Interferencia positiva de las paraproteínas en la determinación de bilirrubina total y su rol en el diagnóstico de gammapatías monoclonales / Positive interference of paraproteins in the determination of total bilirubin and its role in the diagnosis of monoclonal gammopathies / Interferência positiva de paraproteínas na determinação da bilirrubina total e seu papel no diagnóstico de gamopatias monoclonais

Resumen La interferencia por paraproteínas en los análisis clínicos ha sido extensamente informada a nivel mundial. Si bien se han propuesto estrategias metodológicas para evitar el informe de datos erróneos asociados a interferencias (p. ej. confirmación manual, sistema de alerta), en pocos casos se ha propuesto su detección como herramienta diagnóstica de patologías no sospechadas desde la clínica. A partir del trabajo conjunto de dos hospitales de la provincia de Buenos Aires se describió: i) la presencia de interferencia positiva de paraproteínas en la determinación de bilirrubina total con reactivos y autoanalizadores Wiener, y ii) su contribución, en un período inferior a los seis meses, a la detección de cuatro gammapatías no sospechadas (tres monoclonales). Se recomienda dar difusión de esta inferencia a nivel nacional y se propone un esquema de trabajo en laboratorio para identificar la interferencia así como un perfil mínimo de determinaciones para evaluar la existencia de gammapatías desconocidas.

Abstract Paraprotein interference in clinical biochemistry has been widely reported around the world. Methodological strategies have been proposed to avoid reporting erroneous data due to interferences (i.e. manual check, alert system); however, few cases have suggested its use as a diagnostic tool for unsuspected pathologies. Based on the joint work of two hospitals from Buenos Aires Province, the following has been described: i) the presence of positive interference of paraproteins in the assessment of total bilirubin with Wiener chemistry and autoanalizers, and ii) its contribution, in less than six months, to the diagnosis of four gammophaties previously unsuspected (three monoclonal ones). Sharing the occurrence of this interference in our country is recommended. An interference identification workflow is also propose, as well as a set of biochemical assays to evaluate the occurrence of unsuspected gammophaties.

Resumo A interferência da paraproteína na bioquímica clínica tem sido amplamente relatada em todo o mundo. Embora estratégias metodológicas para evitar a comunicação de dados errôneos associados a interferências tenham sido propostas (p. ex., verificação manual, sistema de alerta), em poucos casos sugerem seu uso como ferramenta diagnóstica para patologias não suspeitas a partir da clínica. Com base no trabalho conjunto de dois hospitais da Província de Buenos Aires, foi descrita: i) a presença de interferência positiva de paraproteínas na determinação da bilirrubina total com reagentes e autoanalisadores Wiener e ii) sua contribuição, em um período inferior aos seis meses, para o diagnóstico de quatro gamopatias não suspeitas (três monoclonais). Recomenda-se difundir essa interferência em nível nacional e se propõe um esquema de trabalho em laboratório para identificar a interferência bem como um perfil mínimo de determinações para avaliar a ocorrência de gamopatias desconhecidas.

Paraproteins and electrolyte assays: exclusion effect and effect of paraprotein elimination.

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.

[Monoclonal gammopathies and kidney: a diagnostic challenge without any clues].

Diagnosis of monoclonal gammopathy of renal significance (MGRS) with histopathologic features of proliferative GN with monoclonal immunoglobulin deposits (PGNMID) is a challenge for clinicians because of the absence of laboratory findings suggestive of glomerular involvement in paraproteinemia. Renal biopsy remains the gold standard for diagnosis of PGNMID because it is a monoclonal gammopathy with kidney damage often "without a detectable serum/urine clone". Through this case report, we want to focus on the complexity both in the diagnostic process and in monitoring the renal-hematological response to therapy.

Investigating the utility of saliva immunoglobulins for the detection of myeloma and using myeloma proteins to clarify partition between oral and systemic immunity.

