Monoclonal Gammopathy Of Renal Significance Research Articles

Cytogenetic abnormality in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance: A field needs to be explored.

The role of cytogenetic abnormalities in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance diseases still needs to be clarified. Bhutani etal. present the results of a study investigating the underlying plasma cell cytogenetic abnormalities in monoclonal immunoglobulin deposition disease (MIDD). The results show that translocation (11;14) is a common abnormality in MIDD and affects the presentation and outcomes. Commentary on: Bhutani etal. Translocation (11;14) is a common cytogenetic abnormality in clonal plasma cells in monoclonal immunoglobulin deposition disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19748.

Light chain deposition disease as monoclonal gammopathy of renal significance-a rare disease with scarce therapy; a case report

The kidneys are one of the main organs which involved in light chain deposition disease (LCDD). The usual renal presentations are renal failure with or without nephrotic range proteinuria and microscopic hematuria. There is not a standard therapy of kidney involvement in this disease which named as monoclonal gammopathy of renal significance (MGRS). The present case is focused on a new therapeutic strategy.

The Monoclonal Gammopathies of Renal Significance

Abstract As a heterogeneous group of diseases, monoclonal gammopathy is typical for older age and is characterized by the presence of paraprotein in serum and urine. In addition to damage to the bone marrow, other organs are also affected, whereas in the case of monoclonal gammopathy of renal significance (MGRS), the kidneys are dominant. The clinical presentation of MGRS is diverse depending on the type of renal monoclonal gammopathy. The basis of the diagnosis is the detection of free light chains in the serum, along with electrophoresis and subsequent serum immunofixation. The kappa and lambda serum light chain ratio is evaluated in patients with MGRS within modified reference parameters. A kidney biopsy provides information on the extent of renal parenchymal involvement. The basis of therapy is chemotherapeutics with possible autologous stem cell transplantation to preserve kidney function.

Hemato-Renal Profile of Proliferative Glomerulonephritis with Monoclonal Immunoglobulin Deposits

Background Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a rare entity classified under the umbrella of monoclonal gammopathy of renal significance. The clinical implications of circulating monoclonal immunoglobulin (MIg), light chain restriction on immunofluorescence (IF) microscopy, histopathological pattern, and type of therapy on renal outcomes are not clearly defined. Materials and Methods Sixteen patients of PGNMID diagnosed between 2013 and 2020 were included from a biopsy registry of 11,459 patients at a single center. Follow-up data was collected from electronic medical records until June 2021. Results The mean age of the cohort was 41.7 ± 13.5 years. Forty-four (7/16) percent showed monoclonal protein on serum or urine electrophoresis, 25% (3/12) had IgG kappa by serum immunofixation electrophoresis (IFE) and 38% (5/13) had abnormal kappa: lambda free light chain (FLC) ratio. The predominant light microscopy pattern, membranoproliferative glomerulonephritis (MPGN) was seen in 7/16 (43.7%) patients. The predominant heavy chain detected by IF microscopy was IgG (13/16, 81.3%). Kappa and lambda light chain restriction were seen in 56.3 (9/16) and 43.8 (7/16) percent of patients respectively. Circulating monoclonal kappa light chains were detected in 50 and 29% of kappa-PGNMID patients by IFE and FLC assay respectively. None of the lambda-PGNMID patients had detectable circulating monoclonal lambda light chains. Patients with circulating MIg had more proteinuria, lower estimated glomerular filtration rate, and a higher percentage of plasma cells on bone marrow biopsy. Thirty-eight percent of our cohort (5/13) progressed to kidney failure over a median (range) period of 3 (IQR, 1-7) months. Of these, 4/5 received immunosuppression, and 1/5 were treated with plasma cell-targeted chemotherapy. Conclusion PGNMID is a rare disease with a biopsy incidence of 0.1%. Only a quarter of patients with PGNMID have circulating MIg. Presence of circulating MIg, type of monoclonal light chain restriction in kidney biopsy, and type of therapy did not predict renal outcomes. Patients with MPGN pattern had favorable renal outcomes despite a higher degree of proteinuria at presentation.

