Lambda Free Light Chains Research Articles

Detection of monoclonal free light chains by immunofixation electrophoresis and isoelectric focusing – comparison with the quantitative method of determination

The study aimed to investigate free light chain (FLC) monoclonality in patients with an abnormal free kappa/lambda ratio (FLC ratio). Seventy serum samples with abnormal FLC ratio were examined using an immunoturbidimetry (Binding Site, SPA) and the two different enzyme-linked immunosorbent assays (1. Sebia diagnostic kit; 2. in house methods), the monoclonal or oligoclonal bands of (FLC) by immunofixation electrophoresis (IE) and isoelectric focusing followed by affinity immunoblotting (IEF/AIB). The reference interval was calculated by non-parametric percentile method. 5.7% of samples examined by IE were suspected of monoclonal character of FLCs, but subsequently monoclonality was refuted by more sensitive IEF/AIB method; 7%, resp. 2.9% of samples showed FLC kappa, resp. FLC lambda oligoclonal character of bands. A statistically significant dependence was found between FLC ratio (Sebia) and FLC ratio (SPA), rs = 0.510, p = .001. Kappa statistic evaluated a fair conformity between the FLC ratio (Sebia) and IEF/AIB (kappa = 0.468) and between FLC ratio (in house) and IEF/AIB (kappa = 0.300). The verified reference interval for FLC ratio (Binding Site) is between 0.35 and 2.18. The IEF/AIB is the most sensitive method to discriminate between monoclonal and oligoclonal bands of FLC. The Binding Site and Sebia diagnostic kits do not give consistent results. The Binding Site diagnostic kit provides more results above reference interval of FLC ratios. For routine decision on monoclonality of the FLC ratio (SPA) it is advisable to use a verified reference interval.

Free light chain UV quantification compared with immunochemical measurement: How dimers and monomers may influence the results

Serum κ and λ free light chain (FLC) levels are important for the management of plasma cell disorders. Immunochemical measurements on automated platforms with different reagents occasionally return different results that make them not interchangeable. The reasons for this behaviour are not clear and it is not known which result is the most accurate. The aim of the study is to quantify naturally occurring FLCs with a reference method (UV absorbance) in a sample devoid of other sources of UV absorbance. This was possible on a particular urine sample containing only lambda FLC proteins, dialyzed to clear it from low molecular weight UV absorbing compounds. The sample was submitted to Fast Protein Liquid Chromatography separation with a size-exclusion column in order to separate the FLC monomers and dimers. FLCs were also measured with the Freelite and N Latex FLC methods and the results were compared. The results demonstrated that the amount of FLC calculated on the basis of UV absorbance was overestimated by both immunochemical methods, and that the amount measured by the two reagents was affected by the different proportions of dimers or monomers. The present findings may be useful for the comprehension of the immunochemical measurement of FLC.

Comparison of Circulating Levels of Uremic Toxins in Hemodialysis Patients Treated with Medium Cut-Off Membranes and High-Flux Membranes: Theranova in Sisli Hamidiye Etfal (THE SHE) Randomized Control Study

Introduction: Removal of uremic toxins is a main objective of hemodialysis; however, whether high-flux and medium cut-off (MCO) membranes differ as regards removal of middle and large uremic toxins is not clear. Objective: To compare medium cut-off and high-flux dialyzers as regards their intra- and interdialysis effect on circulating levels of middle and large uremic toxins and serum albumin. Methods: Fifty-two patients were randomized to have hemodialysis with either 3 months of high-flux dialyzer followed by 3 months of MCO or vice versa. Blood samples were taken before and after dialysis at the first and last sessions of each dialyzer for analyses of middle and large uremic toxins including inflammatory mediators and vascular endothelial growth factor (VEGF), and serum albumin. Results: Reduction rates were higher, and postdialysis levels of β-2 microglobulin, free kappa and lambda light chains, and myoglobulin were lower at the first and last sessions with MCO dialyzers compared to high-flux dialyzers (p < 0.05 for all). Last session predialysis levels of β-2 microglobulin, free kappa light chain, and free lambda light chain were lower than first session predialysis levels in MCO dialyzers as compared to high-flux dialyzers (p < 0.05 for all). Last session levels of interleukin-6, interleukin-10, interleukin-17, and interferon-gamma did not differ between dialyzers (p > 0.05 for all). VEGF level was lower in the MCO group compared to the high-flux group (p = 0.043). Last session level of serum albumin with MCO dialyzers was lower than that with high-flux dialyzers (3.62 [3.45–3.88] vs. 3.78 [3.58–4.02] g/L) (p = 0.04) and 6.7% lower (p < 0.001) than at the first session of MCO dialyzers. Conclusion: The decline in circulating levels of several middle and large uremic toxins including VEGF following hemodialysis was more pronounced when using MCO membranes as compared to high-flux membranes while their effect on inflammatory molecules was similar.

Saliva immunoglobulin free light chain analysis for monitoring disease activity and response to treatment in multiple sclerosis

BackgroundImmunoglobulin free light chains (FLC) have recently gained considerable interest as new promising intrathecal biomarkers of multiple sclerosis (MS). However, lumbar puncture is invasive and not practical for monitoring disease course. This study aimed to assess the utility of saliva FLC as a biomarker of disease activity and response to treatment in MS MethodsWestern blotting was used to study saliva FLC monomers and dimers. The intensity of immunoreactive FLC bands was quantified by electrophoresis analysis, and the obtained values were used as FLC indices to account for kappa and lambda FLC monomer and dimer levels. Firth's logistic regression analysis suitable to study small cohorts was applied to compare FLC levels between M.S. patients in relapse, MS patients in remission, and healthy controls. Association between FLC levels and clinical and radiological parameters was analyzed. Results55 MS patients and 40 healthy controls were evaluated. Saliva FLC levels were significantly higher in relapse compared to remission. Logistic regression analysis employing a combination of FLC indices confirmed the significant difference between these two groups. The FLC levels were significantly reduced by treatment with corticosteroids. During remission, patients treated with disease-modifying therapies had lower levels of FLC compared to untreated patients. The increased FLC levels were associated with the presence of gadolinium-enhancing lesions, but not with MRI T2 lesion load and EDSS scores. During individual patient follow-up, the changes of the saliva FLC levels were in concordance with the disease activity status. ConclusionsSaliva FLC levels may be a useful biomarker for discriminating between stable remission and active disease. The developed test may serve as a new, non-invasive, and inexpensive tool for monitoring disease activity and response to treatment in MS.

