Medium Cutoff Versus High-Flux Hemodialysis Membranes and Clinical Outcomes: A Cohort Study Using Inverse Probability Treatment Weighting.

Rationale & Objective: This study investigated the effects on patients' outcomes of using medium cutoff (MCO) versus high-flux (HF) dialysis membranes. Study Design: A retrospective, observational, multicenter, cohort study. Setting & Participants: Patients aged greater than 18 years receiving hemodialysis at the Baxter Renal Care Services dialysis network in Colombia. The inception of the cohort occurred from September 1, 2017, to November 30, 2017, with follow-up to November 30, 2019. Exposure: The patients were divided into 2 cohorts according to the dialyzer used at the inception: (1) MCO membrane or (2) HF membrane. Outcomes: Primary outcomes were the hospitalization rate from any cause and hospitalization days per patient-year. Secondary outcomes were acute cardiovascular events and mortality rates from any cause and secondary to cardiovascular causes. Laboratory parameters were assessed throughout the 2-year follow-up period. Analytical Approach: Descriptive statistics were used to report population characteristics. Inverse probability of treatment weighting was applied to each group before analysis. All categorical variables were compared using Pearson's χ2 test, and continuous variables were analyzed with the t test. Baseline differences between groups with a value of >10% were considered clinically meaningful. Laboratory variables were measured at 5 consecutive time points. A between-patient effect was analyzed using a split-plot factorial analysis of variance. Results: The analysis included 1,098 patients, of whom 564 (51.3%) were dialyzed with MCO membranes and 534 (48.7%) with HF membranes. Patients receiving hemodialysis with MCO membranes had a lower all-cause hospitalization incidence rate (IR) per patient-year (IR = 0.93; 95% CI, 0.82-1.03) than those receiving hemodialysis with HF membranes (IR = 1.13; 95% CI, 0.96-1.30), corresponding to a significant incident rate ratio (MCO/HF) of 0.82 (95% CI, 0.68-0.99; P = 0.04). The frequency of nonfatal cardiovascular events showed statistical significance, with a lower incidence in the MCO group (incident rate ratio = 0.66; 95% CI, 0.46-0.96; P = 0.03). No statistically significant differences in all-cause time until death were observed (P = 0.48). Albumin levels were similar between the 2 dialyzer cohorts. Limitations: Despite the robust statistical analysis, there remains the possibility that unmeasured variables may still generate residual imbalance and, therefore, skew the results. Conclusions: The incidences of hospitalization and cardiovascular events in patients receiving hemodialysis were lower when dialyzed with MCO membranes than HF membranes. A randomized controlled trial would be desirable to confirm these results. Trial Registration: Clinical Trials.gov, ISRCTN12403265.

Effect of a medium cut-off dialyzer on protein-bound uremic toxins and mineral metabolism markers in patients on hemodialysis.

INTRODUCTION: Hemodialysis (HD) with medium cut-off (MCO) dialyzers may expand molecular clearance, predominantly larger middle molecules (molecular weight 25-60 kDa). However, the impact of MCO dialyzers on long-term clearance of various other components of the uremic milieu is unknown. The tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) provided an opportunity to assess the effect of MCO dialyzers on protein-bound uremic toxins and novel markers of mineral metabolism. METHODS: This exploratory sub-study of REMOVAL-HD evaluated changes in protein-bound solutes (total and free indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) and mineral metabolism markers (intact fibroblast growth factor-23 [iFGF23], fetuin-A and endogenous calciprotein particles [CPP-1 and CPP-2]). Mid-week, pre-HD serum samples were collected at baseline and after 12 and 24 weeks of MCO use in stable adult patients. Change from baseline to Week 12 and 24 was estimated using linear mixed effects models. FINDINGS: Eighty-nine participants were studied (mean age 67 ± 15 years, 38% female, 51% diabetic, median urine output 200 ml/24 h). Serum iFGF23 was reduced at Week 12 compared to baseline (-26.8% [95%CI -39.7, -11.1], p = 0.001), which was sustained at Week 24 (-21.7% [95%CI -35.7, -4.5], p = 0.012). There was no significant change in serum IS, PCS, fetuin-A, CPP-1, or CPP-2. DISCUSSION: The use of a MCO dialyzer over 24 weeks was associated with a sustained reduction in FGF23, while other measured components of the uremic milieu were not significantly altered. Further studies are required to determine whether FGF23 reduction is associated with improved patient outcomes.