Clinicopathologic Characteristics of Crystalglobulin-Induced Nephropathy: A Case Series

Crystalglobulinemia is a rare syndrome characterized by intravascular crystallization of monoclonal immunoglobulins (MIgs). Data on kidney involvement are limited to case reports. This series characterizes the clinicopathologic spectrum of crystalglobulin-induced nephropathy (CIN). Case series. Nineteen CIN cases were identified from the nephropathology archives of Mayo Clinic and Columbia University. CIN was defined by intravascular (extracellular) MIg crystals visible by light (LM) and electron microscopy (EM). Among the cases, 68% were male and 65% were Caucasian (median age 56 years). Most patients presented with severe AKI (median creatinine 3.5 mg/dL), hematuria, and mild proteinuria (median 1.1 g). Common extrarenal manifestations were constitutional (67%), cutaneous (56%), and rheumatologic (50%). Fifty percent of cases had hypocomplementemia. The hematologic disorders were monoclonal gammopathy of renal significance (MGRS) (72%), lymphoma (17%), or myeloma (11%), with 65% of these disorders discovered concomitantly with CIN. All patients had MIg identified on SPEP/SIF (IgGκ in 65%). The sFLC ratio was outside the renal range in 40%, and bone marrow biopsy detected the responsible clone in 67%. On LM, crystals involved glomeruli (100%) and vessels (47%), often with an inflammatory reaction (89%) and fibrin (58%). All cases exhibited crystal substructures (mostly paracrystalline) by EM. Immunofluorescence (IF) on paraffin embedded tissue was more sensitive than frozen tissue (92% versus 47%) for demonstrating the crystal composition (IgGκ in 63%). Follow up (median 20 months) was available in 16 patients. Eighty-one percent received steroids, 44% plasmapheresis, 38% hemodialysis, and 69% chemotherapy. Ninety-percent of patients who received clone-directed therapy achieved kidney recovery vs. 20% of those who did not (p=0.017). Retrospective design, small sample size. CIN is a rare cause of nephropathy associated with lymphoplasmacytic disorders (mostly MGRS) and typically presents with severe AKI and extrarenal manifestations. Diagnosis often requires IF performed on paraffin embedded kidney tissue. Prompt initiation of clone-directed therapy, coupled with corticosteroids and plasmapheresis, may lead to recovery of kidney function.

Monoclonal immunoglobulin deposition disease a spectrum? The treatment of an unusual biopsy presentation

Introduction: Monoclonal gammopathy of renal significance (MGRS) is characterized by clonal cell deposition of monoclonal immunoglobulin causing renal manifestations without overt malignancy. MIDD is a subtype of MGRS characterized by deposition of monoclonal light (LCDD), heavy chains (HCDD), or both (LHCDD) along the renal glomerular and tubular basement membranes. Virtually all organs can be involved, and if left untreated, MIDD can progress to MM and end stage renal disease. Although these patients classically did not receive treatment, current MIDD management is primarily focused on controlling the underlying clonal plasma cell disorder. Case description: We present a 56-year-old male with atypical MIDD treated successfully with plasma cell directed therapy consisting of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (DARA-CYBOR-D). Despite a primary diagnosis of diabetic kidney disease, renal biopsy suggested myeloma-related MIDD based on linear immunofluorescent staining for IgG and kappa light chains along the tubular and glomerular basement membranes. Notably there were no electron dense deposits in the mesangium or tubular basement membranes typical to MIDD electron microscopy. Despite the presentation of MIDD on IF only, DARA-CYBOR-D treatment led to hematologic and renal improvement and remission from MIDD, with a GFR increase from 22 to 59 mL/min/BSA and a drop in urine protein from up to 9 to 0.6 g/dL. Conclusions: In conclusion, our case illustrates the efficacy of the DARA-CYBOR-D regimen in a patient with IF-only MIDD. We highlight the importance of obtaining a kidney biopsy when there are other potential causes for real decline and enhance our understanding of pathological and clinical spectrum of MIDD.

#2284 Clinical characteristics and renal survival of patients with monoclonal gammopathy of renal significance (MGRS)

