Monoclonal Immunoglobulin Deposition Disease Research Articles

#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.

#1297 Approaches to renal response assessment in rare monoclonal immunoglobulin related glomerulopathies

Abstract Background and Aims AL-amyloidosis (AL) and monoclonal immunoglobulin (MIg) deposition disease are common types of MIg-related glomerulopathies (MIgG) and are well-studied including approaches to treatment and hematological and renal responses (RR) assessment. Other rare MIgG comprise very diverse patterns of glomerular injury e.g. proliferative glomerulonephritis with MIg deposition (PGNMID), C3-glomerulopathy, fibrillary glomerulonephritis etc. Although RR defined as decrease in 24 h proteinuria by 30% without kidney function decline was validated only for renal AL it is widely used for MIg deposition disease and rare MIgG without validation. Nevertheless, the best approach to RR assessment in rare MIgG is still unclear. To shed some light on this problem we performed this study. Method We retrospectively analyzed 31 patients with rare MIgG who were treated with clone-specific treatment and had available follow-up (FUP) ≥6 months (mo). The following morphological patterns were diagnosed: PGNMID (n = 9), C3-glomerulopathy (n = 9), thrombotic microangiopathy (n = 5), cryoglobulinemic glomerulonephritis (n = 3), fibrillary glomerulonephritis (n = 3), immunotactoid glomerulonephritis (n = 1) and membranous nephropathy (n = 1). Patients’ baseline parameters are shown on Fig. 1 as well as treatment modalities. Hematological response defined according to currently accepted criteria is demonstrated on Fig. 1. We evaluated two approaches to the RR assessment: 1) at least partial renal response (PR) defined as 24 h proteinuria decreased by 50% from the baseline and <3.5 g, and 2) according to Palladini's criteria for AL (AL-RR) i.e. 24 h proteinuria decreased by 30% from the baseline or <0.5 g. Both RR were considered as achieved only in the absence of estimated glomerular filtration rate (eGFR) decline >25%. Time points for RR assessment were 6, 12 and 24 mo from the clone-specific treatment initiation. Renal outcome was estimated as initiation of renal replacement therapy or eGFR <15 ml/min/1.73 m2 at the end of follow-up. Death-censored renal survival was analyzed by the Kaplan-Meier method. Cox regression analysis was applied to determine which RR was independently associated with long-term kidney outcome. P-value was assumed at <0.05. Median FUP was 19 (7; 50) mo. FUP ≥12 and ≥24 mo were available in 26 and 17 patients, respectively. Results Total number of patients who achieved AL-RR at any RR assessment time point was 22 (71%). At 6, 12 and 24 mo the achievement of AL-RR was registered in 17, 16 and 10 patients, respectively. PR cumulatively was achieved in 19 (61%) patients: at time points of 6, 12, and 24 mo it was registered in 14, 14 and 9 cases, respectively. The 5-year cumulative renal survival in those who had AL-RR was better than in not responders (Fig. 2A). Patients who ever achieved PR had better cumulative renal survival compared with patients with no renal remission (Fig. 2B). In univariate Cox regression analysis the achievement of AL-RR (Exp(β) 0.158 (95% CI 0.03; 0.819)) was associated with renal outcome as well as the achievement of PR (Exp(β) 0.074 (95% CI 0.09; 0.626)). In multivariate Cox regression model adjusted for eGFR at the time of kidney biopsy AL-RR vs no response was estimated as an independent predictor of renal long-term prognosis (Exp(β) 0.082 (95% CI 0.009; 0.725)) as well as eGFR (Exp(β) 0.89 (95% CI 0.821; 0.985)). The only independent predictor of renal outcome in the model including eGFR at the time of kidney biopsy (Exp(β) 0.85 (95% CI 0.72; 0.99), p = 0.05) was PR (Exp(β) 0.011 (95% CI 0; 0.547), p = 0.021). Conclusion The classical concept of complete and partial renal remission seems to be more appropriate for rare MIgG and requires further validation studies.

Primary adrenal insufficiency developed 22 years after the diagnosis of light and heavy chain deposition disease: a case report.

