Neutralization, effector function and immune imprinting of Omicron variants.

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift.

The recently emerged SARS-CoV-2 Omicron variant encodes 37 amino acid substitutions in the spike protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody-based therapeutics. Here we show that the Omicron RBD binds to human ACE2 with enhanced affinity, relative to the Wuhan-Hu-1 RBD, and binds to mouse ACE2. Marked reductions in neutralizing activity were observed against Omicron compared to the ancestral pseudovirus in plasma from convalescent individuals and from individuals who had been vaccinated against SARS-CoV-2, but this loss was less pronounced after a third dose of vaccine. Most monoclonal antibodies that are directed against the receptor-binding motif lost in vitro neutralizing activity against Omicron, with only 3 out of 29 monoclonal antibodies retaining unaltered potency, including the ACE2-mimicking S2K146 antibody1. Furthermore, a fraction of broadly neutralizing sarbecovirus monoclonal antibodies neutralized Omicron through recognition of antigenic sites outside the receptor-binding motif, including sotrovimab2, S2X2593 and S2H974. The magnitude of Omicron-mediated immune evasion marks a major antigenic shift in SARS-CoV-2. Broadly neutralizing monoclonal antibodies that recognize RBD epitopes that are conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.

Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury.

Acute kidney injury (AKI), commonly caused by ischemia, sepsis, or nephrotoxic insult, is associated with increased mortality and a heightened risk of chronic kidney disease (CKD). AKI results in the dysfunction or death of proximal tubule cells (PTCs), triggering a poorly understood autologous cellular repair program. Defective repair associates with a long-term transition to CKD. We performed a mild-to-moderate ischemia-reperfusion injury (IRI) to model injury responses reflective of kidney injury in a variety of clinical settings, including kidney transplant surgery. Single-nucleus RNA sequencing of genetically labeled injured PTCs at 7-d ("early") and 28-d ("late") time points post-IRI identified specific gene and pathway activity in the injury-repair transition. In particular, we identified Vcam1+/Ccl2+ PTCs at a late injury stage distinguished by marked activation of NF-κB-, TNF-, and AP-1-signaling pathways. This population of PTCs showed features of a senescence-associated secretory phenotype but did not exhibit G2/M cell cycle arrest, distinct from other reports of maladaptive PTCs following kidney injury. Fate-mapping experiments identified spatially and temporally distinct origins for these cells. At the cortico-medullary boundary (CMB), where injury initiates, the majority of Vcam1+/Ccl2+ PTCs arose from early replicating PTCs. In contrast, in cortical regions, only a subset of Vcam1+/Ccl2+ PTCs could be traced to early repairing cells, suggesting late-arising sites of secondary PTC injury. Together, these data indicate even moderate IRI is associated with a lasting injury, which spreads from the CMB to cortical regions. Remaining failed-repair PTCs are likely triggers for chronic disease progression.

A data-driven approach to identify risk profiles and protective drugs in COVID-19.

As the COVID-19 pandemic is spreading around the world, increasing evidence highlights the role of cardiometabolic risk factors in determining the susceptibility to the disease. The fragmented data collected during the initial emergency limited the possibility of investigating the effect of highly correlated covariates and of modeling the interplay between risk factors and medication. The present study is based on comprehensive monitoring of 576 COVID-19 patients. Different statistical approaches were applied to gain a comprehensive insight in terms of both the identification of risk factors and the analysis of dependency structure among clinical and demographic characteristics. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2), but whether or not renin-angiotensin-aldosterone system inhibitors (RAASi) would be beneficial to COVID-19 cases remains controversial. The survival tree approach was applied to define a multilayer risk stratification and better profile patient survival with respect to drug regimens, showing a significant protective effect of RAASi with a reduced risk of in-hospital death. Bayesian networks were estimated, to uncover complex interrelationships and confounding effects. The results confirmed the role of RAASi in reducing the risk of death in COVID-19 patients. De novo treatment with RAASi in patients hospitalized with COVID-19 should be prospectively investigated in a randomized controlled trial to ascertain the extent of risk reduction for in-hospital death in COVID-19.