OBJECTIVES: Myeloma is characterised by the presence of monoclonal immunoglobulin (M-protein) and the free light chain (FLC) in blood. We investigated whether these M-proteins and FLC are detectable in myeloma patients' saliva to evaluate its utility for non-invasive screening and monitoring of haematological malignancies. METHODS: A total of 57 patients with monoclonal gammopathy and 26 age-matched healthy participants provided paired serum and saliva samples for immunoglobulin characterisation and quantification. RESULTS: Myeloma patients had IgG or IgA M-protein levels ranging up to five times and FLC levels up to a thousand times normal levels of polyclonal immunoglobulins. Despite these highly elevated levels, only two IgG and no IgA M-proteins or FLC could be detected in paired saliva samples. Most patients had reduced levels of serum polyclonal immunoglobulins, but all had normal levels of salivary IgA. CONCLUSIONS: Immunoglobulin transfer from blood is not determined by levels in the systemic circulation and more likely dictated by periodontal inflammation and the integrity of the oral epithelium. Immunoglobulins secreted by bone marrow plasma cells do not substantially enter saliva, which represents a poor medium for myeloma diagnosis. These findings, along with normal salivary IgA levels despite systemic immunoparesis, support a strong partitioning of oral from systemic humoral immunity.

Kinetics of response to first- and second-line therapies in multiple myeloma: Assessment by both M-spikes and light chains.

OBJECTIVES: The prognostic value of kinetics of response to multiple myeloma (MM) therapy is controversial. We aimed to expand the knowledge on this topic by reviewing the kinetics of response to both first- and second-line MM therapy, utilizing a homogeneously treated cohort and analyzing separately both M-spike and light chain (LC) responses for each patient. METHODS: We reviewed all patients who received first-line cyclophosphamide, bortezomib and dexamethasone induction followed by autologous transplant with melphalan and lenalidomide maintenance in our center between 2007 and 2019. RESULTS: Analyzing 360 patients, we observed no correlation between response kinetics to first- versus second-line therapy at the individual patient level. Time to best response to first-line therapy was not a predictor of outcome; however, longer time to best response was highly predictive of a favorable outcome in the second-line setting, independent of other factors. Patients with IgA-MM cleared their M-spike faster than IgG-MM, probably reflecting different half-lives of these isotypes rather than disease biology, as the clearance of LC in both subtypes was similar. CONCLUSIONS: Analyzing both M-spike and LC responses in a homogenously treated cohort, we identified important insights regarding the prognostic value of kinetic patterns. Prospective analysis may shed more light on unsolved questions.

A rare case of persistent pseudohypobicarbonatemia arising from chemistry analyzer-specific interference.

BACKGROUND: Major discrepancies between concentrations of serum total carbon dioxide (tCO2) obtained from chemistry analyzers and calculated bicarbonate from blood gas analyzers should prompt laboratory investigation. Here, we present a rare case of pseudohypobicarbonatemia unrelated to the common causes such as hypertriglyceridemia and hyperproteinemia, but was caused by a low concentration of paraproteins. CASE: A 75-year-old man with persistent fevers was found to have a low concentration of serum tCO2 (<10 mmol/l) with a normal pH and calculated bicarbonate concentrations (23.5 mmol/l) from the blood gas analyzer. His serum tCO2 concentrations remained critically low throughout hospitalization without any evidence of acidosis. Serum tCO2 levels were measured via Siemens ADVIA Chemistry XPT system. RESULTS: Mixing studies revealed non-linearity of serum tCO2, suggesting the presence of interfering substances. Triglyceride concentrations were normal. Serum electrophoresis revealed a 0.4 mg/dl M-protein. The patient's serum tCO2 concentrations were repeated on different chemistry analyzer platforms - including Siemens, Roche, and Abbott - which demonstrated that the interference was specific to the Siemens chemistry analyzer. Serum tCO2 was significantly elevated after ultrafiltration of paraprotein, which confirmed the root cause of pseudohypobicarbonatemia. CONCLUSION: Laboratory professionals should be aware that spuriously low serum tCO2 concentrations may result from unique interfering substances, such as paraproteins, that are both patient- and chemistry analyzer-specific.