P1072COMPARISON OF UREMIC TOXINS, INFLAMMATORY MARKERS AND VEGF LEVEL WITH MEDIUM CUT-OFF MEMBRANES AND HIGH-FLUX MEMBRANES IN HEMODIALYSIS: THERANOVA IN SISLI HAMIDIYE ETFAL (THE SHE) STUDY

Abstract Background and Aims Mortality in hemodialysis have not changed since last 30 years which may be caused by inflammation and accumulation of middle and large uremic toxins. Medium cut-off (MCO) membranes are able to perform hemodialysis as effective as hemodiafiltration. Their effect on inflammatory molecules and vascular endothelial growth factor-C (VEGF), an independent factor effective on mortality, are not well known. The aim of the study was to compare intra and inter dialyzer performances of MCO and high-flux dialyzers regarding middle and large uremic toxin, inflammatory marker, VEGF and serum albumin level. Method This is a randomized, prospective, open-label, cross-over study (ClinicalTrials.gov: NCT03836508) approved by local ethic committee. Patients had hemodialysis with either 36 sessions of high-flux dialyzer followed by 36 sessions of medium cut-off dialyzer or vice versa. Pre and postdialysis levels for urea, creatinine, albumin, total protein, free kappa light chain, free lambda light chain, beta-2 microglobulin, myoglobulin levels were determined at first and last sessions of every dialyzer. Postdialysis level of middle and large uremic molecules have been determined by a formula to prevent hemoconcentration effect. Reduction rate for uremic toxins were calculated. Serum level of human VEGF, fibroblast growth factor-23 (FGF-23), interferon gamma (IFN-g), interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-17A (IL-17A) levels were determined at first and last session of the each dialyzer. Results Fifty-two patients were enrolled to the study. Median age of patients was 56.40 (43.87-67.39) years. Median dialysis vintage was 4.77 (3.08-10.09) years. Reduction rates and postdialysis levels of free kappa and lambda light chain, myoglobulin, beta-2 microglobulin were lower both at first and last sessions in medium cut-off dialyzers compared to high-flux dialyzers (p&amp;lt;0.05 for all) (Table 1). Last session predialysis free kappa, free lambda, beta-2 microglobulin level was lower than first session predialysis levels in medium cut-off dialyzers (p&amp;lt;0.05 for all) (Table 2). Last session IL-6, IL-10, IL-17, IFN-gamma levels did not differ between dialyzers (p&amp;gt;0.05 for all). Vascular endothelial growth factor levels were 500.91 (363.80-679.15) pg/ml in medium cut-off group and 610.60 (450.63-1021.93) pg/ml in high-flux group (p=0,043). Predialysis serum albumin level at first session for MCO and high-flux groups were 3.88 (3.71-4.04) g/L and 3.75 (3.59-3.95) g/L, respectively (p=0.086) (Figure 1). After 3 months of hemodialysis, it was 3.62 (3.45-3.88) g/L in MCO group and 3.78 (3.58-4.02) g/L in high-flux group (p=0.04). Serum albumin level has decreased from 3.88 (3.71-4.04) g/L to 3.62 (3.45-3.88) g/L in 3 months during hemodialysis with MCO dialyzers (p=0.0001). It did not change significantly in high-flux group in the same time period (p=0.861). Conclusion MCO membranes not only decrease post dialysis levels of free kappa, free lambda, beta-2 microglobulin, myoglobulin but also decrease the third month predialysis levels of free kappa, free lambda, beta-2 microglobulin. They do not let the increase in myoglobulin level as seen in high-flux dialyzers. Even though the IL-6, IL-10, IL-17, IFN-gamma, FGF-23 levels did not differ, VEGF levels were lower in MCO dialyzer. The most important side effect of hemodialysis with MCO membranes is decreased serum albumin level.

P0508NEPHROTIC SYNDROME DUE TO HEAVY AND LIGHT CHAIN (AHL) AMYLOIDOSIS

Abstract Background and Aims Kidney diseases with heavy chain deposition are rare, including AHL amyloidosis also. The mutation/deletion of the constant domain (CH1/CH2) of the heavy chain causing high tissue affinity seems most likely in its pathogenesis. The very low serum level is responsible for the difficult diagnosis, which is often based on kidney biopsy or laser microdissection / mass spectrometry. Method Case study of a 76-year-old male patient, examined in January, 2019. Results Besides treatment for Ménière syndrome and benign prostatic hyperplasia there was no other important event in patient’s history. Significant proteinuria and microscopic haematuria were observed from May 2016, but eGFR was 70 ml/min/1,73 m2 at that time. By April, 2018 nephrotic range proteinuria (10 g/day) with full nephrotic syndrome developed. Screening tests for cancer were negative. Despite symptomatic treatment, half year later eGFR decreased to 27 ml/min/1,73 m2, therefore he was referred to nephrology. Serum protein electrophoresis verified IgG lambda (8,1 g/l) and free lambda (0,5 g/l) monoclonal light chains, and in addition the possibility of IgG heavy chain accumulation. Urine electrophoresis showed also IgG lambda (1720,1 mg/l), and free lambda light chain (552,1 mg/l) monoclonality. Serum free lambda and kappa light chain ratio was 0,06, complement serology was normal. Kidney biopsy was done, which showed IgG heavy and light chain restriction, Congo red stain positivity and apple green birefringence under the polarized microscope in the expanded mesangium, in the interstitium and along the tubular basement membrane and the blood vessels. The electron microscope detected fibrillary deposits (10 nm) in the same structures, therefore diagnosis of AHL amyloidosis was established. He had no extrarenal symptoms. Bone marrow aspiration flow cytometry verified 1,11% plasma cell accumulation, 93% of them had pathological immunphenotype. Bone marrow morphology assay showed 30-40% plasma cell infiltration, and chromosome assay detected monoallelic deletion of IgH and MAF and gains of 1q region, suggesting myeloma multiplex in the background of AHL amyloidosis. VCD (bortezomib-cyclophosphamide-dexamethason) treatment was started, so far he has received 8 cycles. He is asymptomatic, proteinuria decreased, kidney function stabilized, eGFR 23 ml/min/1,73 m2. Conclusion only about 20 cases of AHL amyloidosis have been reported in the literature so far. In the context of longstanding kidney failure with nephrotic syndrome, we should consider renal disease associated with plasma cell dyscrasia also. If case of an AHL amyloidosis caused by myeloma multiplex, effective anti-plasma cell therapy can improve the hematological and the renal outcome.

