Concurrent Crystalline Light-Chain Proximal Tubulopathy and Membranous Nephropathy: A Case Report and Literature Review.

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 Immunoglobulin Crystalline Nephropathies.

Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as crystalline inclusions. They can be categorized into lesions with predominant intracellular crystals (light chain [LC] proximal tubulopathy, LC crystal-storing histiocytosis, LC crystalline podocytopathy] and lesions with predominant extracellular crystals (crystalglobulin-induced nephropathy, crystalline variant of LC cast nephropathy). The majority of these lesions are associated with low tumor burden lymphoproliferative disorders, with the exception of crystalline variant of LC cast nephropathy. Extra-renal involvement (eg, skin, cornea) is frequent. Kidney biopsy is the cornerstone for diagnosis, which often requires electron microscopy and antigen retrieval. A thorough hematologic workup and evaluation of extra-renal involvement is mandatory for management. Treatment of these lesions is with clone-directed therapy, with the goal of achieving hematologic very good partial response or complete response which preserve or improve kidney function. In vitro and in vivo studies, animal models, and novel sequencing techniques have been invaluable tools to understand the pathogenesis of LC proximal tubulopathy, and can be utilized to increase our limited knowledge of the pathogenesis of the other MIg crystalline nephropathies. This review will provide an update on the pathology, renal and hematologic characteristics, extra-renal manifestations, prognosis, treatment, and pathogenesis of MIg crystalline nephropathies.

Monoclonal Gammopathy of Renal Significance (MGRS) - Case Series from a Tertiary Center in Kerala.

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.

A Unique Case of Cellulitis Secondary to Mycobacterium chelonae in a Patient With Monoclonal Gammopathy of Undetermined Significance.

We report a case of an 84-year-old patient with Monoclonal Gammopathy of Undetermined Significance (MGUS) treated with multiple courses of antibiotics and steroids before being diagnosed with Mycobacterium chelonae infection. It is known that MGUS affects both humoral and cellular immunity with impairment of antibody production, function of T-cells, natural killer (NK) cells, and dendritic cells. This case report demonstrates the need to consider patients with MGUS as immunocompromised and draws attention to the correlation between MGUS and Mycobacterium infections. The delay in diagnosis exemplifies the importance of considering atypical pathogens and involving sub-specialists early in the treatment of infections in patients with a history of MGUS.

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 case report of biclonal immunoglobulin D lambda/lambda multiple myeloma in patient with liver echinococcosis.

Less than 2% of all symptomatic multiple myeloma (MM) has immunoglobulin D (IgD) as monoclonal protein. Biclonal gammopathy is much rarer. At the time of diagnosis, disease is often in advanced stage, including renal failure, anemia, hypercalcemia and lytic bone lesions. Due to the rarity of myeloma itself, but also due to the fact that anti-IgD antisera is not used in routine practice, there are only a few reports of IgD MM described in the literature. This case report describes a patient with IgD lambda MM with anemia and renal failure. Anemia, renal failure, and > 80 percent plasma cells in bone biopsy in our patient with IgD lambda MM meets International Myeloma Working Group criteria for diagnosis of MM. The patient clinical course was similar to other patients with IgD MM. The final result of serum protein immunofixation (s-IFE) showed IgD lambda and free lambda monoclonal bands. To prevent misdiagnosis, it is necessary to use anti-IgD and anti-IgE antisera whenever the serum protein immunofixation with IgA, IgM, IgG, kappa and lambda antiserums shows a kappa or lambda monoclonal band without monoclonal band in heavy chain.

Regression of Intermediate-High Risk Monoclonal Gammopathy of Undetermined Significance (MGUS) With Long-term Use of Curcumin: A Case Report.

Patients with intermediate-high risk MGUS are not offered therapeutic options to date and standard of care remains observation with re-evaluations of the patient every 3 to 6 months. Given the persistent risk of progression as well as potential complications experienced by some, and anxiety experienced by most patients, early intervention with non-toxic curcumin, aimed at potentially slowing down or stopping disease progression might be therapeutic. We present here an intermediate-high risk MGUS patient who has been taking curcumin for 16 years and has shown a decrease in disease markers and an increase in uninvolved immunoglobulins, adding to the body of evidence of benefit of curcumin to MGUS patients.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

False positive elevation in serum creatinine: a case report.

Background: Paraproteins can interfere with several substances, producing erroneous laboratory measurements. The diagnosis of kidney disease in patients with hematological disorders has important prognosis implications. An elevated creatinine with no other signs of kidney disease should prompt the idea of a spurious creatinine. Communication between the clinical team and the laboratory is key. Case presentation: In this case, we present a 68-year-old woman with an elevated creatinine and an IgM lambda paraprotein. Interestingly, there were no other signs of chronic kidney disease besides the creatinine value, with no albuminuria or microhematuria. A kidney biopsy showed normal parenchyma and ruled out the possibility of paraprotein-related damage. The monoclonal component and creatinine levels raised parallelly during follow-up while maintaining normal urea levels. This prompted the hypothesis of a falsely elevated creatinine. It was confirmed with a normal glomerular filtration rate determined by a radioisotope, a cystatin C measurement and a reduction in creatinine when diluting the sample. Conclusion: It is important to consider the possibility of a falsely elevated creatinine in patients with paraproteinemia and no other signs of kidney disease to avoid unnecessary diagnostic tests and for the prognostic implications.