Expanded Hemodialysis and Its Effects on Hospitalizations and Medication Usage: A Cohort Study.

INTRODUCTION: Expanded hemodialysis (HDx) effectively removes large middle molecular uremic toxins (>25 kDa) while still retaining albumin, potentially reducing their adverse effects. We compare the clinical laboratory parameters, hospitalization rates, and medication use in a cohort of patients switched from high-flux HD to HDx. METHODS: This is a multicenter, observational cohort study of 81 adult patients, across 3 clinics, with end-stage kidney disease (ESKD) on chronic hemodialysis (HD). Patients received high-flux HD for at least 1 year and then switched to HDx and were followed up for 1 year. Patients were excluded if they discontinued therapy, changed provider, underwent kidney transplant, recovered kidney function, or changed to peritoneal dialysis, another dialyzer, or renal clinic. RESULTS: Twelve months after switching to HDx, the rate of hospitalization events per patient-year decreased from 0.77 (95% CI: 0.60-0.98, 61 events) to 0.71 (95% CI: 0.55-0.92, 57 events) (p = 0.6987). The hospital day rate per patient-year was significantly reduced from 5.94 days in the year prior to switching compared with 4.41 days after switching (p = 0.0001). The mean dose of erythropoiesis-stimulating agent (SC epoetin-α) and intravenous iron also significantly decreased (p = 0.0361 and p = 0.0003, respectively). CONCLUSION: Switching to HDx was associated with reductions in hospital day rate and medication use, suggesting HDx has the potential to reduce the burden of ESKD on patients and healthcare systems.

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.

High cutoff versus high-flux haemodialysis for myeloma cast nephropathy in patients receiving bortezomib-based chemotherapy (EuLITE): a phase 2 randomised controlled trial.

BACKGROUND: In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). METHODS: In this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6-8 h) or standard HF-HD and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602. FINDINGS: Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1·09, 95% CI 0·74-1·61; p=0·81). During the 2-year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group. INTERPRETATION: In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these patients. FUNDING: Gambro, Janssen, and Binding Site.

Large uremic toxins: an unsolved problem in end-stage kidney disease.

Patients with end-stage kidney disease (ESKD) on maintenance hemodialysis are subject to a high burden of inflammation and cardiovascular disease, driven at least in part by retention of uremic solutes. Existing dialysis technologies using high-flux membranes offer limited clearance of solutes >15 kDa. New approaches to improve the removal of large uremic toxins include the novel medium cut-off dialysis membranes with pores larger than those in high-flux membranes. These new membranes provide the potential to improve the clearance of large middle molecules up to 50 kDa. In this review, we discuss 18 uremic toxins with molecular weights between 15 and 60 kDa that are retained in ESKD, for which there is evidence of a link to inflammation and/or cardiovascular disease. These include inflammatory proteins, cytokines, adipokines and other signaling proteins. Improved clearance of this group of difficult to remove molecules has the potential to lead to improved outcomes in dialysis patients by reducing the burden of cardiovascular disease, which now needs to be assessed in robust clinical trials.

Exploring the Clinical Relevance of Providing Increased Removal of Large Middle Molecules.

Dialysis technologies have continued to advance over recent decades; however, these advancements have not always been met with improved patient outcomes. In part, the high morbidity and mortality associated with dialysis have been attributed to a group of uremic toxins, which are described as "difficult to remove." With a new generation of hemodialysis membranes now making meaningful clearance of these molecules possible, it is an apt time to review the clinical relevance of these middle molecules. Our review describes the developments in membrane technology that enable the removal of large middle molecules (molecular mass >15 kD) that is limited with high-flux dialysis membranes. Of the known 58 middle molecules, a literature search identified 27 that have molecular mass >15 kD. This group contains cytokines, adipokines, hormones, and other proteins. These molecules are implicated in chronic inflammation, atherosclerosis, structural heart disease, and secondary immunodeficiency in the literature. Single-center safety and efficacy studies have identified that use of these membranes in maintenance dialysis populations is associated with limited loss of albumin and increased clearance of large middle molecules. Larger, robustly conducted, multicenter studies are now evaluating these findings. After completion of these safety and efficacy studies, the perceived clinical benefits of providing clearance of large middle molecules must be assessed in rigorously conducted, randomized clinical studies.