Calculated globulin as a screening tool for hypogammaglobulinaemia or paraproteins in hospitalized patients.

BACKGROUND: Calculated globulin fraction is derived from the liver function tests by subtracting albumin from the total protein. Since immunoglobulins comprise the largest component of the serum globulin concentration, increased or decreased calculated globulins and may identify patients with hypogammaglobulinaemia or hypergammaglobulinaemia, respectively. METHODS: A retrospective study of laboratory data over 2.5 years from inpatients at three tertiary hospitals was performed. Patients with paired calculated globulins and immunoglobulin results were identified and clinical details reviewed. The results of serum electrophoresis testing were also assessed where available. RESULTS: A total of 4035 patients had paired laboratory data available. A calculated globulin ≤20 g/L (<2nd percentile) had a low sensitivity (5.8%) but good positive predictive value (82.5%) for hypogammaglobulinaemia (IgG ≤5.7 g/L), with a positive predictive value of 37.5% for severe hypogammaglobulinaemia (IgG ≤3 g/L). Paraproteins were identified in 123/291 (42.3%) of patients with increased calculated globulins (≥42 g/L) who also had a serum electrophoresis performed. Significantly elevated calculated globulin ≥50 g/L (>4th percentile) were seen in patients with either liver disease (37%), haematological malignancy (36%), autoimmune disease (13%) or infections (9%). CONCLUSIONS: Calculated globulin is an inexpensive and easily available test that assists in the identification of hypogammaglobulinaemia or hypergammaglobulinaemia which may prompt further investigation and reduce diagnostic delays.

Falsely markedly elevated 25-hydroxyvitamin D in patients with monoclonal gammopathies.

OBJECTIVES: Monoclonal immunoglobulins can cause interference in many laboratory analyses. During a 4 month period we observed seven patients with monoclonal disease and falsely extremely elevated 25-hydroxyvitamin D (25(OH)D) results above 160 ng/mL (>400 nmol/L) measured using an immunoassay from Abbott Diagnostics. Based on these findings, we studied the occurrence of falsely elevated 25(OH)D in samples with paraproteins and investigated possible mechanisms of the observed interference. METHODS: 25(OH)D was analyzed using the Architect i2000 platform from Abbott Diagnostics and a higher order method, liquid chromatography-mass spectrometry (LC-MS/MS), in serum samples from 50 patients with known monoclonal disease. Patients with falsely elevated 25(OH)D were included in further studies to elucidate the cause of interference. Spuriously elevated results were in addition analyzed on two alternative platforms (Siemens and Roche). RESULTS: Falsely elevated 25(OH)D levels were present in eight patients on the Abbott analyzer and one on the Siemens platform. Results from Roche were comparable with LC-MS/MS. Additional investigations excluded elevated concentrations of rheumatoid factor and heterophilic antibodies as the cause of interference in the Abbott assay. CONCLUSIONS: Laboratories should be aware of the risk of falsely elevated 25(OH)D in samples run on the Architect analyzer from patients with monoclonal disease. Highly elevated vitamin D results should be diluted and if the dilution is non-linear, rerun by a different method, preferably LC-MS/MS. In patients with spuriously elevated 25(OH)D without known monoclonal disease, the laboratory should consider requesting protein electrophoresis to exclude paraprotein interference.

Paraproteínas: claridad en la nebulosa / Paraproteins: a review

Hematological neoplasms are tumors of cells in different states of maturation and differentiation. Since monoclonal gammopathies (MG) refer to B mature lymphocyte neoplasms, lymphogenesis should be well known. We must keep in mind that the last stage of maturation of these lymphocytes is the plasma cell. This is how a MG could appear in the context of a plasma cell neoplasm, such as multiple myeloma or amyloidosis, but also in relation to a lymphoma. A monoclonal peak is produced by mature B lymphocytes or plasma cells that secrete a monoclonal protein (Immunoglobulin), and represents a MG. But it must be emphasized that, in the correct clinical context, a hypogammaglobulinemia can represent a MG as well. Another important point is the understanding and interpretation of requested tests, such as protein electrophoresis (PEP), immunofixation (IFx) or serum free light chains (sFLC). The current MG screening panel includes these three studies (PEF, IFx, sFLC), although a simpler panel measuring PEF and sFLC has also been proposed, but not yet formally validated. Therefore, screening done only with PEP is insufficient.