Monoclonal immunoglobulin deposition diseases (MIDDs), including light and heavy chain deposition disease (LHCDD), are rare and heterogeneous disorders associated with underlying B-cell clonal disorders. Adrenal involvement is a potential extrarenal manifestation of MIDDs; however, limited data are available regarding its prevalence and clinical presentation. Herein, the present report describes, for the first time, a case of primary adrenal insufficiency that developed twenty-two years after a diagnosis of LHCDD had been made. A 69year-old woman with a 10year history of hemodialysis suddenly became bedridden after falling down stairs in the absence of focal neurological deficits. Subsequently, she experienced appetite loss, nausea, vomiting, a fever of unknown origin, and unexplained hypotension. Several months later, primary adrenal insufficiency and normal pressure hydrocephalus were diagnosed and successfully managed. The long-term clinical prognosis of MIDDs has not been fully elucidated despite recent advances in the management of the disorders. This report may contribute to improving our understanding of the disease course.

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.

Monoclonal Immunoglobulin Deposition Disease - a Review of Current and Emerging Data

Introduction Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of abnormal B and plasma cells, characterized by non-fibrillar, Congo-red negative deposits of monoclonal immunoglobulin molecules. These include light chain (LCDD), heavy chain (HCDD), or combined (LHCDD), and can involve several organs, most notably the kidney. Clone directed treatments for MIDD, including chemotherapy and autologous stem cell transplantation (ASCT), are used to reduce abnormal immunoglobulin deposition and restore organ function. Organ transplantation is considered in select cases. However, data is limited in terms of prognosis, association of MIDD with other hematological disorders, and outcomes in the evolving treatment landscape. Objectives The primary aim of this scoping review is to identify and collate existing data on clinical manifestations, disease associations, and treatment options in MIDD. This will help provide evidence-based recommendations and inform future research. Methods We conducted a literature search through EMBASE, MEDLINE, and CINAHL. Identified studies were imported onto Covidence and screened by two independent reviewers. Primary studies of patients with MIDD were included. Conference abstracts and dissertations were included if they synthesized data on MIDD. Case reports, reviews, and guideline reports were excluded. Outcomes of interest include disease type, risk factors, systemic manifestations, natural history, and prognosis. Data was also collected on disease association, intervention (observation, immunosuppression, chemotherapy, ASCT, organ transplantation, novel agents), and prognostic variables. Standardized scoping review methodology and PRISMA guidelines were used for protocol development. Results A total of 16,673 records were identified through literature search, of which 125 were used. Most studies were case series, with larger retrospective cohort studies providing data on treatment options and transplantation in MIDD. Grey literature search was also performed and yielded no additional results. LCDD was identified as the most common MIDD subtype. Organ involvement was most commonly renal, followed by hepatic and cardiac. Study endpoints included overall survival, renal survival (i.e., time to initiation of renal replacement therapy), hematologic response, and organ response. Biochemical parameters such as serum creatinine and proteinuria were measured. Single organ involvement was more common than multi-organ, and disease response was primarily assessed using laboratory parameters. There was substantial heterogeneity in treatment. These included corticosteroids, plasma exchange, and chemotherapy - typically bortezomib-containing regimens - followed by ASCT in eligible patients. Renal response rates of up to 79% (n=28) were noted in a larger patient cohort. Patients who demonstrated renal response fared better than non-renal responders did (overall survival of 87% vs 60% at 27.3 months, n=255). In patients who underwent ASCT (either as consolidation or in the case of relapse/progression), most patients achieved hematologic CR (71%, n=14). ASCT was relatively well-tolerated, with early transplant-related mortality limited to one patient across 9 studies with data on ASCT (n=69). Patients appeared to have more favorable outcomes with MIDD/MGRS compared to MIDD in the setting of myeloma (VGPR/CR 58.9% vs 47.9%, n=255). Renal response appeared to correlate with deeper hematologic responses. Post renal transplant allograft loss has been noted upon MIDD relapse. Discussion Limited data exists on MIDD and its subtypes. Potential reasons include newer classification schema, low incidence, disease heterogeneity, need for histopathologic diagnosis, and frequently asymptomatic initial course. This scoping review outlines patient characteristics, disease subtypes, and outcomes with treatment options including ASCT and organ transplantation. MIDD appears to respond to chemotherapy and ASCT; however, responses depend on the subtype, associated disease process, and degree of organ involvement. Renal response may have significant prognostic implications. Limitations of this review include a paucity of prospective data, lack of studies using novel plasma cell-directed therapies, and small sample sizes. Further data analysis is ongoing, and emerging prospective data is of interest.