Proximal tubule responses to injury: interrogation by single-cell transcriptomics.

PURPOSE OF REVIEW: Acute kidney injury (AKI) occurs in approximately 10-15% of patients admitted to hospital and is associated with adverse clinical outcomes. Despite recent advances, management of patients with AKI is still mainly supportive, including the avoidance of nephrotoxins, volume and haemodynamic management and renal replacement therapy. A better understanding of the renal response to injury is the prerequisite to overcome current limitations in AKI diagnostics and therapy. RECENT FINDINGS: Single-cell technologies provided new opportunities to study the complexity of the kidney and have been instrumental for rapid advancements in the understanding of the cellular and molecular mechanisms of AKI. SUMMARY: We provide an update on single-cell technologies and we summarize the recent discoveries on the cellular response to injury in proximal tubule cells from the early response in AKI, to the mechanisms of tubule repair and the relevance of maladaptive tubule repair in the transition to chronic kidney disease.

Decreased Renal Gluconeogenesis Is a Hallmark of Chronic Kidney Disease.

INTRODUCTION: CKD is associated with alterations of tubular function. Renal gluconeogenesis is responsible for 40% of systemic gluconeogenesis during fasting, but how and why CKD affects this process and the repercussions of such regulation are unknown. METHODS: We used data on the renal gluconeogenic pathway from more than 200 renal biopsies performed on CKD patients and from 43 kidney allograft patients, and studied three mouse models, of proteinuric CKD (POD-ATTAC), of ischemic CKD, and of unilateral urinary tract obstruction. We analyzed a cohort of patients who benefitted from renal catheterization and a retrospective cohort of patients hospitalized in the intensive care unit. RESULTS: Renal biopsies of CKD and kidney allograft patients revealed a stage-dependent decrease in the renal gluconeogenic pathway. Two animal models of CKD and one model of kidney fibrosis confirm gluconeogenic downregulation in injured proximal tubule cells. This shift resulted in an alteration of renal glucose production and lactate clearance during an exogenous lactate load. The isolated perfused kidney technique in animal models and renal venous catheterization in CKD patients confirmed decreased renal glucose production and lactate clearance. In CKD patients hospitalized in the intensive care unit, systemic alterations of glucose and lactate levels were more prevalent and associated with increased mortality and a worse renal prognosis at follow-up. Decreased expression of the gluconeogenesis pathway and its regulators predicted faster histologic progression of kidney disease in kidney allograft biopsies. CONCLUSION: Renal gluconeogenic function is impaired in CKD. Altered renal gluconeogenesis leads to systemic metabolic changes with a decrease in glucose and increase in lactate level, and is associated with a worse renal prognosis.

Renal gluconeogenesis: an underestimated role of the kidney in systemic glucose metabolism.

Glucose levels are tightly regulated at all times. Gluconeogenesis is the metabolic pathway dedicated to glucose synthesis from non-hexose precursors. Gluconeogenesis is critical for glucose homoeostasis, particularly during fasting or stress conditions. The renal contribution to systemic gluconeogenesis is increasingly recognized. During the post-absorptive phase, the kidney accounts for ∼40% of endogenous gluconeogenesis, occurring mainly in the kidney proximal tubule. The main substrate for renal gluconeogenesis is lactate and the process is regulated by insulin and cellular glucose levels, but also by acidosis and stress hormones. The kidney thus plays an important role in the maintenance of glucose and lactate homoeostasis during stress conditions. The impact of acute and chronic kidney disease and proximal tubular injury on gluconeogenesis is not well studied. Recent evidence shows that in both experimental and clinical acute kidney injury, impaired renal gluconeogenesis could significantly participate in systemic metabolic disturbance and thus alter the prognosis. This review summarizes the biochemistry of gluconeogenesis, the current knowledge of kidney gluconeogenesis, its modifications in kidney disease and the clinical relevance of this fundamental biological process in human biology.

Long-term outcomes of transplant kidneys donated after circulatory death.