Abstract Background and Aims Monoclonal gammopathy of renal significance (MGRS) comprises a diverse group of renal disorders related to a nephrotoxic monoclonal immunoglobulin. Due to the rarity of the disease and the recent definition of MGRS-associated kidney lesions, data about long-term clinical outcomes remain limited. Method A single-center, retrospective cohort study was conducted including data of all patients with biopsy-proven MGRS who were followed at our center between 2005 and 2023. We examined the clinicopathologic characteristics and renal survival of the patients. Disease progression was defined as an eGFR decline >30% or end-stage kidney disease (ESKD). Univariate Cox regression analysis was used to assess the relationship between clinical features and disease progression. Results A total of 23 adults (males 43.5%) with a median age of 65 years (IQR 55-70) were included in our study. At presentation, median eGFR was 51 ml/min/1.73 m2 (IQR 40-80) and proteinuria 3.94 g/24 h (IQR 2.00-6.26). Serum or urine monoclonal protein was not detected in 4 patients (18.2%). MGRS-associated renal lesions included Ig-related amyloidosis (n = 8), monoclonal immunoglobulin deposition disease (n = 7), cryoglobulinemic glomerulonephritis (n = 2), C3 glomerulopathy (n = 2), proliferative glomerulonephritis with monoclonal IgG deposits (n = 1), immunotactoid glomerulopathy (n = 1) and miscellaneous (n = 2). Most patients were treated with a plasma cell-directed regimen (77.3%) and the rest with B-cell-directed (13.6%) or conservative therapy (9.1%). Median follow-up for the cohort was 45 months (IQR 27-67). Thirteen patients responded to treatment (52.1%), achieving a reduction in proteinuria (0.44 vs 3.94 g/24 h, p:001) and maintenance of eGFR (60 vs 56 ml/min, p:0.363) at the last follow-up visit. All responders had received clone-directed therapy. Disease progression occurred in 8 patients (34.8%), three of whom reached ESKD (13.0%). Renal survival, defined as survival without ESKD, was 84.6% at 48 months (CI 73.3-101.7). Factors that were associated with disease progression were Ig-related amyloidosis (HR: 6.94, CI: 1.30-36.84, p:0.023) and eGFR < 45 ml/min at diagnosis (HR: 14.73, CI: 1.62-132.95, p:0.017). Conclusion MGRS is a heterogeneous clinical entity manifesting with varying degrees of proteinuria and kidney injury. Impaired kidney function at diagnosis and Ig-related amyloidosis correlated with worse renal prognosis in our cohort. Early identification and clone-directed treatment of MGRS may improve long-term renal survival.

#2000 Analysis between site-specific N-glycosylation of monoclonal immunoglobulin and complement system activation

Abstract Background and Aims Monoclonal immunoglobulin produced by clonal plasma cells is the main cause in multiple myeloma (MM) and monoclonal gammopathy of renal significance (MGRS). Hypocomplementemia and deposition of complement components in the kidney is observed in some patients with MM or MGRS. Previous studies have suggested that glycosylation of the immunoglobulin was associated with complement-mediated-effector activities. Whereas, site-specific N-glycosylation characterization for monoclonal immunoglobulin in MM or MGRS and its effects on complement system activation still remains unclear. Method We separated plasma monoclonal IgG1 and IgA immunoglobulin from patients with MM and human plasma immunoglobulin from healthy controls (HC). Purified IgG and IgA molecules were digested by trypsin. Tryptic peptides without enrichment of intact N-glycopeptides were analyzed using a combination of electron-transfer/higher-energy collisional dissociation (EThcD) and stepped collision energy/higher-energy collisional dissociation (sceHCD) mass spectrometry (EThcD-sceHCD-MS/MS). N-glycosylation characterization was compared between monoclonal immunoglobulin from MM patients and healthy controls and its association with complement level was evaluated. Results A total of 46 IgG1 digestion samples (HC, n = 16; MM, n = 30) and 38 IgA1 digestion samples (HC, n = 16; MM, n = 22) were analyzed using the EThcDsceHCD-MS/MS. On average, 34 and 37 unique N-glycopeptides of IgG1, 19 unique N-glycans per IgG were identified from HC and MM. The relative abundance of fucosylated N-glycans of IgG1 in MM was significantly higher than HC (94.7% vs 88.8%, p = 0.002). Other types of N-glycans including sialylated, hybrid and complex were similar between the two groups. The types of N-glycans including fucosylated, sialylated, hybrid and complex were similar between patients with hypocomplementemia and normal complement levels. Regarding IgA1, on average, 63 and 52 unique N-glycopeptides of IgA1, 40 and 35 unique N-glycans per IgA were identified from HC and MM. The relative abundance of fucosylated (41.0% vs 26.4%, p < 0.001), sialylated (61.0% vs 45.6%, p = 0.003), mannose (2.44% vs 0.28%, p < 0.001) N-glycans of IgA1 in MM was significantly higher than HC. In MM, the relative abundance of mannose N-glycans of IgA1 in patients with hypocomplementemia was significantly lower than patients with normal complement levels (1.69% vs 7.52%, p < 0.001). The relative abundance of fucosylated and sialylated N-glycans were similar between patients with hypocomplementemia and normal complement levels. Conclusion Site-specific N-glycosylation characterization of monoclonal IgG1 and IgA1 in MM patients were differentially expressed from healthy controls. Certain specific N-glycan types were associated with complement levels. These findings laid a foundation for future investigations of their biological effects.

