Rationale for a New Classification of Solutes of Interest in Chronic Kidney Disease and Hemodialysis.

A hallmark of chronic kidney disease is the retention of solutes that normally are eliminated by the kidneys. The current classification defines uremic toxins based on molecular weight and protein affinity. The retention of solutes is already detected in the early stages of the disease when patients are pauci-symptomatic or asymptomatic but the role of therapies to retard the loss of kidney function in patients with chronic kidney disease (e.g., modulators of the renin-angiotensin-aldosterone system, sodium-glucose cotransporter inhibitors) in reducing uremic toxins is poorly understood. Most of the research evaluating the impact of therapies to lower serum concentrations of those toxic compounds is carried out in patients with kidney failure already undergoing kidney replacement therapy. The removal of those molecules relies in physicochemical mass transfer phenomena, i.e., adsorption, diffusion, and convection. In the past 2 decades, the rise and broad adoption of blood purification strategies with enhanced convective properties, such as high-volume online hemodiafiltration and expanded hemodialysis, considerably amplified the ability to mechanically extract middle molecules (molecular weight >0.5 kDa) from the blood compartment. Nonetheless, the classification of uremic toxins has not evolved in parallel with dialysis advancements. Mounting evidence demonstrates the link between middle molecules with uremic symptoms, cardiovascular and mortality risks. An urgent need for updating the classification exists. Defining the causative relationship between specific solutes and specific clinical outcomes will promote the development of targeted therapies. In parallel, the inclusion of new pertinent dimensions to the classification like the influence of new dialysis membranes, sorbents, and intestinal chelators in the concentration of uremic toxins would improve the understanding of the pathogenesis of chronic kidney disease, setting the pace for future research in nephrology.

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.

The ethics of treating family members.

PURPOSE OF REVIEW: Many medical professionals receive requests from family and friends asking for medical advice and treatment. But should medics treat their family? Ethically can we treat, or refuse to treat, family members? This is a common ethical challenge that most doctors face during their career and there is limited evidence available. By examining ethical principles, we aim to answer these questions and provide a framework that will guide decision making in this area. RECENT FINDINGS: There is a paucity of evidence available. Many ethical systems exist and have been discussed since ancient Greece but in recent years, bioethics has become more prominent in medical thinking and debate. SUMMARY: We examine ethical systems such as virtue ethics, utilitarianism, deontology and principlism and how they relate to treating family members. We then look at cases in different contexts and describe a system for approaching such cases, allowing doctors to conform to moral standards, and consider ethical arguments, prior to embarking upon any treatment course with a relative.

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.

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.

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.

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.

Comparison of Freelite™ and N Latex serum free light chain assays in subjects with end stage kidney disease on haemodialysis.

BACKGROUND: Quantification of serum free light chains (FLC) is important in the diagnosis of plasma cell diseases where an abnormal kappa:lambda ratio infers a population of monoclonal plasma cells. The Freelite™ and N Latex assays have been validated in populations without kidney disease but there is a paucity of data relating to the use of these assays in end stage kidney disease (ESKD). The aim of the study was to compare FLC assay performance in ESKD patients on haemodialysis. METHODS: Cross-sectional multi-centre study comparing the performance of the two assays on 112 haemodialysis patients without known paraproteinaemia. We quantified FLC pre- and post-dialysis using both the N Latex and the Freelite assays. RESULTS: FLC levels were elevated by both assays. Lambda FLC levels were considerably higher by the N Latex assay. Using the proposed renal reference range for Freelite (0.37-3.1) all but one patient had normal kappa:lambda FLC ratios. In contrast, there were no abnormal FLC ratios pre-dialysis using the N Latex assay. This was due to lambda FLC reading significantly higher by the N Latex assay. Kappa and lambda FLC levels decreased with dialysis but remained elevated above the normal range. The excess of lambda FLC by N Latex persisted post-dialysis but was somewhat attenuated. Dialysis adequacy and dialysis modality predicted clearance of kappa and lambda FLC by both assays. CONCLUSIONS: The N Latex assay reported significantly higher pre-dialysis lambda FLC concentrations compared with the Freelite assays. Clinicians should be aware of the need for a separate renal reference range for interpreting FLC ratio using the Freelite assay but not for the N Latex assay in ESKD patients.

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.

Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant.

Multiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.

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.

Immunoglobulin free light chain levels and recovery from myeloma kidney on treatment with chemotherapy and high cut-off haemodialysis.

BACKGROUND: To determine the efficacy of immunoglobulin free light chain (FLC) removal by high cut-off haemodialysis (HCO-HD) as an adjuvant treatment to chemotherapy for patients with acute kidney injury complicating multiple myeloma (MM). METHODS: Sixty-seven patients with dialysis-dependent renal failure secondary to MM were treated with HCO-HD and chemotherapy. RESULTS: The population was predominantly male (62.7%) with new presentation MM (75%) and did not have a history of chronic kidney disease (84%). The mean serum creatinine at presentation was 662 (SD = 349) µmol/L and of the 56.7% of patients who had a renal biopsy, 86.7% had cast nephropathy as the principal diagnosis. Eighty-five percent of patients were treated with a chemotherapy regime consisting of dexamethasone in combination with a novel agent (bortezomib or thalidomide). The median number of HCO-HD sessions was 11 (range 3-45), 97% received an extended dialysis regime. Seventy-six percent of the population had a sustained reduction in serum FLC concentrations by Day 12, of these 71% subsequently became independent of dialysis. In total, 63% of population became independent of dialysis. Factors which predicted independence of dialysis were the degree of FLC reduction at Days 12 (P = 0.002) and 21 (P = 0.005) and the time to initiating HCO-HD (P = 0.006). CONCLUSION: The combination of extended HCO-HD and chemotherapy resulted in sustained reductions in serum FLC concentrations in the majority of patients and a high rate of independence of dialysis.

