 43%). Three patients relapsed within 21.5 months, and 3 progressed: 1 to multiple myeloma, 1 to systemic amyloidosis and another to systemic light-chain deposition disease. Two patients died, both due to infection during induction treatment. There was a higher than expected frequency of patients requiring dialysis. The most common MGRS-related lesion was PGNMD. Early treatment was associated with better response. As a rare disease, increasing awareness and promoting early diagnosis are necessary in LA to improve outcomes. SUMMARY AT A GLANCE A collection of 27 cases of MGRS from Latin America with information on epidemiology, clinical characteristics, treatment and outcome of patients diagnosed of MGRS-related renal lesions.

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.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.

Heavy Chain Deposition Disease: Clinicopathologic Characteristics of a Chinese Case Series

Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China. Case series. 25 patients with biopsy-proven HCDD were studied retrospectively. 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3 was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (γ1, 13; γ2, 2; γ3, 6; γ4, 2; γ1 and γ4, 1; and γ2 and γ4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy. Retrospective study, single-center experience. In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease.

Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits without Conspicuous Mesangial Proliferation, Complicated with Squamous Cell Lung Carcinoma.

We performed a renal biopsy for nephrotic syndrome in a patient with squamous cell lung carcinoma, which can worsen the prognosis. Chemoradiation therapy was effective for the cancer and proteinuria; we thus inferred that the nephrotic syndrome had been closely associated with the carcinoma. A pathological analysis of the kidney showed monoclonality for λ chain, satisfying the diagnostic criteria of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID); however, conspicuous mesangial proliferation was not observed. This is the first case of PGNMID complicated with lung carcinoma; furthermore, our findings underscore the importance of examining renal lesions and assessing monoclonality in cancer patients.

MGCS : an IgG-lambda monoclonal gammopathy associated with renal failure, lung disease and cutis laxa

Renal diseases are frequently associated with monoclonal gammopathies. Heavy chain deposition disease (HCDD) is an extremely rare condition, one of the 3 entities of monoclonal immunoglobulin deposition disease (MIDD). It is characterized by the presence of nodular glomerulosclerosis and glomerular and tubular deposition of monoclonal HC without associated light chains (LC). Here, we reported a case of HCDD associated with other manifestations, e.a. pulmonary fibrosis and cutis laxa. A 38-year-old Polish woman was referred to the emergency room for a 2-month history of fatigue, 10 kg weight gain and NYHA II dyspnea.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a nephrologist perspective.

Proliferative glomerulonephritis (GN) with monoclonal immunoglobulin deposits (PGNMIDs) is a recently described entity among the spectrum of monoclonal gammopathy of renal significance (MGRS). The disease is renal limited and manifests with chronic glomerular disease, altered renal function and albuminuria, sometimes in the nephrotic range. Acute nephritic syndrome is rare. PGNMID occurs mostly in the sixth decade, but it may affect young adults. Histologically, PGNMID is characterized predominantly by membranoproliferative GN and less frequently by diffuse endocapillary GN, mesangioproliferative GN or atypical membranous GN. Immunofluorescence and electron microscopic studies are the cornerstone of diagnosis, showing granular deposits involving glomeruli only, and composed of monotypic immunoglobulin G (IgG), with a single heavy chain subclass (most commonly IgG3) and light chain (LC) restriction (usually κ), admixed with complement deposits. PGNMID variants with monotypic LC-only, IgA or IgM deposits are uncommon. Ultrastructurally, deposits are amorphous with predominant subendothelial and mesangial distribution. PGNMID should be distinguished from type 1 cryoglobulinemic GN and immunotactoid GN, which share some common pathological features. Contrary to other MGRS lesions, the rate of detection of the nephrotoxic monoclonal Ig in the serum or urine, and of an abnormal bone marrow B-cell clone, is only ∼30%. Renal prognosis is poor, with progression to end-stage renal disease in 25% of patients within 30 months and frequent early recurrence on the renal allograft. The pathophysiology of PGNMID is unclear and its treatment remains challenging. However, recent studies indicate that clone-targeted chemotherapy may significantly improve renal outcomes, opening future perspectives for the management of this rare disease.