#410 Novel renal pathology and treatment of TIN with monoclonal plasma cells invasion in a patient with Sjögren's syndrome and IgA monoclonal gammopathy

Abstract Background and Aims Patients with Sjögren's syndrome (SS) may occasionally present with monoclonal gammopathy of undetermined significance (MGUS), of the rare IgA type. Additionally, they may present with tubulointerstitial nephritis (TIN) infiltrated by polyclonal plasmacytes and lymphocytes. Previous reports indicate the development of IgA-type MGUS and TIN with monoclonal plasma cells in some SS patients, which are considered distinct from monoclonal gammopathy of renal significance (MGRS) because there is no evidence that monoclonal gammopathy affects nephropathy. Although treatment with prednisolone (PSL) has shown beneficial effects, the influence of monoclonal plasma cells on nephropathy remains unclear and a standardized treatment approach is lacking. Here we present a new renal pathological insight through a case of such a patient as described above, who underwent renal biopsy before and after PSL treatment. The aim is to propose a treatment strategy based on the findings of the second renal biopsy. Method and Results (Case Presentation) A 75-year-old Japanese man with primary complaint of dry mouth was diagnosed with SS by lip biopsy and anti-Ro/SSA and La/SSB antibody tests. Monoclonal proteins were found in both blood and urine. After immunoelectrophoresis, bone marrow puncture, and 18F-FDG PET/CT, we identified it as IgA kappa-type MGUS. At the same time, he developed renal dysfunction and was admitted to our hospital (week 1, Fig. 1) for a renal biopsy. The biopsy revealed severe and diffuse TIN infiltrated by lymphocytes with abundant interstitial plasma cell invasion (Fig. 2a). Minimal changes were observed in the glomeruli. Periodic acid–Schiff staining revealed Dutcher bodies in the nucleus of plasma cells. Immunohistochemical staining for immunoglobulins and light chains showed predominantly positive results for IgA and kappa (Fig. 2b). Monoclonality was confirmed by in situ hybridization. The infiltrates were positive for CD 45, CD 79a, and CD 138, partially positive for CD 19 and CD 20, and negative for CD 5, CD 10, and CD 23. Congo-red staining showed no evidence of amyloid. Immunofluorescence and electron microscopy revealed no detectable immunological deposits in the glomeruli and tubules. Mutations in the myeloid differentiation primary response gene 88 were not detected in the kidney. We diagnosed the condition as acute TIN by lymphocytes with IgA kappa-positive monoclonal plasma cells, distinct from MGRS. Considering the lack of evidence from previous reports on the impact of monoclonal plasma cells on nephropathy, we decided to treat the patient primarily for TIN with SS, initiating PSL at 30 mg/day (0.5 mg/kg/day). Renal function improved rapidly with the treatment, allowing for a gradual reduction in the dose of PSL; however, a low dose of PSL (10 mg/day) was required to prevent relapse. As a complication of PSL, the patient eventually developed a lumbar compression fracture, prompting us to evaluate the effect of PSL on renal function by a renal re-biopsy. The re-biopsy revealed significant recovery of TIN by lymphocytes (Fig. 2c). Other findings, including abundant interstitial plasma cells invasion were comparable to the initial biopsy. We diagnosed the condition as recovered TIN by lymphocytes with IgA kappa-positive monoclonal plasma cells. We concluded that TIN by lymphocytes, rather than monoclonal plasma cell invasion, primarily affected the nephropathy, and PSL mainly improved the former. The Nudix hydrolase 15 codon139 in blood was identified as Cys/Cys, indicating a high risk of severe adverse reactions to azathioprine in Asians. Therefore, we decided to concurrently administer mycophenolate mofetil, proven effective in the treatment of TIN with SS. Conclusion In the management patients with SS and IgA monoclonal gammopathy, the focus should be on TIN by lymphocytes rather than monoclonal plasma cell invasion. This case, considering similar cases, suggests that it should be defined as a new disease category. We demonstrate new renal pathology and treatment insights based on renal re-biopsy in a patient treated with PSL.