P0642EFFECTIVENESS OF HEMADSORPTION IN REDUCING FREE LIGHT CHAINS IN PATIENTS WITH MULTIPLE MYELOMA A.M.FOMIN, A.V.VATAZIN MOSCOW REGIONAL RESEARCH AND CLINICAL INSTITUTE. MOSCOW, RUSSIAN FEDERATION

Abstract Background and Aims Acute kidney injury is a frequent complication of multiple myeloma with unfavorable prognostic significance. The aim of the present study is to evaluate the effectiveness of hemadsorption to reducing free light chains (FLCs) in patients with multiple myeloma without replacement kidney therapy. Method The research was conducted for 6 patients ages 65- 74 with multiple myeloma. All patients were already suffering from a mild degree of renal insufficiency and elevated free light chains (4 kappa, 2 lambda). All patients didn’t have renal replacement therapy. Patients received VMP induction chemotherapy after two sessions of hemadsorption. The level of creatinine was from 198 µmol/l to 289 µmol/l. The glomerular filtration rate (eGFR) was from 34,8 to 21,3 mL/min/1,73 m2. The level of kappa FLC was 1714 – 5600 mg/L. The level of lambda FLC was 1575 – 3220 mg/L. In CytoSorb therapy, the blood is purified by adsorption in a procedure similar to hemoperfusion. The hemadsorption procedures were carried out on the AK10 device (Gambro, Sweden) with use of CytoSorb adsorbent cartridge. The content of the CytoSorb cartridge consists of a highly porous high-tech polymer. The patients were treated with 2 CytoSorb hemoadsorption treatments for 10 hours each separated and from one another by a pause interval of 12-14 hours. The blood flow rate was 130-160 ml/min. Anticoagulation was ensured by washing the bloodlines and a cartridge with a sorbent with normal saline with heparin – 4,000 units of activity per 1 L. 5,000 units of activity of heparin were injected intravenously at the beginning of the procedure. The FLCs, the level of creatinine and coagulogram test results of patients were studied prior to procedure and upon termination of procedure. Results An extracorporeal blood purification methods reduce elevated levels of FLCs. The cartridge with a total surface of&amp;gt;40,000 square meters, an adsorber is able to effectively and over time lower hydrophobic (water-insoluble) molecules that can be removed up to a size of 55kDa. FLC have high molecular weight (monomeric kappa of 22.5 kDa, dimeric lambda of 45 kDa). FLC removal, combined with chemotherapy may be associated with renal function recovery. As a result of hemadsorption after carrying out two procedures, there was a significant decrease in level kappa FLCs by 78.3 %, lambda FLCs by 64,0 %. All patients were dialysis independent. The level of creatinine decreased and the glomerular filtration rate increased. Other blood chemistry parameters did not show any changes. Throughout the treatment, the study did not show a decrease in dynamics of hemoglobin or platelets. There were not negative dynamics in change of INR (international normalized ratio), APTT (activated partial thromboplastin time), level of fibrinogen, prothrombin, or anti-thrombin III. No bleeding complication occurred in any patient during the procedure of hemadsorption. Other biochemical values did not change significantly. Conclusion The research showed that an extracorporeal blood purification method by CytoSorb therapy reduce elevated levels of FLCs in patients with multiple myeloma. The benefits of this modality need confirmation with a randomized controlled trial.

P1082COMPARISON OF THE REMOVAL OF PROTEIN-BOUND TOXINS AND LARGE MIDDLE MOLECULES WITH HIGH-FLUX PMMA AND MEDIUM CUT-OFF DIALYZERS