Differential diagnosis between bone relapse of breast cancer and lambda light chain multiple myeloma: role of the clinical biochemist.

PURPOSE: The integration of expertise between oncologist and clinical biochemist for the monitoring and diagnosis of plasma cell dyscrasia is crucial. In some cases, medical laboratory scientists can provide an original contribution using the appropriate techniques to arrive at a diagnosis. METHODS: We report a case of 67-year-old woman who was admitted to our hospital for bone pain. Imaging studies showed multiple diffuse bone lytic lesions, and a laboratory screen revealed anemia and altered creatinemia; serum capillary zone electrophoresis confirmed a monoclonal peak in the γ-zone that had been known since 2011, typed as immunoglobulin G kappa by immunosubtraction electrophoresis. The patient had undergone surgery for breast cancer in 2013, and based on her clinical history, the oncologist suspected the presence of bone metastases from the breast cancer and opted for relative therapy. Immunosubtraction, however, showed a very small reduction in lambda free light chains in the beta zone, but it was difficult to establish if was a monoclonal component, and consequently additional tests were performed. DISCUSSION: A monoclonal component composed of only lambda free light chains was evidenced. This result in association with multiple diffuse bone lytic lesions observed led us to suspect multiple myeloma and not bone metastases from the breast cancer. Based on these observations, we encouraged the oncologist to conduct an osteomedullary biopsy, allowing us to make a diagnosis of low-grade stage II lambda light chain multiple myeloma. CONCLUSION: In this report, we show how the expertise of the clinical biochemist was instrumental in solving this case.

Association of Monoclonal Gammopathy with Progression to ESKD among US Veterans.

BACKGROUND AND OBJECTIVES: Whether patients with monoclonal protein are at a higher risk for progression of kidney disease is not known. The goal of this study was to measure the association of monoclonal protein with progression to ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective cohort study of 2,156,317 patients who underwent serum creatinine testing between October 1, 2000 and September 30, 2001 at a Department of Veterans Affairs medical center, among whom 21,898 had paraprotein testing within 1 year before or after cohort entry. Progression to ESKD was measured using linked data from the US Renal Data System. RESULTS: Overall, 1,741,707 cohort members had an eGFR≥60 ml/min per 1.73 m2, 283,988 had an eGFR of 45-59 ml/min per 1.73 m2, 103,123 had an eGFR of 30-44 ml/min per 1.73 m2 and 27,499 had an eGFR of 15-29 ml/min per 1.73 m2. The crude incidence of ESKD ranged from 0.7 to 80 per 1000 person-years from the highest to lowest eGFR category. Patients with low versus preserved eGFR were more likely to be tested for monoclonal protein but no more likely to have a positive test result. In adjusted analyses, a positive versus negative test result was associated with a higher risk of ESKD among patients with an eGFR≥60 ml/min per 1.73 m2 (hazard ratio, 1.67; 95% confidence interval, 1.22 to 2.29) and those with an eGFR of 15-29 ml/min per 1.73 m2 (hazard ratio, 1.38; 95% confidence interval, 1.07 to 1.77), but not among those with an eGFR of 30-59 ml/min per 1.73 m2. Progression to ESKD was attributed to a monoclonal process in 21 out of 76 versus seven out of 174 patients with monoclonal protein and preserved versus severely reduced eGFR at cohort entry. CONCLUSIONS: The detection of monoclonal protein provides little information on ESKD risk for most patients with a low eGFR. Further study is required to better understand factors contributing to a positive association of monoclonal protein with ESKD risk in patients with preserved and severely reduced levels of eGFR.