BACKGROUND: Donation after circulatory death (DCD) represents up to 40% of used kidney grafts. While studies have shown similar outcomes compared with donation after brain death (DBD) in the short term and mid-term, no data on long-term outcomes exist. METHODS: We retrospectively analysed patients transplanted at our institution between January 1985 and March 2000. All DCD recipients were matched one-to-one with patients transplanted with DBD grafts during this period according to sex, age and year of transplantation and followed up until December 2020. During this period, 1133 kidney transplantations were performed, of which 122 were with a DCD graft. RESULTS: The median graft survival after 35 years of follow-up was 23 years [277 months {95% confidence interval (CI) 182-372}] in DBD recipients and 24.5 years [289 months (95% CI 245-333)] in DCD recipients (P = 0.65; hazard ratio 0.91). Delayed graft function occurred in 47 patients in the DCD group compared with 23 in the DBD group (P < 0.001), albeit without a significant long-term outcome difference in graft or patient survival. We could not show any difference in graft function in terms of creatinine levels (133 versus 119 µmol/L), proteinuria (370 versus 240 mg/24 h) and glomerular filtration rate slope (-0.6 versus -0.3 mL/min/year) between the two groups for graft survival >20 years. CONCLUSIONS: This is the first study to show similar graft survival and function in DCD kidneys compared with DBD kidneys after 35 years of follow-up. DCD grafts are a valuable resource and can be utilized in the same way as DBD grafts.

Study protocol for Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) : A multi-center, multinational validation study to assess the accuracy and feasibility of measuring vascular access function in clinical practice.

BACKGROUND: A functioning vascular access (VA) is crucial to providing adequate hemodialysis (HD) and considered a critically important outcome by patients and healthcare professionals. A validated, patient-important outcome measure for VA function that can be easily measured in research and practice to harvest reliable and relevant evidence for informing patient-centered HD care is lacking. Vascular Access outcome measure for function: a vaLidation study In hemoDialysis (VALID) aims to assess the accuracy and feasibility of measuring a core outcome for VA function established by the international Standardized Outcomes in Nephrology (SONG) initiative. METHODS: VALID is a prospective, multi-center, multinational validation study that will assess the accuracy and feasibility of measuring VA function, defined as the need for interventions to enable and maintain the use of a VA for HD. The primary objective is to determine whether VA function can be measured accurately by clinical staff as part of routine clinical practice (Assessor 1) compared to the reference standard of documented VA procedures collected by a VA expert (Assessor 2) during a 6-month follow-up period. Secondary outcomes include feasibility and acceptability of measuring VA function and the time to, rate of, and type of VA interventions. An estimated 612 participants will be recruited from approximately 10 dialysis units of different size, type (home-, in-center and satellite), governance (private versus public), and location (rural versus urban) across Australia, Canada, Europe, and Malaysia. Validity will be measured by the sensitivity and specificity of the data acquisition process. The sensitivity corresponds to the proportion of correctly identified interventions by Assessor 1, among the interventions identified by Assessor 2 (reference standard). The feasibility of measuring VA function will be assessed by the average data collection time, data completeness, feasibility questionnaires and semi-structured interviews on key feasibility aspects with the assessors. DISCUSSION: Accuracy, acceptability, and feasibility of measuring VA function as part of routine clinical practice are required to facilitate global implementation of this core outcome across all HD trials. Global use of a standardized, patient-centered outcome measure for VA function in HD research will enhance the consistency and relevance of trial evidence to guide patient-centered care. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03969225. Registered on 31st May 2019.

Renal Safety of Multimodal Brain Imaging Followed by Endovascular Therapy.