The Association of Serum Free Light Chains With Mortality and Progression to End-Stage Renal Disease in Chronic Kidney Disease: Systematic Review and Individual Patient Data Meta-analysis.

OBJECTIVE: To clarify the associations between polyclonal serum free light chain (sFLC) levels and adverse outcomes in patients with chronic kidney disease (CKD) by conducting a systematic review and individual patient data meta-analyses. PATIENTS AND METHODS: On December 28, 2016, we searched 4 databases (MEDLINE, Embase, CINAHL, and PubMed) and conference proceedings for studies presenting independent analyses of associations between sFLC levels and mortality or progression to end-stage renal disease (ESRD) in patients with CKD. Study quality was assessed in 5 domains: sample selection, measurement, attrition, reporting, and funding. RESULTS: Five prospective cohort studies were included, judged moderate to good quality, involving 3912 participants in total. In multivariable meta-analyses, sFLC (kappa+lambda) levels were independently associated with mortality (5 studies, 3680 participants; hazard ratio [HR], 1.04 [95% CI, 1.03-1.06] per 10 mg/L increase in sFLC levels) and progression to ESRD (3 studies, 1848 participants; HR, 1.01 [95% CI, 1.00-1.03] per 10 mg/L increase in sFLC levels). The sFLC values above the upper limit of normal (43.3 mg/L) were independently associated with mortality (HR, 1.45 [95% CI, 1.14-1.85]) and ESRD (HR, 3.25 [95% CI, 1.32-7.99]). CONCLUSION: Higher levels of sFLCs are independently associated with higher risk of mortality and ESRD in patients with CKD. Future work is needed to explore the biological role of sFLCs in adverse outcomes in CKD, and their use in risk stratification.

The Rationale for Expanded Hemodialysis Therapy (HDx).

As dialysis membrane technologies have advanced, the ability to clear increasing numbers of uremic toxins has occurred. To date, however, the class of uremic toxins known as large middle-molecules has been classified as "difficult to remove." Expanded hemodialysis utilizes a new generation of high-retention-onset hemodialysis membranes; these membranes provide the ability to remove large middle-molecules effectively for the first time, without significant albumin loss. In this review, we evaluate the removal of large middle-molecules by the new high-retention-onset membranes, the clinical relevance of these molecules, and how expanded hemodialysis can be prescribed.

The treatment of paraprotein-related kidney disease.

PURPOSE OF REVIEW: Myeloma kidney and amyloid light-chain (AL) amyloidosis remain the principal kidney complications of paraproteins. In this review, we update readers to many of the recent advances which have occurred in the care and outcomes for patients with these presentations. RECENT FINDINGS: Myeloma kidney has historically caused a severe acute kidney injury with very poor outcomes. The combination of new diagnostic techniques, enabling a rapid diagnosis and novel chemotherapy agents has transformed these poor outcomes for the better. Two multicentre randomized controlled trials have recently evaluated if the removal of free light chains by high cut-off haemodialysis improves renal outcomes beyond effective chemotherapy alone. Although we await the full articles of these studies to be published, abstracts suggested the studies will have contradictory primary results. In the field of AL amyloidosis, there are now novel criteria for the risk stratification of kidney outcomes which can be used in combination with markers of early kidney response to provide clinicians with powerful tools to guide patient discussions. SUMMARY: Across both AL amyloidosis and myeloma kidney patient outcomes continue to improve. Principally this improvement has been driven by the continuing development of novel chemotherapy agents in this field.

Laboratory testing in monoclonal gammopathy of renal significance (MGRS).

Recently, monoclonal gammopathy of renal significance (MGRS) reclassified all monoclonal (M) gammopathies that are associated with the development of a kidney disease but do not meet the definition of symptomatic multiple myeloma (MM) or malignant lymphoma. The purpose was to distinguish the M gammopathy as the nephrotoxic agent independent from the clonal mass. The diagnosis of MGRS obviously depends on the detection of the M-protein. More importantly, the success of treatment is correlated with the reduction of the M-protein. Therefore, familiarity with the M-protein tests is a must. Protein electrophoresis performed in serum or urine is inexpensive and rapid due to automation. However, poor sensitivity especially with the urine is an issue particularly with the low-level M gammopathy often encountered with MGRS. Immunofixation adds to the sensitivity and specificity but also the cost. Serum free light chain (sFLC) assays have significantly increased the sensitivity of M-protein detection and is relatively inexpensive. It is important to recognize that there is more than one assay on the market and their results are not interchangeable. In addition, in certain diseases, immunofixation is more sensitive than sFLC. Finally, novel techniques with promising results are adding to the ability to identify M-proteins. Using the time of flight method, the use of mass spectrometry of serum samples has been shown to dramatically increase the sensitivity of M-protein detection. In another technique, oligomeric LCs are identified on urinary exosomes amplifying the specificity for the nephrotoxic M-protein.

