Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by monoclonal paraprotein production, with IgM and non-IgM variants. While IgM MGUS is often associated with lymphoid neoplasms, non-IgM MGUS can progress to multiple myeloma. Comorbidities include bone mineral density loss and renal complications, such as monoclonal gammopathy of renal significance (MGRS) and peripheral neuropathy. Cardiovascular risks are also elevated. Despite its significance, MGUS often goes undiagnosed due to its asymptomatic nature and overlap with age-related comorbidities. We present a case of IgM MGRS manifesting as rapidly progressive glomerulonephritis, highlighting the diagnostic challenges and clinical implications of MGUS-associated complications.

Light-chain proximal tubulopathy (LCPT) is typically characterized by the intracytoplasmic deposition of light chains within the proximal tubular epithelial cells, which is usually classified into crystalline and noncrystalline subgroups. Membranous nephropathy (MN) is a common glomerular disease characterized by diffused subepithelial electron-dense deposits along the capillary loop accompanied by the effacement and microvillus transformation of the foot process. Here, we report a biopsy-confirmed case of a concurrence of LCPT with crystals (κ light chains restricted) and antigen-undetermined MN in a male patient. The patient presented with low-molecular-weight proteinuria, increased serum creatinine levels, and incomplete Fanconi syndrome. To our knowledge, this is the first report of a concurrence of LCPT and independent MN of unknown target antigens, which may enrich our recognition of monoclonal gammopathy of renal significance with synchronous MN.

Monoclonal gammopathy of renal significance (MGRS) has gained importance because identifying the monoclonal deposit and addressing it, rather than treating renal dysfunction as the primary pathology, has salvaged the patients from progressing into end-stage renal disease. Since it affects elderly population, there could be a propensity to misdiagnose them with cardiorenal syndrome. We present four patients of MGRS diagnosed from our center. They presented with proteinuria or unexplained renal dysfunction. Three of the patients were diagnosed to have amyloidosis, of which two had lambda-type and one had kappa amyloidosis. The fourth patient had fibrillary glomerulonephritis with kappa restriction, further evaluation of which led to diagnosis of chronic lymphocytic leukemia. Absence of \"M\" band in protein electrophoresis and a normal bone marrow study should not stop physicians from further evaluation. Quantitative serum immunofixation electrophoresis and electron microscopic examination of renal biopsy have become a comprehensive diagnostic tool in such patients.

This case report represents the first suspected case of light chain deposition disease relapse associated with mRNA COVID-19 vaccination. The 75-year-old female patient of Greek ethnicity was admitted to the clinic for the investigation of worsening renal function detected on routine lab examinations, two weeks after she received the second dose of the Moderna COVID-19 vaccine (mRNA-1273). Rapidly progressive glomerulonephritis and anemia were the most notable findings. She had a history of LCDD, which had remained stable for four years. Serum protein immunofixation showed monoclonal kappa zones, and a bone marrow biopsy revealed 5% plasma cell infiltration. These, along with other investigations, established the diagnosis of LCDD recurrence. The patient was started on chemotherapy, which improved her immunological profile, but not her renal function. The patient has remained on hemodialysis since. The association between mRNA vaccinations and LCDD relapse may be grounds for investigations into the pathophysiology of MGRS, given the patient\'s previous long-term remission. This case report is not intended to directly inform changes in clinical practice. We must stress the importance of following all standardized vaccination protocols, especially in immunocompromised patients.

Proliferative glomerulonephritis with monoclonal immunoglobulin (mIg) deposits (PGNMID) is a rare glomerular disease characterized by glomerular deposits of mIg. The pathogenesis of PGNMID without circulating mIg is poorly understood but a role for aberrant immune response to infection or another exogenous stimulus has been proposed. We describe a unique case of PGNMID that presented with multiple episodes of acute kidney injury, nephritic syndrome, and hypocomplementemia, associated with self-limited febrile illnesses or COVID-19 vaccination. Monoclonal IgG lambda was detected in the serum and urine, consistent with monoclonal gammopathy of renal significance (MGRS). Consecutive kidney biopsies demonstrated evolving morphologic and immunohistologic features, with monotypic IgG lambda deposits identified only in the third biopsy. Despite the need for dialysis, renal dysfunction and hypocomplementemia resolved after each episode with corticosteroid therapy. This case illustrates infections or COVID vaccination maybe \"second hits\" that promote mIg deposition in PGNMID, possibly due to cytokine release by innate immune cells that promote endothelial cell injury.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease featured by the randomly arranged 12- to 24-nm fibrils under electron microscopy (EM). Up to 10% of FGN patients have monoclonal gammopathy. However, distinguishing between FGN as monoclonal gammopathy of renal significance (MGRS) and FGN from other causes with incidental monoclonal gammopathy of undetermined significance (MGUS) can be challenging, as the current way of demonstrating monoclonality is flawed due to (1) the suboptimal sensitivity of kappa staining by immunofluorescence in frozen tissue (IF-F) as compared to pronase-digested paraffin sections (IF-P), causing incorrect labeling of light chain restriction; (2) the unavailability of immunoglobulin G (IgG) subtyping in some centers; and (3) the unavailability of tests demonstrating the monoclonality of highly variable VH or VL domains in immunoglobulin structures in clinical use. The discovery of DnaJ homolog subfamily B member 9 (DNAJB9) allows diagnosis for FGN with less reliance on EM, and the summary of recent studies revealed that genuine MGRS is extremely rare among FGN. Further research integrating IF-P, IgG subtyping, VH or VL domain monoclonality confirmation, and DNAJB9 as diagnostic modalities, with corresponding clinical data including treatment response and prognosis, is required for a better understanding of this subject.