One Case of Heavy Chain Deposition Disease Treated with Dara+KD Regimen and Literature Review

Background: Heavy chain deposition disease (HCDD) is a systemic disease caused by the deposition of monoclonal immunoglobulin heavy chains in tissues.It is a rare monoclonal immunoglobulin deposition disease. The mechanism of HCDD is still unclear, which may be related to the deletion of heavy chain constant region 1 and the activation of the Complement system by monoclonal heavy chains. Renal biopsy remains the gold standard for diagnosing HCDD at present. There are significant individual differences in the formation of abnormal heavy chains in HCDD patients, and FLC, M protein, and complement detection have certain reference significance for the evaluation of diagnosis and treatment processes. The chemotherapy scheme represented by Bortezomib has a certain effect. HDM/ASCT and kidney transplantation can be used as second-line treatment for some patients. At present, there is no report on the use of CD38 monoclonal antibody combined with KD regimen. Objective: To explore the efficacy and toxicity of CD38 monoclonal antibody combined with KD regimen in the treatment of heavy chain deposition disease. Methods: The diagnosis, treatment and efficacy of HCDD who hospitalized in the Hematology Department of the First Affiliated Hospital of Sun Yat-sen University was analyzed, and the value of CD38 monoclonal antibody combined with KD regimen in the treatment of HCDD was discussed. The patient was male, 44 years old, due to “depressed edema of both lower limbs and eyelid edema for more than two months”. Results: Heavy chain deposition disease is a rare malignant Plasma cell disease. CD38 monoclonal antibody combined with KD regimen can rapidly alleviate the disease,.This patient got CR and obvious improvement of clinical symptoms after 1 cycle chemotherapy, and has no obvious side effects.We be expected to do 4 cycle chemothetaphy and would do ASCT.until now,this patient has got 3 cycles. Conclusion: Heavy chain deposition disease is a rare malignant Plasma cell disease. CD38 monoclonal antibody combined with KD regimen can rapidly alleviate the disease, with fast onset time, high CR rate, obvious improvement of clinical symptoms, and no obvious side effects.

Randall-Type Monoclonal Immunoglobulin Deposition Disease in Bone Scintigraphy.

Bone scintigraphy is recognized as a noninvasive alternative to endomyocardial biopsy for the diagnostic of wild-type (wATTR) and hereditary ATTR amyloidosis (hATTR). Light chain amyloidosis (AL), Randall-type monoclonal immunoglobulin deposition disease, sarcoidosis, hemochromatosis, Fabry disease, and mucopolysaccharidoses are differential diagnosis of ATTR amyloidosis. Bone scintigraphy allows visualization of extracardiac involvements of AL amyloidosis: pleural, retroperitoneal, liver, spleen, and soft tissue. We report the case of a patient who underwent bone scintigraphy for suspected ATTR amyloidosis. Bone scan showed cardiac (Perugini score 2), hepatic, and renal hyperfixation. A cardiac biopsy demonstrated a Randall-type deposit, without amyloid deposit.

#3922 CLINICOPATHOLOGICAL CHARACTERISTICS OF LIGHT AND HEAVY CHAIN DEPOSITION DISEASE: A CASE SERIES FROM A SINGLE CENTER

Abstract Background and Aims Light and heavy chain deposition disease (LHCDD) is the rarest form of monoclonal immunoglobulin deposition disease (MIDD) characterized by the deposition of the monoclonal light chain and heavy chain. At present, the large-scale clinical research data of LHCDD is limited. We explore the clinical-pathologic characteristics and outcome of LHCDD in a single center of China, to obtain a better understanding of this disease. Method We reviewed 65291 native kidney biopsies from January 2008 to December 2022. Ten patients with biopsy-proven LHCDD diagnosed were studies retrospectively. Results 4 males and 6 females, with an average age of 52.5 ± 8.9 years were enrolled. The patients were presented with hypertension (80%), anemia (90%), elevated serum creatinine (70%), proteinuria (100%), nephrotic syndrome (30%) and microscopic hematuria (90%). Serum immunofixation electrophoresis showed that 8 (80%) patients were positive for monoclonal immunoglobulin (IgG-κ/IgG-λ/IgA-λ: 3/2/3). Serum free light chain (FLC) ratio was abnormal in 9 (90%) patients. Among them, 5 patients had an Elevated FLC ratio (κ:λ > 1.65), and an FLC ratio < 0.26 was observed in 4 patients. Two patients were diagnosed with multiple myeloma. Histologically, nodular mesangial sclerosis was identified in 9 (90%) patients. Immunofluorescence showed that 6 patientshad depositions of heavy chain IgG (γ1-κ/γ1-λ/γ2-κ/γ2-λ/γ3-κ:2/1/1/1/1), and 4 patients of heavy chain IgA (α-κ/α-λ:1/3). During a median of 28 months of follow-up (range, 6–104 months) in 9 patients, 8 patients received chemotherapy. Three (33%) patients had complete hematologic remission (CR), 2 (22%) had very good partial hematologic response (VGPR) or partial hematologic response (PR), and 4 (44%) had no response (NR). One (11%) had stable/improved renal function, 6 (67%) had worsening renal function, and 3 (33%) progressed to ESRD. All 9 patients survived. Conclusion In this case series of LHCDD in a single center in China, light and heavy chain deposition in renal tissues was most frequent with IgG-κ, followed by IgA-λ, IgG-λ and IgA-κ. More than half patients had hematologic response but poor renal prognosis.