Patients with multiple myeloma have excellent long-term outcomes after recovery from dialysis-dependent acute kidney injury.

OBJECTIVES: The aim of this study was to report the long-term outcomes in patients with multiple myeloma (MM) who receive dialysis treatment for acute kidney injury (AKI) due to myeloma cast nephropathy and subsequently recover renal function. METHODS: Patients presenting with dialysis-dependent AKI secondary to myeloma cast nephropathy and subsequently recovering independent renal function between January 2005 and December 2012 were included in this study. Both renal and haematological parameters were collected at multiple time points as part of routine clinic practice. Factors associated with renal function and overall survival (OS) were determined. RESULTS: Twenty-four patients fulfilled the criteria for inclusion. Mean age was 62.1 years; 75% were male and 75% were of White ethnicity. The median OS was 64.1 months (95% confidence interval [CI] 34.8-93.3). Twenty-three (95.8%) patients remained dialysis-independent until death or end of follow-up; one patient required further haemodialysis treatment during the follow-up period. The independent determinant of worse OS was a known history of chronic kidney disease (CKD) at presentation. Shorter length of time on haemodialysis and higher percentage reduction in clonal serum FLC at day 21 from baseline predicted better excretory renal function (estimated glomerular filtration rate) at 6 months. CONCLUSION: In this series, the large majority of patients with MM and dialysis-dependent AKI secondary to myeloma cast nephropathy who recovered independent renal function had no requirement for further dialysis. Survival following recovery of renal function is good, and early variables are independently associated with survival and future renal function.

The Association between Polyclonal Combined Serum Free Light Chain Concentration and Mortality in Individuals with Early Chronic Kidney Disease.

A major component of increased mortality risk in people with chronic kidney disease (CKD) is associated with non-traditional cardiovascular risk factors including markers of inflammation. We studied whether a novel marker of systemic inflammation, elevated serum combined polyclonal immunoglobulin free light chains (cFLC), was an independent risk factor for increased all-cause mortality in people with CKD stage 3. In a prospective community based cohort study, 1695 participants with stage 3 CKD and no cases of monoclonal gammopathy had cFLC concentrations measured. cFLC levels were determined using the summation of Freelite kappa and lambda assays. All other bioclinical variables were collected at the time of sample collection. Kaplan-Meier plots and Cox proportional hazards analysis was used to assess the relationship between high cFLC levels (>43.3 mg/L) and mortality. There were 167 deaths (10%) after a median of 1375 days. cFLC levels at recruitment were higher in participants who died compared with those who were alive at the end of the study; median: 46.5 mg/L (IQR: 36.1-65.4 mg/L) and 35.4 mg/L (28.1-46.6 mg/L) respectively, P <0.001. Kaplan-Meier survival analysis demonstrated participants with cFLC >43.3 mg/L levels had an increased risk of mortality compared to people with normal cFLC levels (P <0.001). Elevated cFLC levels were independently associated with worse survival (Hazard ratio: 1.50; 95% confidence interval: 1.04-2.16; P=0.03). Other independent risk factors for worse survival were: older age, male gender, previous cardiovascular event, lower eGFR and higher high sensitivity C-reactive protein (hsCRP). To conclude, high cFLC levels predict increased mortality in people with stage 3 CKD, independent of established risk factors and other markers of inflammation.

Diagnosis of monoclonal gammopathy of renal significance.

Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.

Extended high cut-off haemodialysis for myeloma cast nephropathy in Auckland, 2008-2012.

Myeloma cast nephropathy contributes to high morbidity and early mortality associated with the development of end-stage renal disease. Treatment with extended high cut-off haemodialysis coupled with novel anti-myeloma therapies enables significant reduction of serum-free light chains and has been shown to improve renal outcomes. In this case series, medical records of 6 patients who received high cut-off haemodialysis for biopsy-proven cast nephropathy were retrospectively reviewed. Patients received a total of 344 hours of high cut-off haemodialysis and concurrent chemotherapy. Only 50% became dialysis independent following treatment. One patient who achieved sustained remission remained dialysis dependent. The added benefit of high cut-off haemodialysis in the light of novel anti-myeloma therapies requires further evaluation.

