RESUMO
Paraproteinemias are a group of complex diseases associated with an overproduction of a monoclonal immunoglobulin that can cause a diversity of kidney disorders and end-organ damage. In this review, we focus on paraprotein-mediated glomerular diseases. Kidney biopsy plays a crucial role in diagnosing these disorders, enabling the identification of specific histological patterns. These lesions are categorized into organized (such as amyloidosis, immunotactoid glomerulopathy, fibrillary glomerulonephritis, cryoglobulinemic glomerulonephritis, and monoclonal crystalline glomerulopathies) and nonorganized deposits (such as monoclonal Ig deposition disease and proliferative glomerulonephritis with monoclonal Ig deposits) based on the characteristics of immunofluorescence findings and the ultrastructural appearance of deposits on electron microscopy. This review aims to provide an update, highlight, and discuss clinicopathological aspects such as definition, epidemiology, clinical manifestations, mechanisms of kidney injury, histological features, and diagnostic procedures.
Assuntos
Glomerulonefrite , Glomérulos Renais , Paraproteinemias , Humanos , Paraproteinemias/patologia , Paraproteinemias/diagnóstico , Paraproteinemias/metabolismo , Glomerulonefrite/patologia , Glomerulonefrite/metabolismo , Glomerulonefrite/diagnóstico , Glomérulos Renais/patologia , Glomérulos Renais/metabolismo , Paraproteínas/metabolismo , Nefropatias/patologia , Nefropatias/metabolismo , Biópsia , Amiloidose/patologia , Amiloidose/metabolismo , Amiloidose/diagnósticoRESUMO
We report a man in his 70s who presented with discrepant serum creatinine concentrations in different hospitals at the same time. Further examinations of these discrepancies revealed turbidity of the serum sample and, thus, a reagent reaction and false hypercreatinine caused by paraprotein interference were suspected. Serum protein electrophoresis revealed a small amount of monoclonal γ globulin (2.9 g/L), which may have been involved in paraprotein interference. Monoclonal λ-type IgG was detected in the serum, resulting in a diagnosis of monoclonal gammopathy of undetermined significance. Previous studies indicated paraprotein interference in serum containing monoclonal IgM or a large amount of IgG (> 25 g/L). Although this case of paraprotein interference induced by a small amount of IgG is rare, a discrepancy in creatinine results may be an indicator leading to the diagnosis of plasma cell proliferative diseases.
Assuntos
Creatinina , Gamopatia Monoclonal de Significância Indeterminada , Paraproteínas , Humanos , Masculino , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/sangue , Creatinina/sangue , Paraproteínas/análise , Idoso , Imunoglobulina G/sangue , Eletroforese das Proteínas SanguíneasRESUMO
BACKGROUND: Serum Protein Electrophoresis (SPE) is crucial for the diagnosis and follow-up of monoclonal gammopathy (MG), as it helps to separate and identify these paraproteins. Currently, Pakistan lacks standardized guidelines for SPE reporting and analytical performance. This survey aims to analyze reporting variations from Consultant Chemical Pathologists in Pakistani laboratories. METHODS: This cross-sectional survey was conducted by the section of Chemical Pathology, Department of Pathology and Laboratory Medicine, at Aga Khan University Hospital, Karachi. A previously validated and published tool was used with some modifications to assess analytical techniques, reporting patterns, and interpretations provided with SPE by different laboratories. Frequency and percentages were calculated for each response and descriptive results were also evaluated. Differences between laboratories were also assessed qualitatively. RESULTS: Out of the eight laboratories contacted, seven participated in the survey, yielding a response rate of 87.5%. Immunofixation Electrophoresis (IFE) was used by all labs for serum immunotyping. All labs reported a new small abnormal band in patients with no known monoclonal gammopathy or with a known M-protein. Variations were found in terminologies used to label paraprotein, terminologies used to report normal and pathological SPE patterns, electrophoretic technique, methods for quantifying paraprotein in the gamma region on SPE and for albumin quantification. Similarly, the number of decimal places reported, reporting of multiple monoclonal proteins and small paraprotein in the beta region or monoclonal proteins less than 1 g/L, approach for screening, number of fractions reported in gamma region and reporting of interferences were also not standardized and var-iations were noticed. CONCLUSIONS: Our survey highlighted variations in practices of SPE reporting. These differences in laboratory practices could result in inconsistent test results, which could adversely affect patient care.