#2800 AL amyloidosis with renal involvement: TAPSE and new therapies

Abstract Background and Aims Light chain (LA) deposition amyloidosis is the most common type of renal amyloidosis. It may be associated with monoclonal gammopathy of uncertain significance (MGUS), meeting criteria for monoclonal gammopathy of renal significance (MGRS), or present in the course of multiple myeloma. The therapy of choice is autologous hematopoietic stem cell transplantation (TAPSE), although given the associated risks, not all patients are considered candidates, and different therapeutic regimens may be used as an alternative or induction prior to TAPSE (Bortezomib/dexamethasone, daratumumab/bortezomib, cyclophosphamide-bortezomib-Dexamethasone (CyBorD). Method Retrospective observational study of a cohort of patients with AL amyloidosis evidenced by renal biopsy by spectrometry or immunohistochemistry. Data extracted from the HUVM biopsy registry (2017-2022). Results 12 patients. Median age: 64 years. 6 women and 6 men. Mean creatinine 1.14 ± 0.6 mg/dl and proteinuria 3.8 ± 2.9 g/24 h. Median monoclonal peak 0.348 g/dl. Light chain involved: 7 Lambda and 5 Kappa. 2 patients met criteria for MM. 2 Bence-Jones positive. The 4 patients who did not have a renal response achieved a renal response, while of the 6 who did have a response, only 3 had a response (p = 0.091), 2 of them with previous induction with DARATUMUMAB, representing 100% of the total number of patients with this scheme. 3 patients died, with a median from diagnosis of 508 days. 1 of them had previously received TAPSE, out of a total of 6, while among the 5 patients who did not undergo this therapy, we found 2 exitus (p = 0.387). Conclusion The most common form of presentation in our sample was as MSG, with only 2 patients with MM criteria at the time of diagnosis. It also associated a reduced monoclonal component, and the Bence-Jones study was mostly negative. We did not find significant prognostic differences between the different therapeutic groups, although it is worth noting the worse renal response in the TAPSE group (p = 0.091) and the better data associated with the DARATUMUMAB group.

#1346 Inpatient and outpatient service review of a Greek reference centre for glomerular diseases

Abstract Background and Aims The glomerulonephritis (GN) is a rare and complicated disease with high demand of hospital resources while the chronic kidney disease and end-stage renal disease present increased prevalence in these patients. Method We retrospectively assessed the inpatient and outpatient service of a Greek reference centre for glomerular diseases during the pre-Covid-19 period 2018-2020. Results 267 patients (38% female, median age 65 ± 23 years) included. All patients underwent a kidney biopsy by the nephrologist without complications. ANCA associated GN (18%), Focal Segmental Glomerulosclerosis/Minimal Change Disease (17.5%), IgA nephropathy (17%), Membranous Nephropathy (12.6%), Lupus Nephritis (5%), Membranoproliferative GN (3%), Fibrillary GN (3%), Monoclonal Gammopathy of Renal Significance (3.3%) and IgG4-related disease (2%.) are encompassed. We reported median 75 new patients per year. Regarding the inpatient service, we observed an increasing trend to the hospitalizations during this period (274, 452, 461 hospitalizations in 2018, 2019, 2020 respectively). The AAGN was the most common disease of hospitalizations through this period (53% in 2018, 33% in 2019, 39% in 2020), whereas the second most common was the FSGS/MCD (28% in 2018, 13% in 2019, 23.8% in 2020). The outpatient's service review also revealed an increasing number of visits per person per year (279, 456 and 464 total visits in 2018, 2019 and 2020 respectively). The disease with the highest number of visits per person was reported the AAV (median 3.25 visits per patient per year). All the patients were managed in adherence to the latest guidelines for GN in collaboration with a multidisciplinary team, consisting of nephrologist, rheumatologist, cardiologist, and pathologist. Finally, we reported complete response at 76% of the patients and in terms of renal improvement, 46% presented eGFR≥60 ml/min/1.73 m2, 45% eGFR<60 ml/min/1.73 m2 and only 9% progressed to ESRD after the first year of treatment. Conclusion Patients with GN present an increased need for hospitalization and regular outpatient visits. Addressing these diseases necessitates the expertise of a multidisciplinary team to provide comprehensive care that maximizes the potential for sustained positive long-term outcomes.

Clinicopathological characteristics and prognosis in patients with monoclonal gammopathy and renal damage in central China: a multicenter retrospective cohort study

Renal involvement is common in monoclonal gammopathy (MG); however, the same patient may have both MG and non-paraprotein-associated renal damage. Accordingly, distinguishing the cause of renal damage is necessary because of the different clinical characteristics and associated treatments. In this multicenter retrospective cohort study, we described the clinicopathological characteristics and prognosis of 703 patients with MG and renal damage in central China. Patients were classified as having MG of renal significance (MGRS), MG of undetermined significance (MGUS), or hematological malignancy. 260 (36.98%), 259 (36.84%), and 184 (26.17%) had MGRS, MGUS, and hematological malignancies, respectively. Amyloidosis was the leading pattern of MGRS (74.23%), followed by thrombotic microangiopathy (8.85%) and monoclonal immunoglobulin deposition disease (8.46%). Membranous nephropathy was the leading diagnosis of MGUS (39.38%). Renal pathological findings of patients with hematological malignancies included paraprotein-associated lesions (84.78%) and non-paraprotein-associated lesions (15.22%). The presence of nephrotic syndrome and an abnormal free light chain (FLC) ratio were independently associated with MGRS. The overall survival was better in patients with MGUS than in those with MGRS or hematological malignancies.