Data on kidney transplantation outcomes among patients with monoclonal gammopathy of renal significance (MGRS) are lacking.
Case series of patients with MGRS, some of whom received clone-directed therapies before kidney transplantation.
28 patients who underwent kidney transplantation from 1987 through 2016 after diagnosis with MGRS-associated lesions including light-chain deposition disease (LCDD), C3 glomerulopathy with monoclonal gammopathy (C3G-MG), and light-chain proximal tubulopathy (LCPT).
Of the 19 patients with LCDD, 10 were treated before kidney transplantation and 9 were treatment-naive. Among the treated patients with LCDD, 3 (30%) experienced histologic recurrence, 2 (20%) grafts failed, and 2 (20%) died during a median follow-up of 70 (range, 3-162) months after transplant. In the treatment-naive LCDD group, 8 (89%) had histologic recurrence, 6 (67%) grafts failed, and 4 (44%) patients died during a median follow-up of 60 (range, 35-117) months. Of the 5 patients who had a complete response before transplant, none died, and only 1 experienced graft failure, 162 months after transplant. Of 5 patients with C3G-MG, 3 were treatment-naive before transplant. Both patients who were treated before transplant had histologic recurrence, and 1 experienced graft failure and died. Among the 3 patients with treatment-naive C3G-MG, histologic recurrence occurred in all, and graft loss and death were observed in 2 and 1, respectively. In the LCPT group (n=4), histologic recurrence was observed in all 3 patients who did not receive clone-directed therapies before transplant, and 2 of these patients died, 1 with a functioning kidney. The 1 patient with LCPT who received therapy before transplant did not have histologic recurrence or graft loss and survived.
Small sample size, nonstandardized clinical management, retrospective design.
Recurrence is very common in all MGRS-associated lesions after kidney transplant. Achieving a complete hematologic response may reduce the risks of recurrence, graft loss, and death. More studies are needed to determine the effects of hematologic response on outcomes for each MGRS-associated lesion.

We report a case of membranous nephropathy with monoclonal immunoglobulin (Ig)M lambda deposits in a patient with IgM monoclonal gammopathy, in whom histological changes were observed on repeat renal biopsy. A 72-year-old Japanese woman was referred to our hospital because of massive proteinuria. A prominent increase in monoclonal IgM lambda level was identified, and she was diagnosed as having IgM monoclonal gammopathy of undetermined significance. Renal biopsy showed glomerular subepithelial electron-dense deposits that were found to be granular deposits of IgM lambda but not kappa or IgG by immunofluorescence staining, resulting in a diagnosis of membranous nephropathy with monoclonal IgM deposits. The second biopsy, which was performed 2 years later because of exacerbation of her nephrotic syndrome, demonstrated less immunofluorescence staining of IgM, and dominant IgG2 deposition without light chain restriction. Interestingly, immunostaining for thrombospondin-type-1-domain-containing-7A was positive in both renal biopsy tissues, although the second biopsy showed clearly stronger immunoreactivity. The effect of steroid therapy was limited; however, rituximab treatment improved both the hematological and renal abnormalities. Solitary deposition of IgM in membranous nephropathy is a quite rare condition. To our knowledge, this is the first case of monoclonal gammopathy of renal significance presenting as membranous nephropathy with monoclonal IgM deposits, in which chronological immunohistochemical changes were observed and rituximab therapy was effective.

There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.

Monoclonal Gammopathy of Renal Significance (MGRS) is a group of heterogeneous disorders characterized by renal dysfunction secondary to the production of a monoclonal immunoglobulin by a nonmalignant B cell or plasma cell clone. We report the clinical and histological outcomes of two patients with biopsy-proven MGRS: one patient showed membranoproliferative glomerulonephritis with monoclonal k-light chain and C3 deposits, the second patient showed immunotactoid glomerulopathy. Both patients were treated with a 9-month chemotherapy protocol including bortezomib, cyclophosphamide, and dexamethasone. Renal biospy was repeated after 1 year. The estimated glomerular filtration rate (eGFR) increased from 22.5 (baseline) to 40 ml/min per 1.73 m2 after 12 months, then to 51.5 ml/min per 1.73 m2 after 24 months; proteinuria decreased from 4.85 (baseline) to 0.17 g/day after 12 months, then to 0.14 g/day after 24 months. Repeat renal biopsies showed a dramatic improvement of the glomerular proliferative lesions and near complete disappearance of the immune deposits. A bortezomib-based treatment proved very effective and was well-tolerated in the two patients presenting with clinically and histologically aggressive MGRS.