Assuntos
Paraproteinemias , Humanos , Paquistão , Estudos Transversais , Eletroforese , Paraproteinemias/diagnóstico , Paraproteínas/análise , Paraproteínas/metabolismoRESUMO
Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.
Assuntos
Crioglobulinemia , Linfoma de Células B , Gamopatia Monoclonal de Significância Indeterminada , Macroglobulinemia de Waldenstrom , Humanos , Crioglobulinas , Crioglobulinemia/etiologia , Macroglobulinemia de Waldenstrom/patologia , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Imunoglobulina M , Anticorpos Monoclonais , ParaproteínasRESUMO
BACKGROUND: Mass spectrometry-based techniques are increasingly reported in the literature for identifying paraproteins due to their improved specificity and sensitivity. The present study demonstrates the capability of ultra performance liquid chromatography (UPLC) electrospray ionization triple quadrupole mass spectrometry for the qualitative analysis of paraproteins. METHODS: Paraproteins from patient serum (n = 40) were immunopurified using agarose beads coated with camelid antibodies that are specific for various subtypes of immunoglobulins (Igs; G, A, M, and light chains κ, λ). The extracted Igs are reduced to separate light chains from heavy chains in solution. The reduced sample was subjected to UPLC and mass measured using electrospray ionization-mass spectrometry. The mass spectral peaks at specific retention times were deconvoluted after clean-up to obtain the mass of light chains. The interpretation of liquid chromatography peaks and LC-MS data was validated by comparing them with immunofixation electrophoresis (IFE) results. RESULTS: The interpretation from the chromatographic pattern had a 92.5% (37/40) agreement when compared with mass information. The correlation of mass spectrometry data to IFE was 90% (36/40). The high mass of light chains (>25â kDa) was suggestive of glycosylation. Patient sera positive for IgGκ on IFE (n = 15) were analyzed for the interference of tAbs. The mass of Daratumumab observed in a sample was confirmed by the treating physician. A biclonal of same isotype (IgGκ) was identified. CONCLUSIONS: The feasibility of using liquid chromatography triple quadrupole mass spectrometry for the identification of the subtype of paraproteins has been demonstrated. The method's applicability to screen for interference from tAbs and identification of biclonals of the same isotype has been highlighted.
Assuntos
Espectrometria de Massa com Cromatografia Líquida , Paraproteínas , Humanos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Cromatografia LíquidaRESUMO
Subsets of patients diagnosed with a monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or multiple myeloma (MM), present with a monoclonal immunoglobulin (Ig) specific for an infectious pathogen, including hepatitis C and B viruses (HCV, HBV), Helicobacter pylori and several Herpesviruses. Such cases are likely initiated by infection, since in the context of HCV- or HBV-infected patients, antiviral therapy can lead to the disappearance of antigenic stimulation, control of clonal plasma cells, and reduced or suppressed monoclonal Ig production. Complete remission has been obtained with anti-HCV therapy in refractory MM with a HCV-specific monoclonal Ig, and antiviral treatments significantly improved the probability of survival of MM patients infected with HCV or HBV prior to the diagnosis of MM. Monoclonal Igs may also target glucolipids, particularly glucosylsphingosine (GlcSph), and GlcSph-reducing therapy can lead to complete remission in SMM and MM patients presenting with a GlcSph-specific monoclonal Ig. The present review describes the importance of determining the target of the monoclonal Ig of MGUS, SMM and MM patients, and discusses the efficacy of target-reducing treatments in the management of MGUS, SMM and MM cases who present with a monoclonal Ig reactive against a treatable infectious pathogen or GlcSph.
Assuntos
Hepatite C , Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Mieloma Múltiplo Latente , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/terapia , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Paraproteínas , Anticorpos Monoclonais/uso terapêuticoRESUMO
INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Assuntos
Nefropatias , Mieloma Múltiplo , Paraproteinemias , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imunoglobulinas , Rim/patologia , Nefropatias/patologia , Mieloma Múltiplo/complicações , Paraproteinemias/complicações , Paraproteinemias/epidemiologia , Paraproteínas , Estudos RetrospectivosRESUMO
In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60â min (glucose 216â mg/dL) and hypoglycaemia at 300â min (52â mg/dL) concurrent with an apparent plasma insulin concentration of 52 850â pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 × 10-6â mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.