Immunochemical Diagnosis of Multiple Myeloma.

The diagnostic potentialities of complex immunochemical analysis of the serum and daily urine were evaluated in 118 patients with multiple myeloma. In 95 patients, we observed secretion of monoclonal intact immunoglobulins with heavy chains G (N=69), A (N=19), and M (N=4) and biclonal secretion of paraproteins G and A (N=3). Bence-Jones protein was detected in the sera and daily urine of 16 patients and Bence-Jones proteinuria alone was detected in 3 patients. The diagnostic sensitivity of serum immunoelectrophoresis in multiple myeloma is 94.1%. Analysis of paraproteinuria is particularly important in Bence-Jones myeloma, when paraprotein excretion may be not associated with paraproteinemia. Complex study by immunoelectrophoretic and immunoturbidimetric methods in multiple myeloma increases the diagnostic sensitivity to 99.2%.

Gamma heavy-chain disease accompanied with follicular lymphoma: a case report.

Heavy chain diseases (HCD) are B-cell lymphoprolipherative disorders characterized by the production of monoclonal heavy chains without associated light chains. Some cases of gamma-HCD (γ-HCD) are concurrent with other lymphoid neoplasm. The monoclonal component is not always detectable by serum electrophoresis, and often an immunofixation procedure is necessary to detect this component. Prognosis is variable, and no established guidelines for follow-up are available. We describe a case of a challenging diagnosis of γ-HCD due to the absence of clinical signs frequently reported in the disease (anaemia and palatal oedema among others). Haematological malignancy was the first suspicion but bone marrow examination was negative. In addition, the presence of an autoimmune bicytopenia and a Klinefelter syndrome complicated the clinical context of the patient. A thoracoabdominal computed tomography reported many small adenopathies whose pathological and immunohystochemical study revealed a follicular lymphoma. Shortly after, serum inmunofixation secondary to an abnormal electrophoretic pattern revealed a gamma paraprotein without light chains. Eventually, γ-HCD in association with follicular lymphoma was the final diagnosis. This is the first case reporting this association.

Cinderella in Serum Protein Electrophoresis.

Paraproteinemia is characterised by clonal proliferation of plasma cells. A common laboratory finding in paraproteinemia being a monoclonal peak in serum protein electrophoresis (M band). But there are factors which produce a peak similar to M spike in serum protein electrophoresis and these factors are known as pseudoparaproteins. This case report discusses a rare cause of pseudo M spike in a known case of autoimmune hemolytic anaemia due to administration of drug-Rituximab, a monoclonal antibody by itself.

Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients.

The significance of HIV associated paraproteins and their risk of progression to hematological malignancies remains unclear. We compared the development of hematological malignancies among HIV+ (n = 266) and HIV- (n = 537) patients with monoclonal gammopathies. HIV+ and HIV- patients with a positive serum protein electrophoresis test (SPEP) were studied. HIV+ SPEP+ were more likely to have faint and oligoclonal paraproteins (F-SPEP) and less likely to have discrete bands (D-SPEP) compared to HIV- SPEP+. The incidence of hematological malignancies was significantly lower in the HIV+ compared to the HIV- (6.4% vs 15.4%, p < 0.0002). Upon subgroup analysis, the lower incidence of hematological malignancies was noted for HIV+ patients with F-SPEP but not for those with D-SPEP. Copyright © 2015 John Wiley & Sons, Ltd.

Paraprotein-Related Kidney Disease: Attack of the Killer M Proteins.

Paraproteins are monoclonal Igs or their components (light or heavy chains) that are produced by a clonal population of mature B cells, most commonly plasma cells. These paraproteins or monoclonal proteins are secreted into the blood and subsequently filtered by the glomerulus before entering into urine, where they can cause various types of kidney disease, including both glomerular and tubulointerstitial injuries. Furthermore, a monoclonal protein that causes a specific glomerular or tubulointerstitial lesion in a human can reproducibly cause the same pathology when injected into an animal, supporting unique paraprotein characteristics. This Moving Points in Nephrology will provide an update for the Clinical Journal of the American Society of Nephrology readership on some of the clinically relevant kidney lesions associated with monoclonal paraprotein production and the pathophysiology underlying these kidney lesions.