#5788 MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE: A SINGLE CENTER EXPERIENCE

Abstract Background and Aims Monoclonal gammopathy of renal significance is an organ-threatening manifestation of paraproteinemia. It can be secondary to the clonal proliferation of either plasma cells or mature B-lymphocytes. The underlying clonal disorder does not meet the current hematologic criteria for immediate myeloma-specific therapy. With the advent of routine use of light chain detection by immunofluroscence technique in tissue biopsy, more cases of monoclonal gammopathy of renal significance are being diagnosed but there remains a therapeutic uncertainty. Data regarding the prognosis and outcomes of the various clinical manifestations of monoclonal gammopathy of renal significance is limited due to its rarity and under diagnosis. MGRS if left untreated can lead to end-stage renal disease and premature death. Method This is a retrospective study conducted at the Institute of Nephro-urology, Bangalore by retrieving the data from the digital medical records of our institute. Demographic and clinical details of the patients diagnosed with monoclonal gammopathy of renal significance from 1 st January 2018 to 31 st October 2022 were collected. Myeloma related light chain cast nephropathy was excluded from the study. Follow-up data were collected usingout patient data base, through telephone, and from the records at the cancer institute where the patient was referred post-diagnosis at our institute. The data collected was entered in excel and analyzed using SPSS software version 27.0. Results Fifty eight patients (n = 52) were diagnosed with the disease during the study period. MGRS contributed to 1.27% of all the renal biopsies conducted at our institute during the study period. The mean age of the study population was 52.1 with 95% CI [48.5 to 55.6] with a male: female ratio of 1.36:1 and 36.5% (n = 19) ofstudy cohort aged above 60 years. Among clinical presentations CKD (n = 23) was the main clinical presentation followed by AKI, Nephrotic syndrome, Nephritic syndrome and RPGN as the other presentations. Dialysis requirement was noted in 35% at initial presentation. Most common histiopathological presentation was Amyloidosis (n = 15) followed by Light chain deposition disease LCDD (n = 14), monoclonal non-amyloid deposition disease NADD (n = 6), Light chain proximal tubulopathy LCPT (n = 5), Proliferative glomerulonephritis with monoclonal immunoglobulin deposition disease PGNMIDD (n = 9) and others (n = 3). The patient survival at the time of analysis was 22.7% and death censored renal survival was 80%. Conclusion MGRS contributed to 1.27% of all the renal biopsies conducted at our institute during the study period. Because of its variable clincal presentation,one needs high degree of clinical suspicion for early diagnosis. MGRS unlike MGUS carries significant morbidity and mortality.

A Case of Light Chain Deposition Disease Leading to Acute Liver Failure and Review of Literature

Light chain deposition disease (LCDD) is a monoclonal immunoglobulin deposition disease characterized by light chain deposition in soft tissues and viscera, causing systemic organ dysfunction with an underlying lymphoproliferative disorder. While the kidney is the most affected organ, cardiac and hepatic involvement is also seen with LCDD. Hepatic manifestation can range from mild hepatic injury to fulminant liver failure. Herein, we are presenting a case of an 83-year-old woman with a monoclonal gammopathy of undetermined significance (MGUS), who presented to our institution with acute liver failure progressing to circulatory shock and multiorgan failure. After an extensive workup, a diagnosis of hepatic LCDD was determined. In conjunction with the hematology and oncology department, chemotherapy options were discussed, but given her poor prognosis, the family decided to pursue a palliative route. Though establishing a prompt diagnosis is important for any acute condition, the rarity of this condition, along with paucity of data, makes timely diagnosis and treatment challenging. The available literature shows variable rates of success with chemotherapy for systemic LCDD. Despite chemotherapeutic advances, liver failure in LCDD indicates a dismal prognosis, where further clinical trials are difficult owing to the low prevalence of the condition. In our article, we will also be reviewing previous case reports on this disease.