Abstract Background and Aims Dialytic clearance of protein-bound toxins and large middle molecules is poor by diffusive treatment and limited by high-flux hemodialysis (HD) and on-line hemodiafiltration (OL-HDF), and only a few studies have examined how to improve their removal by other extracorporeal strategies. Since 2017, there is a new generation of polymethyl methacrylate (PMMA) membranes that suppress platelet adhesion on the membrane surface improving hemocompatibility and permeability, while also maintaining adsorption properties related to conventional PMMA membranes. Expanded HD (HDx) with medium cut-off (MCO) membranes has also recently been incorporated into clinical practice and may improve the removal of uremic toxins in HD treatments. The aim of this pilot study was to compare the efficacy of a new high-flux PMMA dialyzer (Filtryzer® NF-2.1H) in a post-dilution OL-HDF session with a new MCO membrane (Theranova® 400) in a HDx session. Method In an open, cross-over, single-center, controlled, prospective clinical study, 40 adult stable HD patients were assigned to be treated by post-dilution OL-HDF with the NF-2.1H dialyzer or by HDx with the Theranova 400 dialyzer. All other dialysis parameters, including blood and dialysate flow rates, length of dialysis session, and ultrafiltration rate remained unchanged during both sessions. P-cresyl sulfate (PCS), indoxyl sulfate (IS), and kappa (κ) and lambda( λ) free light chains (FLC) reduction rates were intraindividually compared for the two dialyzer types (primary outcomes). Secondary outcomes included the kt and the reduction ratio of blood urea nitrogen, phosphate and β2 -microglobulin (β 2-m). Results The reduction ratio of protein-bound toxins ranges from 60% to 67%, with no differences between membranes (Figure). PMMA membrane achieved greater FLC reduction ratios than MCO membrane, reaching significance for λFLC (56.6% vs. 77.4%; p &amp;lt; 0.001). Conversely, β2M reduction ratio was slightly but significantly higher with MCO membrane (68.5 vs. 72.1%; p = 0.002). Small molecules removal including urea and phosphate were similar in both groups, achieving an optimal Kt with no differences between groups (61.3±9.2 Vs. 59.7±9.3; p=0.16). Albumin reduction ratio tended to be higher with PMMA membrane without reaching significance (10.1±5.9% Vs. 7.8±12.3%; p=0.17). The mean convective volume achieved with PMMA was 23.5±4.4 L. Conclusion This study suggested that new high-flux PMMA dialyzer in post-dilution OL-HDF mode might achieve better FLC reduction ratios than MCO dyalizer in HDx mode, whereas both techniques may equally remove protein-bound toxins. OL-HDF with new PMMA membranes could be a good dialysis strategy for adding convective transport to the well-known mechanisms of diffusion and absorption previously described with conventional PMMA membranes, enabling an adequate substitution volume.

P0480LENALIDOMIDE PLUS DEXAMETHASONE FOR PROLIFERATIVE GLOMERULONEPHRITIS WITH MONOCLONAL IG DEPOSITS

Abstract Background and Aims To evaluate the efficacy and safety of lenalidomide plus dexamethasone (LD) in patients with proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID). Method Retrospectively analyzed the clinicopathological data of 6 PGNMID patients who treated with LD protocol from January 2010 to October 2019. Results All of the patients received LD treatment for ≥3 months after renal biopsy. 3 patients achieved renal remission. The renal remission rate was 50%. Light microscopy showed membranoproliferative glomerulonephritis and immunofluorescence showed single kappa type IgG3 was deposited in the mesangial region and the vascular loop. Before taking LD scheme, the median urinary protein were 7.76 (1.27,14.57) g/24h, the median serum creatinine 1.34 (0.8,3.27) mg/dL, the median albumin 34.5 (22.4,37.5) g/L. In 5 patients the concentration of serum free kappa and lambda light chain increased, but no patients with abnormal serum free light chain ratio. Complement C3 deteriorated in 2 patients, 2 cases of patients with monoclonal plasma cells, 0.7% and 0.5%, respectively. Immunofixation electrophoresis suggested that 1 patient had positive serum M protein for kappa type IgG3. At the last follow-up, median urine protein was 3.33 (0.33,11.23) g/24h, median serum creatinine was 1.23 (0.91,1.82) mg/dL, and median albumin was 35.9 (24.5,45.6) g/L. The concentration of 4 patients with elevated serum free light chain was lower than that before taking the drug. Two patients with decreased complement C3 increased to normal concentration at the last follow-up. However, the other two patients had a slight decrease in complement C3. The M spike did not turn negative during the follow-up in one patients. Adverse events included anemia, neutropenia, limb numbness, upper respiratory tract infection. Conclusion This study reported that lenalidomide plus dexamethasone may be effective in treating proliferative glomerulonephritis with monoclonal Ig deposits for the first time. More attention needs to be paid to the hematological adverse events during lenalidomide treatment.

P1114HA-130 HEMOPERFUSION CARTRIDGE IN THE TREATMENT OF CAST NEPHROPATHY IN A 58-YEAR-OLD MALE WITH MULTIPLE MYELOMA: A CASE REPORT

Abstract Background and Aims Multiple myeloma is a plasma cell neoplasm that results in the production of monoclonal immunoglobulin. Renal failure is a common complication of multiple myeloma, occurring in approximately one-half of patients on initial presentation and is associated with increased mortality. Cast nephropathy in particular, is considered to be one of the major mechanisms of renal failure in multiple myeloma, and is characterized by precipitation of free light chains in the distal nephron, leading to intratubular obstruction, inflammation and fibrosis. Recent studies have demonstrated the use of extracorporeal methods such as plasmapheresis and high-cutoff membrane dialysis as an adjunctive therapy to chemotherapy in the management of cast nephropathy, however currently there are no existing guidelines in the use of extracorporeal therapies in the management of complications of multiple myeloma. Hemoperfusion is an extracorporeal treatment technique which utilizes adsorption in the removal of specific toxins. The HA 130 cartridge in particular has a resin pore size distribution of 500Da- 40 KDa and is able to remove molecules at 5-30kDa. In this case report we describe the use of HA 130 hemoperfusion cartridge in the treatment of cast nephropathy in Multiple Myeloma. Method A 58-year-old male, diabetic, non-hypertensive came in for 5-day history of generalized body weakness, associated with myalgia, lumbar pain and undocumented fever, with 1-day history of loose stools and vomiting. Upon admission blood tests done revealed anemia with a hemoglobin of 7.8g/dl, creatinine of 9.97mg/dL and potassium of 5.5mmol/L. He was diagnosed with acute renal failure and underwent hemodialysis on the second hospital day. On workup he had lytic bone lesions in the spine, pelvis and cranium on CT scan and x-ray. Serum Protein Electrophoresis (SPEP) and Serum Free Light Chain (sFLC) tests showed a monoclonal gammopathy. Serum beta 2 microglobulin was elevated at 12,618ng/ml. Free kappa and lambda light chains were also elevated at 19,250mg/L and 25.7mg/L, respectively. Bone marrow biopsy was done, with findings of markedly hypercellular marrow with 80% plasma cells confirming the diagnosis of Multiple Myeloma. Combined hemodialysis with hemoperfusion were done using HA 130 filter and hi flux dialyzer for 2.5 hours then hemodialysis for three times a week. Patient was also started on chemotherapy using Bortezomib with Dexamethasone for 2 cycles. Results Patient had a total of 14 sessions of combined hemoperfusion with hemodialysis. On repeat free kappa light chains decreased to 212.5mg/L. Patient was maintained on hemodialysis three times a week and was discharged after 55 hospital days. Outpatient hemodialysis was continued three times a week, and after 2 weeks, patient showed signs of renal recovery with a repeat creatinine of 2.1mg/dL. Four weeks after discharge, patient was independent of hemodialysis with a repeat creatinine of 1.3mg/dL. Conclusion This report highlights the use of hemoperfusion using HA 130 cartridge in combination with chemotherapy using Bortezomib in reducing free light chain levels in a 58-year-old male that developed renal failure secondary to cast nephropathy. Patient was able to achieve reduction in free light chain levels, improvement in renal function and eventually independence from hemodialysis four weeks after the last hemoperfusion treatment. Further studies using a randomized control trial on the use of hemoperfusion in directly reducing serum free light chain levels is recommended. The value of hemoperfusion on the rate of independence from hemodialysis, as well as survival rates among patients with renal failure secondary to multiple myeloma may also be worth investigating using larger studies.