A Rare Case of Immunotactoid Glomerulopathy Associated with Monoclonal Gammopathy of Renal Significance and Potential Multiorgan Involvement

The term MGRS (Monoclonal Gammopathy of Renal Significance) is a newly recognized entity characterized by the renal deposition of a monoclonal protein. It arises in the context of hematologic disorders that do not meet the diagnostic criteria for plasma cell dyscrasias or lymphoma. Numerous disease entities fall under the MGRS category, each associated with a specific type of monoclonal protein that causes renal injury. This category also includes Immunotactoid Glomerulopathy (ITG), a rare glomerular disorder identified by the existence of immunoglobulin deposits in the glomeruli. These deposits have a substructural arrangement resembling microtubules with diameters ranging from 15 to 50 nm with a hollow center and organized in parallel arrays. Patients diagnosed with MGRS should undergo treatment targeting the clone producing the nephrotoxic monoclonal immunoglobulin. This is essential in preventing renal failure, as well as the progression to more advanced monoclonal gammopathies. We present the case of a 49-year-old female diagnosed with ITG associated with monoclonal gammopathy. The condition followed an indolent course for approximately 8 years before the diagnosis. At the time of presentation to the hematologist, she also exhibited a macular skin eruption and peripheral nerve impairment Except for the renal biopsy, other biopsies were not performed. However, during treatment and post-treatment, we observed an improvement and even the disappearance of cutaneous lesions, as well as a clinical improvement in neurological symptoms. These observations suggest a potential multiorgan involvement in the context of monoclonal gammopathy.

Clinical Significance of Serum Free Light Chain in Monoclonal Gammopathy

To investigate the expression and clinical significance of serum free light chain (sFLC) in patients with monoclonal gammopathy (MG). The peripheral blood of 98 patients with MG and 30 healthy volunteers were collected. The level of sFLC was detected by immunoturbidimetry, and the value of sFLC in diagnosis, disease severity, and efficacy evaluation was analyzed. Among 98 MG patients, there were 58 males and 40 females, 45 cases of monoclonal gammopathy of renal significance (MGRS), 33 cases of monoclonal gammopathy of undetermined significance (MGUS), 20 cases of hematological malignancy (HM), 58 cases of IgG type, 26 cases of IgA type, 7 cases of IgM type, 5 cases of light chain type, 2 cases of non-secreting type, 35 cases of κ type, 63 cases of λ type, 53 cases of renal insufficiency, 45 cases of normal renal function. The expression levels of sFLC-κ and sFLC-λ in MG patients were significantly higher than those of the control group (P <0.01). The expression levels of sFLC-κ and sFLC-λ in HM patients were significantly higher than MGRS and MGUS patients, and in MGRS patients were also significantly higher than MGUS patients (P <0.05). Patients with abnormal renal function had higher expression levels of sFLC-κ and sFLC-λ than patients with normal renal function (P <0.01). sFLC-κ and sFLC-λ were positively correlated with the expression level of globulin (r =0.392, r =0.435) and β2-MG (r =0.403, r =0.468) in MG patients, as well as serum creatinine in patients with abnormal renal function (r =0.586, r =0.631), while no significant correlation was found with age, sex, albumin, lactate dehydrogenase, and serum calcium. After treatment, the levels of sFLC-κ and sFLC-λ were significantly decreased (P <0.01). sFLC is significantly elevated in MG patients and can be quickly detected with high sensitivity, which is helpful for the diagnosis of disease type, judgment of disease severity, and evaluation of therapy.