Diagnostic accuracy of monoclonal antibody based serum immunoglobulin free light chain immunoassays in myeloma cast nephropathy.

BACKGROUND: The development of serum immunoassays for the measurement of immunoglobulin free light chains has led to a paradigm shift in the diagnosis, assessment and monitoring of patients with plasma cell dyscrasias. The impact of these immunoassays which employ polyclonal antibodies was most notable for those patients who were previously classified as non-secretory multiple myeloma. Recently new monoclonal antibody based assays have become available. The purpose of this study was to compare the diagnostic sensitivity of these new assays with those already in clinical practice. METHODS: Sera from 30 patients who present with severe acute kidney injury and multiple myeloma were identified for analysis. A head to head comparison of the two commercially available free light chains assays was then undertaken to determine if their diagnostic sensitivity and specificity were comparable. RESULTS: In this first assessment of the utility of these new assays, we found that one of 17 patients with a lambda monoclonal free light chain resulting in acute kidney injury were not identified and a further 12% of patients were wrongly classified as having levels below those associated with disease specific acute kidney injury. CONCLUSION: These results suggest that caution should be applied to the use of new free light chain assays in the assessment of patients with a monoclonal gammopathy.

Early reduction of serum-free light chains associates with renal recovery in myeloma kidney.

Myeloma kidney is the major cause of severe irreversible renal failure in patients with multiple myeloma. This tubulointerstitial injury is a direct consequence of high concentrations of circulating monoclonal free light chains (FLCs) produced by a clonal expansion of plasma cells. Early reduction of serum FLCs associates with renal recovery, but the target threshold of reduction to facilitate renal recovery is unknown. To determine the relationship between the achieved FLC reduction and renal recovery, we identified 39 patients with biopsy-proven myeloma kidney, the majority of whom had severe renal failure at presentation (median estimated GFR 9 ml/min per 1.73 m²). In a multivariable analysis incorporating demographic, hematologic, and renal variables, only the achieved FLC reduction significantly predicted renal recovery (P = 0.003). The relationship between renal recovery and FLC reduction was linear with no absolute threshold for FLC reduction. A 60% reduction in FLCs by day 21 associated with recovery of renal function for 80% of the population. Patient survival strongly associated with renal recovery: the median survival was 42.7 months (range 0 to 80) among those who recovered function compared with 7.8 months (range 0 to 54) among those who did not (P < 0.02). Cox-regression analysis demonstrated that the first presentation of myeloma, the kappa isotype of FLC, and renal recovery were independent predictors of survival. In conclusion, recovery of renal function in myeloma kidney depends on early reduction of serum FLCs, and this recovery associates with a significant survival advantage.

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.

The biology of immunoglobulin free light chains and kidney injury.

Kidney injury caused by immunoglobulin free light chains (FLCs) in the setting of plasma cell dyscrasias is common and associated with increased morbidity and mortality. All compartments of the kidney may be affected, from the glomerulus to the tubulointerstitium, in a wide variety of disease patterns. Here, we review our current knowledge of the biological effects of FLCs and the mechanisms that lead to kidney injury.

Aggregated serum free light chains may prevent adequate removal by high cut-off haemodialysis.

Free light chain (FLC) removal by high cut-off haemodialysis has been described as an adjuvant therapy for the management of patients with severe renal failure complicating multiple myeloma. The two cases reported here are the first patients in whom this treatment did not remove FLCs. In both patient's sera, size-exclusion chromatography identified large FLC aggregates, with molecular weights above the cut-off of the dialyser. It is important for clinicians to be aware of FLC aggregates as a reason for failure to remove FLCs by this new modality.

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.

Classification of Uremic Toxins and Their Role in Kidney Failure.

Advances in our understanding of uremic retention solutes, and improvements in hemodialysis membranes and other techniques designed to remove uremic retention solutes, offer opportunities to readdress the definition and classification of uremic toxins. A consensus conference was held to develop recommendations for an updated definition and classification scheme on the basis of a holistic approach that incorporates physicochemical characteristics and dialytic removal patterns of uremic retention solutes and their linkage to clinical symptoms and outcomes. The major focus is on the removal of uremic retention solutes by hemodialysis. The identification of representative biomarkers for different classes of uremic retention solutes and their correlation to clinical symptoms and outcomes may facilitate personalized and targeted dialysis prescriptions to improve quality of life, morbidity, and mortality. Recommendations for areas of future research were also formulated, aimed at improving understanding of uremic solutes and improving outcomes in patients with CKD.

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.