P0712TRANSGELIN AS A POTENTIAL MARKER OF RENAL IMPAIRMENT IN MULTIPLE MYELOMA PATIENTS

Abstract Background and Aims Transgelin (SM22) is a cytoskeletal actin-binding protein involved in differentiation of smooth muscle cells, osteoblasts and adipocytes. It is present in fibroblasts, some epithelium, immune cells and acts as a tumor suppressor. It was found as a marker of interstitial fibrosis and glomerulosclerosis. Transgelin upregulation depends on the etiology of the disease in various cells (glomerular parietal or visceral, or tubular interstitial cells). Elevated SM22 expression was detected in glomerular and in tubulointerstitial injury. Among patients with multiple myeloma (MM) up to 50% suffer from renal insufficiency (RI) in early stages. Free light chains (FLCs), potential nephrotoxic substances, where lambda light chains are more commonly associated with renal damage, appear to have a prognostic value in MM and indicate the stages of MM. The aim of the study was to analyse the utility of transgelin in case of renal impairment in MM patients and investigate its relationship with acclaimed parameters of renal failure and markers of MM stages. Method The analysis included 126 patients (73 women and 53 men) in mean age 66 ± 10 years. Symptomatic MM was diagnosed in 119 patients, including 84 (67%) with ISS stage 1, 20 (16%) with stage 2 and 15 (12%) with stage 3; 7 (6%) patients had smoldering MM. Mean baseline eGFR (CKD-EPICr) was 74 ± 24 ml/min/1.73 m2 and 31 (25%) patients had eGFR &amp;lt;60 ml/min/1.73 m2. The examined parameters included creatinine, urea, NGAL urine, serum and urine cystatin C, periostin, FLC kappa and lambda in serum and urine. The association between transgelin, markers of renal failure, MM were determined by the Pearson's test and multivariate stepwise regression analysis. The p-value &amp;lt;0.05 was considered statistically significant. Results Median serum transgelin in the whole studied group was 84.1 (IQR: 65.4; 116.4) ng/ml. Transgelin concentrations were higher in men (median 96.2 versus 78.8 ng/ml; p=0.022) and in patients with smoldering MM (median 149.2 versus 82.4 ng/ml; p=0.003). Transgelin did not differ according to ISS stage (p=0.3) or disease state (regression, stable disease or progression) (p=0.3). Significant correlations were detected between transgelin and serum creatinine (R=0.29; p=0.001), eGFR (CKD-EPICr) (R=-0.25; p=0.007), uric acid (R=0.19; p=0.036), alanine (R=0.18; p=0.048) and aspartate (R=0.26; p=0.003) aminotransferases, ferritin (R=-0.22; p=0.049), hepcidin (R=-0.25; p=0.033), and urine cystatin C (R=0.19; p=0.042). Moreover, after exclusion of patients with smoldering MM, transgelin significantly correlated with serum FLC lambda (R=0.18; p=0.047) and serum periostin (R=-0.22; p=0.013). After median follow-up of 21 (IQR: 15; 24) months, eGFR decreased in 47 (37%) of patients and increased in 71 (56%) patients (no follow-up data were available in 8, i.e. 6% of patients). Patients in whom eGFR decreased had higher transgelin (median 106.6 versus 83.9 ng/ml), although the difference was marginally significant (p=0.05). However, baseline transgelin positively correlated with serum creatinine after follow-up (R=0.37; p&amp;lt;0.001) and negatively correlated with eGFR after follow-up (R=-0.33; p&amp;lt;0.001). Moreover, higher baseline serum transgelin (beta=-0.11 ± 0.05; p=0.032) significantly predicted lower eGFR values after the follow-up, independently of baseline eGFR and the duration of follow-up. Conclusion Transgelin may be useful in investigating renal damage because of its proven role in regulation of fibrosis, especially in kidney. As a biomarker it may indicate diagnosis and etiology of MM-related chronic kidney disease, which can lead to beginning of early therapeutic interventions and improved overall survival and quality of life in patients with MM. Moreover, elevated transgelin at the beginning of the disease may induce future development of chronic kidney disease.