Treatment of idiopathic light chain deposition disease: complete remission with bortezomib and dexamethasone / Tratamento da doença de depósito de cadeia leve idiopática: remissão completa com bortezomib e dexametasona

Abstract Light chain deposition disease (LCDD) is a rare clinical entity characterized by the deposition of light chain immunoglobulins in different tissues and primarily affects the kidneys, followed by the liver and heart. This disease often manifests as nephrotic syndrome with marked proteinuria and rapid deterioration of renal function. More than 50% of cases are secondary to multiple myeloma or other lymphoproliferative diseases, with a well-established treatment aimed at controlling the underlying disease. In rare cases, there is no detection of an associated hematological disease, referred to as idiopathic LCDD. In these cases, there is no evidence-based consensus on the therapeutic approach, and management is based on the clinical experience of reported cases. Here we report a case of idiopathic LCDD treated with bortezomib and dexamethasone with complete hematologic responses, significant reduction of proteinuria, and improved renal function.

Resumo A doença de deposição de cadeia leve (DDCL) é uma entidade clínica rara caracterizada pela deposição de cadeias leves das imunoglobulinas em diferentes tecidos e afeta principalmente os rins, seguido pelo fígado e coração. Manifesta-se frequentemente como síndrome nefrótica com proteinúria marcante e rápida deterioração da função renal. Mais de 50% dos casos são secundários ao mieloma múltiplo ou outras doenças linfoproliferativas, tendo seu tratamento bem estabelecido, voltado para o controle da doença de base. Em casos raros, não há detecção de uma doença hematológica associada, sendo referida como DDCL idiopática. Nestes casos, não há um consenso baseado em evidências sobre a abordagem terapêutica, tendo sua conduta baseada na experiência clínica dos casos relatados. Aqui, nós relatamos um caso de DDCL idiopática tratado com bortezomib e dexametasona atingindo resposta hematológica completa, redução significativa da proteinúria e recuperação da função renal.

Paraprotein-Related Kidney Disease: Diagnosing and Treating Monoclonal Gammopathy of Renal Significance.

Paraprotein-related kidney disease represents a complex group of diseases caused by an abnormal paraprotein secreted by a clone of B cells. The disease manifestations range from tubulopathies, such as the Fanconi syndrome, to a spectrum of glomerular diseases that can present with varying degrees of proteinuria and renal dysfunction. Diagnosis of these diseases can be challenging because of the wide range of manifestations as well as the relatively common finding of a serum paraprotein, especially in elderly patients. Thus, renal biopsy along with detailed hematologic workup is essential to link the presence of the paraprotein to the associated renal disease. Recent advances in treatment with more effective and targeted chemotherapies, as well as stem cell transplantation, have improved the renal and overall prognosis for many of these disorders.

Paraprotein-Related Kidney Disease: Glomerular Diseases Associated with Paraproteinemias.

Paraproteins are monoclonal Igs that accumulate in blood as a result of abnormal excess production. These circulating proteins cause a diversity of kidney disorders that are increasingly being comanaged by nephrologists. In this review, we discuss paraprotein-related diseases that affect the glomerulus. We provide a broad overview of diseases characterized by nonorganized deposits, such as monoclonal Ig deposition disease (MIDD), proliferative GN with monoclonal Ig deposits (PGNMID), and C3 glomerulopathy, as well as those characterized by organized deposits, such as amyloidosis, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemic GN, and rarer disorders, such as monoclonal crystalline glomerulopathies, paraprotein-related thrombotic microangiopathies, and membranous-like glomerulopathy with masked IgGκ deposits. This review will provide the nephrologist with an up to date understanding of these entities and highlight the areas of deficit in evidence and future lines of research.

Paraprotein-Related Kidney Disease: Kidney Injury from Paraproteins-What Determines the Site of Injury?

Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.