A rare case of monoclonal immunoglobulin deposition disease identified on renal biopsy

Monoclonal light chain immunoglobulin deposition disease (MIDD) is a rare disease disorders in which monoclonal light chains are deposited within the basement membranes of renal structures, including glomeruli, tubules and vessel walls.1 The vast majority of patients diagnosed with MIDD will have renal insufficiency (80%) and half of MIDD patients have myeloma.2 We present the case of a 52-year-old female with a subacute history of impaired renal function and recent creatinine of 220. A renal biopsy performed at Flinders Medical Centre showed 50% renal cortical scarring with prominent tubular atrophy and peritubular basement membrane thickening on light microscopy. Regions containing periglomerular eosinophilic material were seen that labelled with kappa, favouring periglomerular light chain deposition. Direct immunofluorescence revealed linear labelling with kappa along the tubular basement membranes and electron microscopy showed punctate electron-dense deposits in areas, including the glomeruli and tubular basement membranes. The combined light microscopy, immunofluorescence, and electron microscopy results confirmed the diagnosis of MIDD. A discussion of MIDD is presented.

Assessment of renal outcome following therapy in monoclonal immunoglobulin deposition disease: Emphasizing the need for a consensus approach.

Monoclonal immunoglobulin deposition disease (MIDD), often associated with plasma cell dyscrasias, predominantly affects the kidneys. In this disease, hematologic response (HR) to treatment can be reliably assessed by International Myeloma Working Group (IMWG) consensus criteria, while uniform criteria for assessing renal response are lacking. We report a retrospective analysis of renal outcomes among 34 patients with MIDD. With most patients treated with bortezomib and autologous stem cell transplantation, 26 of 28 (94%) achieved very good partial HR or better. We demonstrate that both IMWG (based on estimated glomerular filtration rate, eGFR) and amyloid (based on proteinuria) criteria are needed to capture renal response: among 28 evaluable patients, 6 (21%) had isolated proteinuria, while 13 (46%) had isolated decreased eGFR. Using both criteria, which were concordant in patients with both decreased eGFR and proteinuria, 22 of 28 patients (79%) achieved a renal response, including 2 of 7 discontinuing dialyses. All 6 patients (100%) with isolated proteinuria and 7 of 13 (54%) with isolated decreased eGFR achieved renal response, suggesting that isolated proteinuria is an early manifestation of MIDD associated with reversible renal damage. Baseline eGFR predicted renal response (p= .02 by quartile) and survival (p= .02), while HR (CR vs. non-CR) did not, probably because of high HR rate. With a median follow-up of 110 months, the median overall survival was 136 months (95% CI: 79-NR) and median renal survival had not been reached. Prospective studies using uniform renal response criteria are needed to optimize the management of MIDD.

Heavy chain deposition disease (HCDD) of the kidney in a patient of treated chronic myeloid leukemia with imatinib

Chronic myeloid leukemia is a clonal disorder of myeloid origin which transforms into more aggressive phenotypes, either acute myeloid leukemia or acute lymphoblastic leukemia. The long-term outcome of chronic myeloid leukemia has significantly improved with tyrosine kinase inhibitor imatinib. In contrast, heavy chain deposition disease is a disorder of lymphoid origin due to a plasma cell clone classified under monoclonal immunoglobulin deposition disease with truncated monoclonal heavy chain deposition along basement membranes of many organs, predominantly the kidneys causing significant organ dysfunction. The connection between the two disorders seems to be vague and undefined. We report a novel case of treated chronic myeloid leukemia with imatinib in sustained clinical and cytogenetic remission who presented with heavy chain deposition disease of the kidney, causing renal dysfunction and nephrotic range proteinuria that responded to clone-directed therapy. Given these disorders’ two different cell lines, their association could be fortuitous only. However, in the light of a few dozen cases published thus far in which the prototypical plasma cell disorders multiple myeloma and monoclonal gammopathy of undetermined significance have evolved from cases of treated CML, this association seems to be genuine, the possible genesis of which is discussed in this manuscript. Long-term exposure of chronic myeloid leukemia patients to imatinib could predispose some rare, vulnerable patients to a plasma cell disorder, including heavy chain deposition disease.