Immunoglobulin free light chains as an inflammatory biomarker of heart failure with myocarditis

BackgroundIn this study, we measured immunoglobulin free light chains (FLC), a biomarker of inflammation in the sera of patients with heart failure due to myocarditis. MethodsFLC kappa and FLC lambda were assayed in stored serum samples from patients with heart failure with myocarditis from the US myocarditis treatment trial by a competitive-inhibition multiplex Luminex® assay. ResultsThe median concentration of circulating FLC kappa/lambda ratio was significantly lower in the sera from patients with heart failure with myocarditis than in healthy controls, and FLC kappa/lambda ratio had good diagnostic ability for identification of heart failure with myocarditis. Further, FLC kappa/lambda ratio was an independent prognostic factor for overall survival, and allowed creation of three prognostic groups by combining with N-terminal pro-B-type natriuretic peptide. ConclusionsThis study suggests that FLC kappa/lambda ratio is a promising biomarker of heart failure with myocarditis.

MON-469 Rapidly Expanding Thyroid Goiter as the First Manifestation of Systemic Amyloidosis

INTRODUCTIONAmyloidosis is a condition manifesting with extracellular tissue deposition of fibrils of low molecular weight proteins. In Ig light chain amyloidosis (AL), the deposition of Ig light chains can cause organ dysfunction, and patients can have involvement of a range of organs including kidney (70%), liver (70%), heart (60%), peripheral nerves (20%), the tongue, skin, and the coagulation system (1). We describe a unique case of AL amyloidosis, which first presented with thyroid involvement.CLINICAL CASEA 78 year old female patient with hx of small lymphocytic lymphoma and normal thyroid function presented with an expanding symptomatic goiter and compressive symptoms (positive Pemberton sign) for which a total thyroidectomy was performed. Pathology showed Congo red-birefringent amyloid deposition. SPEP showed a small amount of M protein, with circulating monoclonal free lambda light chain on immunofixation. The free kappa lambda light chain ratio was low (0.04) with an elevated serum free lambda light chain (283.93). Mass spectrometry confirmed AL light chain amyloidosis - lambda type. A work up was initiated to assess other organ involvement. Echocardiogram showed mild thickening of left ventricle with a preserved EF and EKG showed low voltage in limb leads. Creatinine (1.05) was minimally elevated from baseline with minimal proteinuria (396 mg/24 hours). Alkaline phosphatase, APTT, and PT were normal. The patient described tongue enlargement and scalloping of the tongue from tooth impingement was seen. Biopsies of tongue and bone marrow also showed amyloidosis thereby securing the diagnosis of systemic amyloidosis, and chemotherapy was initiated.CONCLUSIONThis case illustrates the importance of considering amyloid goiter in the differential for a rapidly enlarging thyroid, even when there is no history of amyloidosis. Although extremely uncommon, a few case reports have described amyloid goiter. In our case, thyroid AL was the initial presentation of systemic amyloidosis. Because disease can be localized or systemic, work up should include an assessment for the presence of a monoclonal gammopathy and an assessment for amyloid mediated organ dysfunction. Tissue should be sent for amyloid typing – there are 35 different proteins known to form amyloid fibrils and prognosis and treatment depends on amyloid type (2). Typing using Liquid Chromatography-Tandem Mass Spectrometry, is the most sensitive and specific methodology, though, in experienced hands, typing by immune histochemistry is an option.REFERENCES1. Rajkumar, S.V., Dispenzieri, A. Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis. Uptodate. 2019.2. Winter, M., Tholey, A., Kristen, A., Röcken, C. MALDI Mass Spectrometry Imaging: A Novel Tool for the Identification and Classification of Amyloidosis. Proteomics 2017, 17, 1700236.

Randomized controlled trial of medium cut-off versus high-flux dialyzers on quality of life outcomes in maintenance hemodialysis patients

Medium cut-off (MCO) dialyzers help remove larger middle molecules associated with symptoms related to the accumulation of uremic retention solutes. We investigated the effect of an MCO dialyzer on the improvement of quality of life (QOL) in maintenance hemodialysis (HD) patients. Forty-nine HD patients with high-flux dialysis were randomly assigned to either an MCO (Theranova 400, Baxter) or a high-flux (FX CorDiax 80 or 60, Fresenius Medical Care) dialyzer and completed the study. QOL was assessed at baseline and after 12 weeks of treatment using the Kidney Disease Quality of Life Short Form-36, and pruritus was assessed using a questionnaire and visual analog scale. The reduction ratios of middle molecules were also evaluated. Laboratory markers, including serum albumin, did not differ between the two groups after 12 weeks. Removals of kappa and lambda free light chains were greater for MCO dialyzer than high-flux dialyzer. The MCO group had higher scores than the high-flux group in the domains of physical functioning and physical role (75.2 ± 20.8 vs. 59.8 ± 30.1, P = 0.042; 61.5 ± 37.6 vs. 39.0 ± 39.6, P = 0.047, respectively), and the MCO group had lower mean scores for morning pruritus distribution and the frequency of scratching during sleep (1.29 ± 0.46 vs. 1.64 ± 0.64, P = 0.034; 0.25 ± 0.53 vs. 1.00 ± 1.47, P = 0.023, respectively). MCO dialyzers may improve patient-reported outcomes, particularly the physical components of QOL and uremic pruritus, in patients with high-flux dialyzers.