Sporadic Late-onset Nemaline Myopathy Associated with Sjögren's Syndrome: A Case Report.

We report the case of a 46-year-old female patient who developed a subacute progression of axial and proximal muscle weakness. Laboratory findings revealed mildly elevated serum creatine kinase levels. No monoclonal gammopathy was detected. A muscle biopsy revealed that she had nemaline myopathy. Serological tests and a lip biopsy revealed Sjögren's syndrome (SjS). We diagnosed her as having sporadic late-onset nemaline myopathy without monoclonal gammopathy of undetermined significance associated with SjS. Her symptoms improved after methylprednisolone pulse therapy followed by intravenous immunoglobulin therapy. A good response to immunotherapy demonstrates the necessity of making a correct diagnosis, for which a muscle biopsy is required.

Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia.

PURPOSE OF REVIEW: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM. RECENT FINDINGS: Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.

[Scleromyxedema]. / Skleromyxödem.

Scleromyxedema or generalized diffuse lichen myxoedematosus is a rare mucinosis that is associated with monoclonal gammopathy and which frequently affects multiple extracutaneous organ systems. The pathogenesis of scleromyxedema has not been fully elucidated, but includes stimulation of glycosaminoglycan synthesis. The clinical course of scleromyxedema is chronic and often progressive, leading to severe morbidity and even death. The characteristic skin findings encompass multiple waxy papules often on indurated plaques, while thickening of skin leads to conspicuous folds on glabella and dorsal aspects of finger joints. Microscopical manifestations are dermal deposits of glycosaminoglycans between collagen bundles in reticular dermis, increased numbers of fibroblasts and fibrosis as well as loss of elastic fibers. Progressive skin involvement results in decreased mobility of the mouth and joints and even contractures. Extracutaneous manifestations occur in the musculoskeletal or cardiovascular system, in the gastrointestinal or respiratory tract, in the kidneys or in the central and peripheral nervous system. There are no in-label or evidence-based treatments available for scleromyxedema, but by expert consensus high-dose immunoglobulins are considered as treatment of choice, followed in case of insufficient efficacy by systemic glucocorticosteroids and then lenalidomide or thalidomide. In severe and refractory cases, autologous hematopoietic stem cell transplantation has been performed. Long-term maintenance treatment is usually required to prevent recurrences. Close interdisciplinary follow-up is recommended.

[Clinical Significance of Serum Free Light Chain in Monoclonal Gammopathy].

OBJECTIVE: To investigate the expression and clinical significance of serum free light chain (sFLC) in patients with monoclonal gammopathy (MG). METHODS: 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. RESULTS: 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 ß2-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). CONCLUSION: 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.

A case of benign immunoglobulin D monoclonal gammopathy of undetermined significance with 26 years of follow-up.

The presence of a serum immunoglobulin D (IgD) monoclonal protein (M-protein) is seen in < 1% of patients with monoclonal gammopathies and is usually indicative of a malignant plasma cell disorder. Only a few cases of well-documented benign monoclonal gammopathy of undetermined significance (MGUS) of IgD subtype have been reported, and only 2 of those had over 5 years of follow-up at the time they were reported. Herein we describe longer-term follow-up of one of those 2 patients who has subsequently passed away from unrelated causes but never developed multiple myeloma or amyloidosis after 26 years of follow-up. Although IgD MGUS is extremely rare, this case confirms that presence of an IgD M-Protein is not always synonymous with a malignant plasma cell process.

Long Term Remission of Capillary Leak Syndrome Associated with Monoclonal Gammopathy with Progression to Multiple Myeloma After Autologous Stem Cell Transplantation: a Case Report and Review of the Literature.

BACKGROUND: Clarkson's disease is a very rare entity characterised by acute episodes of systemic oedema and severe hypotension associated with paraproteinaemia. Its classical treatment relies on methylxanthine combined with terbutaline. Although this prophylactic therapy reduces the mortality rate, relapses are frequent. Eighty percent of patients with Clarkson's disease present with monoclonal gammopathy of unknown significance (MGUS). The risk of progression to multiple myeloma is 1% per year. CASE DESCRIPTION: Here, we present a 49-year-old woman who suffered multiple such episodes requiring treatment in the intensive care unit. Treatment with terbutaline and theophylline was ineffective. She was diagnosed with multiple myeloma (MM) 8 years after the first of these acute episodes. Antimyeloma treatment with bortezomib and dexamethasone was started, followed by autologous haemopoietic transplantation, with no further acute episodes since then. CONCLUSION: Our case is, to our knowledge, unique because eradication of MM was followed by complete disappearance of acute episodes of capillary leakage. Our case report is also the first to support the use of bortezomib and dexamethasone in this setting. Furthermore, autologous peripheral blood progenitor cell transplantation consolidated the MM stringent complete remission achieving a very long progression-free survival (> 11 years) of both MM and Clarkson's disease.