Clinicopathological Profile of Paraprotein-Associated Kidney Disease in Monoclonal Gammopathies: An Observational Study.

Background Renal involvement in monoclonal gammopathies presents with different clinico-morphological patterns and can manifestat the onset or the late phase of hematological disease, or after chemotherapy. The spectrum is ever-expanding with advancements in diagnostic methods. Renal biopsy is needed for accurate diagnosis, as each of these patterns carries therapeutic and prognostic implications. Methods A total of 41 cases of monoclonal gammopathies were included in the study. Clinical, biochemical, and hematological details were obtained, and pathological variables were observed. Patients were followed till the maximum possible period, and treatment history and follow-up creatinine details were collected. Results The spectrum of renal biopsy lesions observed included light chain cast nephropathy (LCCN) n=19, amyloidosis n=11, monoclonal immunoglobulin deposition disease (MIDD) n=6, andproliferative glomerulonephritis with monoclonal immunoglobulin deposition (PGNMID) n=5; 10 of these cases can be categorized asmonoclonal gammopathy of renal significance (MGRS). Acute kidney injury (AKI) (41%) is the predominant clinical presentation in general whereas the majority of amyloidosis cases presented with nephrotic and sub-nephrotic proteinuria. LCCN cases had high serum creatinine and calcium, positivity for M-spike, as well as a high FLC ratio, compared to the other types. Around 100% of LCCN and MIDD patients had myeloma and 100% of PGNMID cases had normal marrow. Conclusion More than three-fourths of patients were diagnosed with monoclonal gammopathies with biochemical and hematological workups after an initial kidney biopsy. The clinicopathological profile of these patients had a broad spectrum but there were still some consistent findings within the different types. A subgroup of patients(MGRS) had undetectable serum paraproteins but had monoclonal immunoglobulin deposition in the kidney.

Multiple Myeloma Presenting as Acute Kidney Failure Secondary to Lambda Light Chain Deposition

Renal monoclonal immunoglobulin deposition disease (MIDD) is a rare disease defined by deposition of monoclonal light chains and/or heavy chains on basement membranes and vascular walls of the kidney. We describe a case of a 71-year-old woman with kidney failure secondary to monoclonal immunoglobulin deposition disease lambda in association with plasma cell dyscrasia. Her initial serum protein electrophoresis did not demonstrate a monoclonal protein, and classic cast nephropathy was absent on renal biopsy. However, lambda light chain deposits and associated changes confirmed MIDD. She achieved a very good partial response (VGRP) after 8 cycles of CyBorD (cyclophosphamide, bortezomib, dexamethasone) and her kidney function improved. This case highlights the importance of an early diagnostic with renal biopsy to prevent end-stage renal disease. A review of the existing literature and a discussion on the management of the disease is presented.

A multidisciplinary case report of multiple myeloma with renal and cardiac involvement: a look beyond amyloidosis

BackgroundMultiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury.Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by light chain deposit or amyloid. Thromboembolic complications such as deep vein thrombosis or pulmonary embolism are also described.Case presentationWe present an unusual multidisciplinary case of a woman with a newly diagnosed MM associated with severe proteinuria and high natriuretic peptide. A renal and fat pad biopsy with Congo red staining were performed but amyloid deposition was not discovered. While immunofluorescence on fresh frozen unfixed tissue was not contributory, the immunofluorescence on fixed tissue and electron microscopy revealed the correct diagnosis.During subsequent investigations, two intracardiac right-sided masses and massive pulmonary embolism were also detected.ConclusionsThis case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, renal diseases induced by monoclonal gammopathies are a group of complex and heterogeneous disorders. Their subtle presentation and their potential multiorgan involvement require the expertise of a multidisciplinary team able to provide the most appropriate diagnostic and therapeutic assessment.