Systematic review and meta-analysis of the clinical features of MGRS

BackgroundIt is crucial to identify patients with monoclonal gammopathy of renal significance (MGRS) from those without MGRS but with monoclonal gammopathy and concomitant kidney diseases. However, there have been few studies with large sample sizes, and their findings were inconsistent. This study aimed to conduct a meta-analysis of MGRS to describe the general characteristics of MGRS and its predictive factors.MethodsCohort or case-control studies published through December 2022 and related to clinicopathological features of MGRS were retrieved from the PubMed, Cochrane Library, Web of Science, Scopus, and Embase databases. Two researchers searched for studies that met the inclusion criteria. In the univariate analysis, fixed- or random- effects models were used to obtain pooled estimates of the weighted mean difference (WMD) and odds ratio (OR) for risk factors. In the multivariate analysis, the ORs of the independent risk factors from each study were pooled after transforming the original estimates.ResultsThe meta-analysis included six studies. Univariate analysis showed that the following variables were statistically significant in MGRS: age (WMD = 1.78, 95%CI 0.21–3.35), hypertension (OR = 0.54, 95%CI 0.4–0.73), diabetes (OR = 0.42, 95%CI 0.29–0.59), albumin (WMD = − 0.26, 95%CI − 0.38–−0.14), urinary protein level (WMD = 0.76, 95%CI 0.31–1.2), urinary protein ≥ 1.5 g/d (OR = 1.98, 95%CI 1.46–2.68), lambda-chain value (WMD = 29.02, 95%CI 16.55–41.49), abnormal free light-chain ratio (OR = 4.16, 95%CI 1.65–10.47), bone marrow puncture rate (OR = 5.11, 95% CI 1.31–19.95), and abnormal bone marrow outcome rate (OR = 9.63, 95%CI 1.98–46.88). Multivariate analysis showed urinary protein ≥ 1.5 g/d (OR = 2.80, 95%CI 1.53–5.15) and an abnormal free light-chain ratio (OR = 6.98, 95%CI 4.10–11.91) were associated with predictors of MGRS.ConclusionsCompared with non-MGRS patients with monoclonal gammopathy and concomitant kidney diseases, patients with MGRS were older, had fewer underlying diseases, more urinary protein, more abnormal free light-chain ratio, and more abnormal bone marrow results. Urinary protein ≥ 1.5 g/d and an abnormal free light-chain ratio were independent risk factors for MGRS.

Development and validation of a diagnostic nomogram model for predicting monoclonal gammopathy of renal significance

In patients with kidney disease, the presence of monoclonal gammopathy necessitates the exploration of potential causal relationships. Therefore, in this study, we aimed to address this concern by developing a nomogram model for the early diagnosis of monoclonal gammopathy of renal significance (MGRS). Univariate and multivariate logistic regression analyses were employed to identify risk factors for MGRS. Verification and evaluation of the nomogram model's differentiation, calibration, and clinical value were conducted using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. The study encompassed 347 patients who underwent kidney biopsy, among whom 116 patients (33.4%) were diagnosed with MGRS and 231 (66.6%) with monoclonal gammopathy of undetermined significance. Monoclonal Ig-related amyloidosis (n = 86) and membranous nephropathy (n = 86) was the most common renal pathological type in each group. Notably, older age, abnormal serum-free light chain ratio, and the absence of microscopic hematuria were identified as independent prognostic factors for MGRS. The areas under the ROC curves for the training and verification sets were 0.848 and 0.880, respectively. In conclusion, the nomogram model demonstrated high accuracy and clinical applicability for diagnosing MGRS, potentially serving as a valuable tool for noninvasive early MGRS diagnosis.

PARAKID: Navigating the relation between paraproteins and kidney lesions: A multi-center retrospective observational study.

Monoclonal gammopathy is a heterogeneous group of disorders due to the clonal proliferation of immunoglobulin-producing plasma cells or B lymphocytes. Patients develop kidney disease not only due to malignant transformation but also due to the idiosyncratic properties of the M protein and the host factors. We aim to study the spectrum of kidney diseases in patients with paraproteinemia. A retrospective observational study was performed at three tertiary care centers in Southern India. Kidney biopsies conducted in these three centers were reviewed from June 1, 2020 to November 30, 2022. All biopsies suggestive of monotypic immunoglobulin or light chain restriction were included in the study. A total of 122 patients were included in the study with an incidence of 2.4%. The mean age was 52.27 ± 13.27 years, and majority (63.1%) were males. AL amyloidosis was most common in the monoclonal gammopathy of renal significance (MGRS) group, and cast nephropathy was most common in the multiple myeloma (MM) group. On histopathology, 83.6% had a single lesion, followed by 14.8% with double lesion, and 1.6% with triple lesion. Paraproteinemia is associated with a myriad of kidney lesions. MGRS and MM are usually present in the 6th decade of life and beyond, while proliferative glomerulonephritis with monoclonal immunoglobulin deposits is more common in the younger age group. Older age group, high creatinine, hyperuricemia, hyperphosphatemia, presence of more than one lesion on kidney biopsy, and presence of cast nephropathy was significantly associated with the requirement of kidney replacement therapy.

Successful autologous stem cell transplantation for light chain proximal tubulopathy with severe kidney injury

Key Clinical MessageLight chain proximal tubulopathy (LCPT) is a rare type of monoclonal gammopathy of renal significance. Clinicians should consider LCPT in the differential diagnosis of patients with renal or proximal tubular dysfunction with monoclonal gammopathy. They should confirm diagnosis by renal biopsy and initiate chemotherapy before disease progression.