Assuntos
Doenças do Sistema Endócrino , Hipoglicemia , Gamopatia Monoclonal de Significância Indeterminada , Mieloma Múltiplo , Paraproteinemias , Masculino , Humanos , Idoso , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/terapia , Paraproteinemias/complicações , Paraproteinemias/terapia , Paraproteínas , Doenças do Sistema Endócrino/complicações , Insulina , Hipoglicemia/tratamento farmacológico , Hipoglicemia/complicações , Glucose , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnósticoRESUMO
BACKGROUND: To explore the reason and treating method for the negative value of uric acid in a patient patient. METHODS: The serum of a patient with a negative uric acid detection value was diluted 5 times with "sterilized water" and with "normal saline". Additionally, the serum was treated with PEG6000 protein, and uric acid was detected. RESULTS: Elevated IgM paraprotein in the patient resulted in abnormal uric acid response curves in serum samples or diluted serum samples. After the serum was precipitated with PEG600, the uric acid response curve was basically normal. CONCLUSIONS: The negative value of the patient's uric acid test was caused by the IgM paraprotein. After removing the interference by PEG6000 protein a true and accurate uric acid result was obtained.
Assuntos
Paraproteínas , Ácido Úrico , Humanos , Imunoglobulina MRESUMO
Genogroup II (GII) noroviruses are a major cause of diarrheal disease burden in children in both high- and low-income countries. GII.17 noroviruses are composed of distinct genetic clusters (I, II, IIIa, and IIIb) and have shown potential for replacing historically more prevalent GII.4 strains, but the serological basis for GII.17 antigenic diversity has not been studied in children. Utilizing samples from a birth cohort, we investigated antibody and B-cell responses to GII.17 cluster variants in confirmed GII.17 infections in young children as well as demonstrated that the distinct genetic clusters co-circulate. Polyclonal serum antibodies bound multiple clusters but showed cluster-specific blockade activity in a surrogate virus neutralization assay. Antibodies secreted by immortalized memory B cells (MBCs) from an infant GII.17 case were highly specific to GII.17 and exhibited blockade activity against this genotype. We isolated an MBC-derived GII.17-specific Immunoglobulin A (IgA) monoclonal antibody called NVA.1 that potently and selectively blocked GII.17 cluster IIIb and recognized an epitope targeted in serum from cluster IIIb-infected children. These data indicate that multiple antigenically distinct GII.17 variants co-circulate in young children, suggesting retention of cluster diversity alongside potential for immune escape given the existence of antibody-defined cluster-specific epitopes elicited during infection.
Assuntos
Linfócitos B , Norovirus , Criança , Lactente , Humanos , Pré-Escolar , Anticorpos Monoclonais , Células B de Memória , Imunoglobulina A , Paraproteínas , Epitopos , Genótipo , Norovirus/genéticaRESUMO
An 81-year-old man was admitted to hospital with symptomatic coronavirus disease (COVID-19) infection. He had a background of progressive chronic inflammatory demyelinating polyneuropathy associated with Waldenstrom's macroglobulinaemia. His plasma creatinine on four separate samples was inconceivably low (all ≤13 µmol/L), as measured by a Beckman Coulter enzymatic assay) after being 72 µmol/L 3 months earlier. On further investigation, his serum immunoglobulin M (IgM) was 15.4 g/L and his plasma creatinine measured by Roche enzymatic and Roche Jaffe methods was 62 µmol/L and 64 µmol/L, respectively. This was consistent with results post dilution studies and polyethylene glycol (PEG) precipitation on the Beckman Coulter assay. There was no evidence of similar interference when reviewing creatinine results from 10 other patients with IgM paraproteinaemia who had been tested in our laboratory. Clinicians and laboratorians are reminded that enzymatic creatinine is not free from interferences. IgM paraprotein negative interference of enzymatic creatinine is rare and specific to a patient's IgM and assay combination, but should be considered in patients with an unexplained low enzymatic creatinine result. Useful investigations to identify an interference include dilution studies, PEG precipitation and measuring creatinine on an alternative method such as Jaffe, mass spectrometry or an enzymatic method from a different platform.