Outcomes in Patients with Renal Monoclonal Immunoglobulin Deposition Disease

BACKGROUND: Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the production of abnormal monoclonal immunoglobulins that deposit in the kidney and other organs. MIDD causes proteinuria, renal damage and eventually renal failure. Currently, there are few studies on the outcomes of patients (pts) with renal MIDD (R-MIDD). METHODS: We performed a single-center retrospective analysis on patients that were seen at the University of California San Francisco Hematology clinic for MIDD from 2010 to 2020. All pts must have had biopsy-proven R-MIDD. Demographic and disease-related characteristics at diagnosis were collected as well therapies administered. Diagnosis of multiple myeloma was per IMWG criteria (Rajkumar et al. Lancet Oncology 2014). Hematologic response and renal response were assessed per previously published criteria (Palladini et al. J Clin Oncol 2012; Palladini et al. Blood 2014). Overall survival (OS), time-to-next treatment (TTNT), time-to-renal progression (TTRP), time-to-dialysis (TTD) were estimated using the Kaplan-Meier method. TTRP was defined as time from the start of treatment to renal progression censored by last follow-up or date of renal transplant. TTD was defined as time from start of treatment to dialysis or last follow-up. Pts already on dialysis at diagnosis were excluded from TTRP and TTD. RESULTS: Thirty-four pts with R-MIDD were identified, 31 light chain deposition disease, 2 heavy chain deposition disease and 1 light and heavy chain deposition disease. Median age at diagnosis was 63 (IQR 58-70) with 13 (38.2%) females. Median creatinine and estimated GFR at diagnosis were 2.80 mg/dL (IQR 3.17-5.57) and 25 ml/min/1.73m2 (IQR 13-40) respectively. Median involved free light chain (FLC) was 819 mg/L (IQR 130-2870), and difference in FLC 433 mg/L (IQR 85-1022). All pts had abnormal serum free light chains and 25 (73.5%) pts had kappa R-MIDD. Median bone marrow plasma cells percentage was 19% (IQR 10-38%). The most common cytogenetic abnormality was del 13 in 6/25 pts (24.0%). A concurrent diagnosis of myeloma was presented in 10 (32.3%) pts. Pts underwent a median of 2 lines of treatment (IQR 1-2). Median follow-up was 5.95 years (range 0.27 - 22.3 years). Pts were treated at induction with the following therapies: Group 1) immunomodulatory drug (IMiD) +/- bortezomib (Bor) (8/34, 23.5%); Group 2) Bor without IMiD (24/34, 70.6%) or Group 3) other (2/34, 5.9%). Autologous stem cell transplant (ASCT) was performed in 82.4% of pts. The 3- and 6-month hematologic response of ≥VGPR was 30.4% (7/23) and 55.6% (15/27) respectively. At the 6-month, Group 1, 2 and 3 had a ≥VGPR of 14.3%, 26.3% and 100% respectively though Group 3 only had 2 pts. Of the 29 pts assessed for best renal response, 9 pts (31.0%) had a renal response. Best renal response for group 1, 2, and 3 occurred in 0%, 38.1% and 100% of pts, respectively. Median TTNT was 2.9 years. Of 34 pts, only 5 died and median overall survival was not reached (Fig.1A). Improved median OS was associated with diagnosis after 2010 v ≤2010 (p=0.1) (Fig. 1B), >60 years old at diagnosis v ≤60 (p=0.1) (Fig. 1C) and treatment with ASCT (p=0.058) (Fig. 1D), though none met statistical significance. Renal progression occurred in 63.3% pts with median TTRP of 1.8 years. Dialysis dependence occurred in 33.3% pts with median TTD not reached (Fig. 2A). TTD did not differ significantly for pts diagnosed >2010 v ≤2010 (p=0.9) (Fig. 2B), ASCT (p=0.7) (Fig. 2D) though was better for pts who were diagnosed >age 60 vs ≤60 (p=0.027) (Fig. 2C). Five pts had a renal allograft, 3 of whom received the allograft after chemotherapy initiation, with 1 graft failure. In a landmark analysis at 6 months, OS and TTRP was better in pts with ≥VGPR compared to <VGPR, though both did not meet statistical significance (p=0.3 and p=0.2, respectively) (data not shown). No significant difference between ≥VGPR compared <VGPR was observed in TTD (p=0.5) (data not shown). CONCLUSION: In this limited retrospective study, we showed that R-MIDD pts were diagnosed late in the disease when pts already developed severe CKD. R-MIDD pts frequently had a concomitant diagnosis of multiple myeloma. Despite treatment with novel agents and ASCT, only a third of pts had a renal response and a third of pts required eventual dialysis. This study highlights the need for early diagnosis of R-MIDD and better treatments for this disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Case of Monoclonal Immunoglobulin Deposition Disease – on Bortezomib regimen, A Novel strategy in Multisystemic Involvement

Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare and sporadic phenomenon often manifesting in individuals who are in their 5th – 6th decade of life. MIDD along with restrictive cardiomyopathy and Renal AL amyloidosis as in the present case is also an unaccustomed phenomenon. Often, the patient presents with unusual symptoms and is more prone to misdiagnosis. The congo red (-) deposition of the monoclonal light chain can be frequently noted in multiple organs including the heart and kidney. The light chain deposition can be either isolated lambda or gamma chain and they are classified accordingly. While serum electrophoresis at an early presentation may reveal underlying monoclonal gammopathy, the immunofluorescence and histopathological examination of renal biopsy remain the mainstay diagnostic tool. Objective: The case study was done because of its uniqueness in the usage of a novel strategy in the treatment of MIDD. Results: In the current case, a 52-year-old male presented with chest pain and NYHA grade 3 dyspnea for 8 days along with bilateral lower limb pitting oedema since 3 months. In certain prevailing situations, a patient can be misdiagnosed with ischemic heart disease or acute on chronic renal failure. However, detailed history and time-bound investigation will act as a safeguard. Conclusion: When patients have no co-morbidities and no addictions, and the patient’s investigation reveals heavy proteinuria, the rheumatological and haematological etiologies must be ruled out to establish a final diagnosis for timely treatment. As in our case, the rheumatological work-up was negative but we found an M band spike on serum electrophoresis, which expedited our search for underlying plasma-cell dyscrasia.

Clinicopathological manifestations of coexistent monoclonal immunoglobulin deposition disease and immunotactoid glomerulopathy.

Combination of monoclonal immunoglobulin deposition disease (MIDD) and immunotactoid glomerulopathy (ITG) is a rare form of monoclonal immunoglobulin (MIg)-associated renal disease. We retrospectively reviewed the native kidney biopsy specimens at Peking University People’s Hospital from 2011 to 2020. Five patients were diagnosed as MIDD + ITG. Their clinical and pathological characteristics were studied. The typical clinical features were nephritic syndrome and renal dysfunction with prominent anemia, but hematuria was mild. Unlike single MIDD and single ITG, on light microscopy, segmentally distributed mesangial nodular sclerosis on the basis of mesangial matrix hyperplasia was the major lesion. Others including membranoproliferative glomerulonephritis (MPGN)-like lesion, glomerular basement membrane thickness, and mild to moderate mesangial and endothelial proliferations might presented at the same time and in the same glomeruli. On immunofluorescence, MIg, usually monoclonal light chains, deposited along glomerular basement membranes and tubular basement membranes, while the intact MIg or monoclonal heavy chain deposited in the mesangial regions. Corresponding to the depositions on immunofluorescence, punctate “powdery” deposits along glomerular basement membranes and tubular basement membranes under electronic microscopy indicated the presence of MIDD. Microtubular substructures (diameters of 20–50 nm) exhibiting hollow cores arranged in parallel arrays in mesangial regions indicated the presence of ITG. Patients treated with bortezomib-based regimen seemed to have better outcomes. In conclusion, MIDD + ITG is a rare combination form of MIg-associated renal disease. Accurate diagnosis requires the comprehensive pathological investigations.

Histological Findings in Kidney Biopsies of Patients with Monoclonal Gammopathy-Always a Surprise.

Background: The simultaneous occurrence of impaired kidney function and paraproteinemia is common in our constantly aging society. Both can be independent entities; however, renal insufficiency can also be caused by the paraprotein. We assessed all kidney biopsies in patients with monoclonal gammopathy in our clinic over the past 20 years and evaluated the histological results. Methods: Biopsies were systematically performed in nearly all patients with paraproteinemia and impaired kidney function (n = 178). The histological findings were systematically evaluated and correlated with the initial clinical diagnosis. Results: We found cast nephropathy (CN) in n = 66 (37.1%) biopsies, AL amyloidosis in n = 31 (17.4%) biopsies, monoclonal immunoglobulin deposition disease (MIDD) in n = 7 (3.9%) biopsies and other renal diseases (ORDs) in n = 74 (41.6%) biopsies. In the latter group, paraprotein-associated changes were found in 37 of 74 (50%) patients, whereas paraprotein-independent changes were found in the other half. Whereas, in the group of patients with MGUS, the findings were heterogenous, most of the patients with known multiple myeloma (MM) or B-NHL showed malignancy-associated changes in the kidney. The biopsy changed the diagnoses in a significant proportion of the patients: The group of patients with MM grew from 71 to 112 patients, whereas, in the MGUS group, only 31 of 44 patients remained. Conclusion: Kidney biopsies in patients with paraproteinemia and renal impairment show a wide range of findings that can lead to a change in diagnosis.