Value of antibodies to free light chains in immunoperoxidase studies of renal biopsies.

AIMS: Because immunoglobulin abnormalities may affect the kidney, investigation of renal biopsies requires immunohistological study of light chains. A problem is that most antibodies to light chains react with whole immunoglobulins as well as free light chains, and there are generally many more whole immunoglobulins than free light chains. The usefulness of antibodies that only detected free light chains was investigated. METHODS: Antibodies to free light chains were used in an immunoperoxidase method on paraffin sections of 198 renal biopsies, and compared with conventional antibodies against light chains examined by immunofluorescence on 13 frozen sections and by immunoperoxidase on 46 paraffin sections. RESULTS: Immunofluorescence and immunoperoxidase were concordant on 10 of 13 biopsies. Immunofluorescence detected slight deposition of light chains in three biopsies not shown by immunoperoxidase, of undetermined clinical significance. Using immunoperoxidase, the free light chain antibodies were more sensitive than conventional antibodies, giving much cleaner staining and better detection of deposits in AL amyloid, light chain deposition disease and cryoglobulinaemic glomerulonephritis. The free light chain antibodies showed discordance or ambiguity between immunohistological and clinical findings in seven (4%) of 185 patients with known immunoglobulin status. These included two of 28 cases of AL amyloid that showed no light chain deposition. The method was not designed for detection of light chain restriction in neoplastic plasma or lymphoplasmacytic cells. CONCLUSIONS: Polyclonal antibodies to free light chains are an improvement on conventional antibodies in immunoperoxidase study of paraffin sections of renal biopsies and are useful in everyday practice.

Serum polyclonal immunoglobulin free light chain levels predict mortality in people with chronic kidney disease.

OBJECTIVE: To determine whether elevated serum polyclonal free light chain (FLC) levels predict mortality in a population of individuals with chronic kidney disease (CKD). PATIENTS AND METHODS: From January 2, 2006, through July 31, 2007, we recruited a cohort of 848 people with CKD who were not receiving renal replacement therapy and did not have monoclonal gammopathy. We measured serum kappa FLC and lambda FLC isotype levels to determine combined FLC (cFLC) levels. The cohort was prospectively followed up for a median of 63 months (interquartile range, 0-93 months). Cox regression analysis was performed to determine variables predictive of mortality. RESULTS: High cFLC levels were an independent risk factor for death (hazard ratio [HR], 2.71; 95% CI, 1.98-3.70; P<.001). Other independent risk factors were age (HR, 1.79; 95% CI, 1.52-2.10; P<.001), South Asian ethnicity (HR, 0.33; 95% CI, 0.14-0.64; P=.02), preexisting cardiovascular disease (HR, 1.59; 95% CI, 1.09-2.31; P=.02), and high-sensitivity C-reactive protein (HR, 1.13; 95% CI, 1.00-1.28; P=.04). Neither estimated glomerular filtration rate nor albuminuria was an independent risk factor for death. CONCLUSION: High cFLC levels independently predict mortality in people with CKD.

Elevated serum free light chains predict cardiovascular events in type 2 diabetes.

OBJECTIVE: Elevated polyclonal serum immunoglobulin free light chains (FLCs; combined FLCκ+FLCλ [cFLC]) are associated with adverse clinical outcomes and increased mortality; we investigated cFLC and cardiovascular disease (CVD) events in type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort study of 352 south Asian patients with type 2 diabetes, serum cFLC, high-sensitivity C-reactive protein (hsCRP), and standard biochemistry were measured. CVD events over 2 years were recorded and assessed using multiple logistic regression. RESULTS: cFLC levels were elevated significantly in 29 of 352 (8%) patients with CVD events during 2 years of follow-up (50.7 vs. 42.8 mg/L; P = 0.004). In multivariate analysis, elevated cFLC (>57.2 mg/L) was associated with CVD outcomes (odds ratio 3.3 [95% CI 1.3-8.2]; P = 0.012) and remained significant after adjusting for age, albumin-to-creatinine ratio, diabetes duration, or treatment. CONCLUSIONS: cFLC elevation is a novel marker for CVD outcomes in type 2 diabetes that warrants further investigation.