Post-Transplant Monoclonal Gammopathy of Renal Significance: A Case Report

The term monoclonal gammopathy of renal significance has been used to classify the presence of a monoclonal gammopathy or lymphoproliferative disorders that do not meet hematological criteria for myeloma but instead cause kidney damage. Mostly, post-transplant monoclonal gammopathy of renal significance occurs due to recurrent disease. In contrast, the incidence of de novo post-transplant monoclonal gammopathy of renal significance has not been established, as it is considered a rare disease, presenting a unique challenge in terms of diagnosis, management, and potential impact on graft survival. Here, we report a case of de novo monoclonal gammopathy of renal significance diagnosed after kidney transplantation and its complexity due to a concomitant chronic active antibody-mediated rejection.

Outcomes Associated with Clone-Directed Therapies for Monoclonal Gammopathy of Renal Significance

Background: Monoclonal Gammopathy of Renal Significance (MGRS) is a category of diseases not meeting criteria for cancer, in which a clonal population of B-lymphoid or plasma cells produces a nephrotoxic protein leading to kidney injury. Informal consensus has arisen that therapy targeting the causal clone is most likely to be efficacious, and the primary goal of therapy is to prolong renal survival. Light chain (AL) amyloidosis has been extensively studied, yet there is a paucity of data describing outcomes associated with clone-directed therapy for the various subtypes of non-AL MGRS. Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis was excluded. The primary outcome was renal survival, defined as time from diagnosis of MGRS to requiring renal replacement therapy (RRT) or renal transplant, with patients censored at last follow up or death. Baseline characteristics were described, including 24-hour proteinuria, estimated glomerular filtration rate (eGFR), whether a clonal population of B cells or plasma cells could be identified on histopathologic examination of marrow or lymph node biopsy, concentration of monoclonal protein, and involved serum free light chain concentration. Initial therapy was reported, although differences in outcomes across therapeutic strategies were not compared. Baseline clinical characteristics between patients who required RRT and those who did not were compared. Baseline clinical variables and time to RRT were compared across the two most common MGRS subtypes in the cohort: proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain deposition disease (LCDD). Continuous variables were compared across subgroups using Wilcoxon rank-sum test. Time-to-event outcomes were analyzed according to the Kaplan-Meier method. All analyses were conducted using R version 3.6.1. Results: In total, 65 patients were included, 23 (35%) of whom ultimately required RRT or transplant. Four patients died, all after RRT. Median baseline proteinuria was 2802 mg/24h (IQR 972.5 - 4492.0) and median eGFR was 33.0 mL/min (IQR 23 - 53) for the entire cohort. In all cases proteinuria was mostly albumin. Median baseline involved light chain concentration was 8.3 mg/dL (IQR 3.1 - 26.4). A majority of patients (n=33, 51%) had no identifiable serum monoclonal protein. The two most common MGRS subtypes were PGNMID (n = 26) followed by LCDD (n = 21). Clonal populations thought to be causing MGRS were identified in 41/64 patients (64%), including 37 (58%) with plasma cell clones, 1 (2%) with a lymphoplasmacytic lymphoma clone, and 3 (4.7%) with other B-cell clones. Clones were not identified in 23 (36%). The most common chemotherapy agents included bortezomib (n=42, 64%) and rituximab (n=14, 22%). Compared to patients not requiring RRT, patients requiring RRT had higher baseline proteinuria (median 3531 vs. 1980 mg/24h, p&amp;lt;0.001) and lower eGFR (median 16 v. 44 mL/min, p&amp;lt;0.001); differences in serum free light chain concentrations were not significant ( Figure 1). A clonal population thought to be causing MGRS was identified on bone marrow biopsy in a majority of LCDD patients (n = 20, 95%), while clones were infrequently found in PGNMID (n = 6, 23%). The vast majority (n=20, 95%) of patients with LCDD received bortezomib-based therapy. Initial therapy in patients with PGNMID was more evenly divided: 9 (35%) received bortezomib-based therapy, 10 (38%) received rituximab-based therapy, and 6 (23%) received other regimens. Despite differences in therapeutic approach, patients with LCDD and in patients with PGNMID had similar risk of RRT (cumulative risk 35% v. 43%, p=0.54; HR 0.83 (95% CI 0.52-1.33); p =0.44) ( Figure 2). Conclusion: Patients with MGRS remain at high risk of requiring RRT even with clone-directed therapy. Despite differences in pathogenic clones and therapeutic strategies, outcomes of patients with PGNMID and LCDD are similar. Because the severity of baseline renal function across MGRS histologies predicts renal survival, early diagnosis and treatment is likely critical to improving renal outcomes.