Assuntos
Paraproteínas , Masculino , Humanos , Idoso de 80 Anos ou mais , Imunoglobulina M , Creatinina , Testes de Função Renal , Espectrometria de MassasRESUMO
Background: Human Immunoglobulin E monoclonal antibodies (hIgE mAb) are unique tools for investigating IgE responses. Here, the biological activity of hIgE mAb, derived from immortalized B cells harvested from the blood of allergic donors, targeting three allergens (Der p 2, Fel d 1 and Ara h 2) was investigated. Methods: Three Der p 2-, three Fel d 1- and five Ara h 2-specific hIgE mAb produced by human B cell hybridomas, were combined in pairs and used to passively sensitize humanized rat basophilic leukemia cells and compared with sensitization using serum pools. Sensitized cells were stimulated with corresponding allergens (recombinant or purified), allergen extracts or structural homologs, having 40-88% sequence similarity, and compared for mediator (ß-hexosaminidase) release. Results: One, two and eight pairs of Der p 2-, Fel d 1- and Ara h 2-specific hIgE mAb, respectively, produced significant mediator release (>50%). A minimum hIgE mAb concentration of 15-30 kU/L and a minimum antigen concentration between 0.01-0.1 µg/mL were sufficient to induce a pronounced mediator release. Individual sensitization with one Ara h 2-specific hIgE mAb was able to induce crosslinking independently of a second specific hIgE mAb. Der p 2- and Ara h 2-specific mAb showed a high allergen specificity when compared to homologs. Mediator release from cells sensitized with hIgE mAb was comparable to serum sensitization. Conclusion: The biological activity of hIgE mAb reported here provides the foundation for novel methods of standardization and quality control of allergen products and for mechanistic studies of IgE-mediated allergic diseases, using hIgE mAb.
Assuntos
Basófilos , Imunoglobulina E , Animais , Humanos , Ratos , Alérgenos , Anticorpos Monoclonais , ParaproteínasRESUMO
Paraproteins are a potential source of error for electrolyte analyses. The exclusion effect itself causes a discrepancy between direct and indirect ion selective electrode assays (dISE and iISE, respectively). We tested the applicability of different pretreatment methods and the difference of dISE and iISE with paraprotein-rich samples. We analysed chloride (Cl-), potassium (K+), and sodium (Na+) on 46 samples with paraproteins up to 73 g/L. We compared pretreatment methods of preheating, precipitation, and filtration to the native sample. All induced a statistically significant difference (p-value <0.05). Clinically significant difference was induced by precipitation for all analytes, and filtration for Cl- and Na+, but for none by preheating. The difference in electrolyte measurements with either dISE or iISE on native samples was explained by total protein concentration (TP). There was a statistically significant difference in all electrolyte measurements. On average, there was a clinically significant difference in Na + but not in Cl- and K + measurements. Paraprotein concentration (PP) or heavy chain class did not induce a statistically significant effect. The regression analysis and comparison to the theoretical exclusion effect supported the conclusion that TP is the only explanatory factor in the difference between dISE and iISE. We conclude that preheating is a suitable pretreatment method for all the studied analytes. Precipitation is not valid for any of them, and filtration can be considered only for K+. Because the difference between dISE and iISE was explained by the exclusion effect caused by TP, dISE is the more suitable method to analyse paraprotein-rich samples.
Assuntos
Eletrólitos , Paraproteínas , Humanos , Paraproteínas/análise , Sódio , PotássioRESUMO
Membranoproliferative glomerulonephritis (MPGN) is subdivided into immune-complex-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G). Classically, MPGN has a membranoproliferative-type pattern, but other morphologies have also been described depending on the time course and phase of the disease. Our aim was to explore whether the two diseases are truly different, or merely represent the same disease process. All 60 eligible adult MPGN patients diagnosed between 2006 and 2017 in the Helsinki University Hospital district, Finland, were reviewed retrospectively and asked for a follow-up outpatient visit for extensive laboratory analyses. Thirty-seven (62%) had IC-MPGN and 23 (38%) C3G (including one patient with dense deposit disease, DDD). EGFR was below normal (≤60 mL/min/1.73 m2) in 67% of the entire study population, 58% had nephrotic range proteinuria, and a significant proportion had paraproteins in their serum or urine. A classical MPGN-type pattern was seen in only 34% of the whole study population and histological features were similarly distributed. Treatments at baseline or during follow-up did not differ between the groups, nor were there significant differences observed in complement activity or component levels at the follow-up visit. The risk of end-stage kidney disease and survival probability were similar in the groups. IC-MPGN and C3G have surprisingly similar characteristics, kidney and overall survival, which suggests that the current subdivision of MPGN does not add substantial clinical value to the assessment of renal prognosis. The high proportion of paraproteins in patient sera or in urine suggests their involvement in disease development.