SAT-205 POEMS: A Medical Odyssey

Introduction: POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome is a rare disorder with poorly understood pathogenesis. The incidence of endocrinopathy associated with POEMS syndrome has been recognized more frequently in the last two decades, ranging between 67-84%. The cause of endocrine dysfunction associated with the syndrome is not known, but has been described to include hypogonadism, hypothyroidism, abnormalities of glucose metabolism, hyperprolactinemia, gynecomastia in men, hyperestrogenemia, calcium abnormalities and adrenal insufficiency (AI).Case: A 38 y/o Hispanic male was initially referred to nephrology with complaint of leg swelling. Subsequently, the patient was referred to endocrinology for abnormal thyroid function studies and ongoing fatigue. Patient had prior medical history of recently diagnosed hypothyroidism treated with levothyroxine 100 mcg daily. The most bothersome complaint was pitting edema in the lower extremities with associated pain. He also endorsed right shoulder pain exacerbated by use of the right arm. He reported unintentional weight loss of about 30 pounds in the past 2-3 years, denying night sweats. He did endorse feeling fatigued, skin darkening, and erectile dysfunction. On exam patient was afebrile, BP 120/71 mm/Hg, HR 87 bpm, no goiter, no gynecomastia, skin hyperpigmentation, darkening creases of the palms, pitting edema in lower extremities. Work up showed abnormal lambda monoclonal bands in plasma and monoclonal lambda free light chain in urine. Bone survey showed lytic lesion in right scapula. [prolactin 15.6 ng/ml (normal (NL)= 0-25), free testosterone 23.1 pg/ml (NL= 35.0-155.0), total testosterone 205 ng/dl (NL= 250-1100), LH 8.2 MIU/ml (NL= 1.2-8.6), FSH 4.3 MIU/ml (NL=1.3-19.3), TSH 17.8 uIU/ml (NL= 0.45-5.33), free T4 0.62 ng/dl (NL= 0.58-1.64), free T3 3.05 pg/ml (NL=2.5-3.9), TPO antibody (AB) negative, IGF-1 41 ng/ml (NL=53-331), AM cortisol 8.2 ug/dl (NL=6.7-22.6), ACTH 99 pg/ml (NL=6-50), aldosterone 3 ng/dl (NL ≤28), renin activity 2.78 ng/ml/h (NL=0.25-5.82), 21-hydroxylase AB negative, 17-hydroxyprogesterone 54 ng/dl (NL=42-196), DHEA-S 88 mcg/dl (NL=106-464)]. ACTH stimulation test (250 mcg) was performed with basal cortisol 8.0 ug/dl (NL= 5.0- 21.0), basal ACTH 93 pg/ml (NL=6-50), 30min cortisol 9.7 ug/dl (NL=13.0-30.0), 60min cortisol 10.2 ug/dl (NL=14.0-36.0). Pt was diagnosed with primary AI and started on hydrocortisone. CT abdomen and pelvis with contrast showed normal adrenal glands.Discussion: Physicians should be cognizant of a unifying diagnosis in a syndrome of such a broad presentation. Endocrinopathies vary in extent of dysfunction and may fluctuate during the course of POEMS syndrome. Multidisciplinary management as well as regular reassessment of endocrine function is integral in managing this complex disease.

Prognostic significance of the frontal QRS-T angle in patients with AL cardiac amyloidosis

IntroductionCardiac involvement is a leading cause of morbidity and mortality in primary light chain (AL) amyloidosis. The electrocardiographic spatial QRS-T angle reflects changes in the direction of the repolarization sequence and is a powerful predictor of outcome in patients with heart failure. We examined the significance of the frontal QRS-T angle in predicting the clinical outcome in patients with AL cardiac amyloidosis. MethodsForty-three consecutive patients with cardiac involvement of AL amyloidosis were studied. Patients were followed for survival. ResultsPatient median age was 62 years, 56% were males. After a median follow up of 56 months, 16 out of 43 patients had died (37%). The median QRS-T angle was 102° (interquartile range 35–148). QRS-T angle>102° was associated with increased prevalence of lambda free light chain disease and the presence of a pleural effusion. It was also associated with increased interventricular septum thickness, smaller left ventricle end-diastolic diameter, echocardiographic myocardial sparkling texture, pericardial effusion, elevated NT-Pro-BNP and increased restrictive physiology evident by increased E/A and E/e`. A QRS-T angle>102° was a significant predictor of increased mortality by Kaplan-Meier survival analysis (71.6 ± 11.1% vs. 45.7 ± 11.1%, P = .02). A QRS-T angle>102° was an independent predictor of mortality by Cox regression analysis (HR 3.00, 95% CI 1.01–8.89, P < .05). ConclusionsThe QRS-T angle is associated with indices of advanced amyloid disease and is an independent predictor of survival.

A tRial Evaluating Mid Cut-Off Value Membrane Clearance of Albumin and Light Chains in HemoDialysis Patients: A Safety Device Study

Background: A new class of dialysis membrane, the mid cut-off (MCO) dialyzer, has been developed to improve the clearance of uremic toxins in hemodialysis (HD). The a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) study aimed to determine if regular use of MCO dialyzer was safe and specifically did not result in a significant loss of albumin. Methods: This investigator initiated, crossover, longitudinal, device study was conducted across 9 centers in Australia and New Zealand (n = 89). Participants had a 4-week wash-in with high-flux HD, followed by 24-week intervention with MCO HD and a subsequent 4-week wash-out with high-flux HD. The primary outcome was change in serum albumin between weeks 4 and 28. Secondary outcomes included trends in serum albumin, changes in kappa- and lambda-free light chains (FLC), 6-min walk test (6MWT), malnutrition inflammation score (MIS), restless legs score and quality of life. Results: Participants had a mean age of 66 ± 14 years, 62% were men, 45% were anuric, and 51% had ­diabetes. There was no reduction in serum albumin following treatment with MCO HD (mean reduction –0.7 g/L, 95% CI –1.5 to 0.1). A sustained, unexplained reduction in serum albumin (>25%) was not observed in any participant. A reduction in FLC was observed 2 weeks into MCO HD (lambda-FLC: Δ –9.1 mg/L, 95% CI –14.4 to –3.7; kappa-FLC: Δ –5.7 mg/L, 95% CI –9.8 to –1.6) and was sustained for the rest of the study intervention. Both FLC increased after the cessation of MCO use. There was no improvement in restless legs symptoms, quality of life, 6MWT or MIS scores. Conclusions: Regular HD using the MCO dialyzer did not result in a significant fall in serum albumin. There were no effects on quality of life, functional status or nutrition. Trial Registration: Australian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482.

UTILITY OF SERUM AND URINARY FREE LIGHT CHAINS AS NON-INVASIVE BIOMARKERS OF ACTIVITY IN LUPUS NEPHRITIS

BACKGROUND: Current laboratory biomarkers for lupus nephritis like proteinuria, urine protein to creatinine ratio, creatinine clearance, anti-ds DNA and complement levels lack sensitivity and specificity for predicting disease activity and damage. Free light chains (FLCs) released in circulation during antibodies production play a key role in the pathogenesis of autoimmune diseases. Expression of serum and urinary FLCs in lupus nephritis can act as non-invasive diagnostic and prognostic indicators and alleviate the dependency on the invasive procedure of biopsy to guide management. AIMS & OBJECTIVES: Present study intends to adjudge the implications of serum and urinary FLCs as non-invasive biomarkers of disease activity in lupus nephritis. MATERIALS & METHODS: Histomorphological diagnosis of lupus nephritis was done as per ISN-RPS classification. Cases were divided into 2 subgroups, classes I/II and III/IV in accordance with low to high histological grades and activity/chronicity scores. Concurrent serum and urinary FLCs levels were estimated by immunonephelometry and correlated with clinical presentation and histological grades of lupus nephritis. Control cases were selected from a pool of other native renal diseases with a non-immunological basis. RESULTS: Urinary kappa and lambda FLCs were significantly elevated in lupus nephritis class III/IV as compared to class I/II and controls. Serum kappa FLCs exhibited significant/near significant increments on comparison of classes III/IV and I/II with controls, however, intra-comparison of classes I/II and III/IV was insignificant. Serum lambda FLCs showed significance only for the comparison of class III/IV with controls. CONCLUSION: Urine FLCs have definite potential to be established as a non-invasive biomarker of activity in lupus nephritis. The role of serum FLCs needs further validation.

P712 When Popeye had shortness of breath

Abstract A 61-year-old man presented to our clinic with progressive shortness-of-breath in the last 3 months. He had a history of hospitalization and endotracheal intubation due to acute pulmonary edema and type – I respiratory failure a week ago and discharged after diagnostic coronary angiography which demonstrating normal coronary arteries. Physical examination revealed bunching of the left biceps when he flexed his left arm which is consistent with rupture of distal biceps tendon (Panel A, Popeye Sign). A 12-lead electrocardiography (ECG) showed low QRS voltage in the limb leads and ST segment depression and asymmetrical T wave inversion in the anterolateral leads (Panel B). Transthoracic echocardiography (TTE) showed concentric left ventricular hypertrophy with left ventricular ejection fraction of 60% (Panel C). Pulsed wave-Doppler obtained from the mitral valve demonstrated restrictive filling pattern with high early diastolic velocity (E-wave) and low late diastolic filling (A-wave) peaks with E/A ratio &amp;gt; 2.0 and reduced lateral mitral annular diastolic velocities with E/e’ ratio &amp;gt; 15 which are compatible with impaired left ventricular diastolic function with elevated left ventricular filling pressures (Panel D-E). Biceps tendon rupture, low QRS voltage and left ventricular hypertrophy with restrictive filling pattern were considered suggestive of cardiac amyloidosis and patient was referred to hematology clinic for diagnostic work-up. Protein electrophoresis demonstrated monoclonal gammopathy in the serum and immunoelectrophoresis showed free lambda light chains. The patient diagnosed as AL amyloidosis with cardiac and musculoskeletal involvement. Biceps tendon rupture is a rare finding of amyloidosis due to musculoskeletal involvement. In the setting of acute pulmonary edema and/or heart failure with preserved ejection fraction with massive left ventricular hypertrophy, restrictive filling pattern, low QRS voltage and spontaneous tendon rupture should raise clinical suspicion of amyloidosis with cardiac and musculoskeletal involvement. Abstract P712 Figure.

A randomized cross-over study with objective quantification of the performance of an asymmetric triacetate and a polysulfone dialysis membrane using different anticoagulation strategies.

BackgroundDifferent strategies can be used to counteract coagulation of extracorporeal systems. Systemic anticoagulation is most widely used in routine clinical practice, but can be contraindicated in specific settings. The Solacea™ dialyser, containing the asymmetric triacetate membrane, claims improved biocompatibility, which should result in decreased tendency for coagulation. We quantified the performance of the Solacea™ versus the FX800CORDIAX dialyser regarding resistance to fibre blocking as assessed by micro-computed tomography (CT).MethodsThis cross-over study with four arms randomized consecutively 10 maintenance haemodialysis patients to a 4-h post-dilution haemodiafiltration session at midweek, using either Solacea™ 19 H or FX800CORDIAX, with either regular or half dose of anticoagulation (EC2017/1459-NCT03820401). Dialyser fibre blocking was visualized in the dialyser outlet potting using a 3D CT scanning technique on micrometre resolution. Extraction ratios of middle molecules [myoglobin, lambda and kappa free light chains (FLCs)] were determined.ResultsThe relative number of open fibres post-dialysis was lower in FX800CORDIAX versus Solacea™ dialyser, and this was irrespective of the anticoagulation dose used or the threshold for counting open fibres. Extraction ratios of FLCs were not different at regular anticoagulation between Solacea™ and FX800CORDIAX (21% ± 4% for kappa and 32% ± 8% for lambda with Solacea™ versus 23% ± 7% and 38% ± 6% for FX800CORDIAX), but were superior with the Solacea™ (34% ± 12% versus 22% ± 8% with FX800CORDIAX; P = 0.02) for myoglobin in case of halving anticoagulation dose. No clinically relevant albumin loss was detected.ConclusionsThe Solacea™ dialyser seems to be promising for use in conditions where systemic anticoagulation is contraindicated, as even under conditions of low systemic anticoagulation, virtually no signs of fibre blocking could be observed using the sensitive micro-CT scanning technique. This finding is in line with its presumed good performance in terms of biocompatibility.