BACKGROUND AND PURPOSE: Contrast-enhanced noninvasive angiography and perfusion imaging are recommended to identify eligible patients for endovascular therapy (EVT) in extended time windows (>6 hours or wake-up). If eligible, additional intraarterial contrast exposure will occur during EVT. We aimed to study the renal safety in the DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) population, selected with contrast-enhanced multimodal Imaging and randomized to EVT versus medical management. METHODS: In the randomized DEFUSE 3 trial population, we compared changes in serum creatinine between baseline (before randomization) and 24 hours later. The primary outcome was the relative change in creatinine level between baseline and 24 hours in the EVT versus medical arm. The secondary outcome was a comparison between computed tomography (CT) versus magnetic resonance imaging selection in the EVT arm. The safety outcome was a comparison of the proportion of patients with criteria for contrast-associated kidney injury in the EVT versus medical arm and a comparison between CT versus magnetic resonance imaging selection in the EVT arm. RESULTS: In the DEFUSE 3 population (n=182, age 69±13, 51% female), mean creatinine decreased from a baseline of 0.98±0.33 mg/dL to 0.88±0.28 mg/dL at 24 hours (P<0.001). There was no difference in change between treatment groups: relative to baseline, there was a 6.3% reduction in the EVT group versus 9.2% in the medical group, P=0.294. Absolute decrease -0.08±0.18 in EVT versus -0.12±0.18 in medical, P=0.135; Among patients treated with EVT, there was no difference in 24-hour creatinine level changes between patients who were selected with CT angiography/CT perfusion (-0.08±0.18) versus magnetic resonance imaging (-0.07±0.19), P=0.808 or 6.8% reduction versus 4.8%, P=0.696. In the EVT arm, contrast-associated kidney injury was encountered in 4 out of 91 (4.4%) versus 2/90 (2.2%) in the medical arm P=0.682. In the EVT arm, contrast-associated kidney injury was evenly distributed between magnetic resonance imaging (1/22, 4.6%) versus CT 3 out of 69 (4.4%), P=1.0. CONCLUSIONS: Perfusion imaging before EVT was not associated with evidence of decline in renal function. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02586415.

Vascular endothelial growth factor D is a biomarker of fluid overload in haemodialysis patients.

BACKGROUND: Improved understanding and assessment of the complex physiology of volume regulation in haemodialysis (HD) patients are required to improve patient care and reduce mortality associated with fluid overload (FO). METHODS: We searched for FO-related biomarkers among 184 peptides associated with cardiovascular disease in a cohort of 30 HD patients. First, we assessed the direct impact of HD on the peptides of interest by comparing plasma concentrations before and after treatment. Then, we compared cardiovascular peptide profiles between patients with and without FO as defined by bioimpedance analysis (BIA). The plasma concentration of selected candidate biomarkers for FO was determined by enzyme-linked immunosorbent assay (ELISA) and correlated with previously described FO-related clinical and laboratory parameters. For validation, results were confirmed in an independent cohort of 144 HD patients. RESULTS: We found seven peptides positively [NT-proBNP, B-type natriuretic peptide (BNP), vascular endothelial growth factor D (VEGFD), tumour necrosis factor-related apoptosis-inducing ligand receptor 2, growth differentiation factor 15, tumour necrosis factor ligand superfamily member 13B, chitinase-3-like protein 1] and five negatively (leptin, renin, epidermal growth factor receptor, interleukin-1 receptor antagonist, myeloblastin) correlated to FO. In addition to natriuretic peptides, VEGFD emerged as third peptide highly correlated with BIA (ρ = 0.619, P < 0.0001). In line with this, VEGFD concentration verified by ELISA correlated with BIA, BNP and soluble CD146 but not with vascular endothelial growth factor C (VEGFC). Notably, levels of VEGFD were unrelated to cardiac systolic function (P = 0.63), contrary to BNP (P = 0.0003). Finally, we observed that 1-year all-cause mortality was higher in patients with high BNP (P = 0.0002), FO (defined by BIA, P = 0.04) and high VEGFD (P = 0.02), but not with high VEGFC (P = 0.48). CONCLUSION: VEGFD is a novel FO-related biomarker with unique diagnostic and prognostic properties.

Differential role of nicotinamide adenine dinucleotide deficiency in acute and chronic kidney disease.

BACKGROUND: Nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme involved in electron transport and a co-substrate for sirtuin function. NAD+ deficiency has been demonstrated in the context of acute kidney injury (AKI). METHODS: We studied the expression of key NAD+ biosynthesis enzymes in kidney biopsies from human allograft patients and patients with chronic kidney disease (CKD) at different stages. We used ischaemia-reperfusion injury (IRI) and cisplatin injection to model AKI, urinary tract obstruction [unilateral ureteral obstruction (UUO)] and tubulointerstitial fibrosis induced by proteinuria to investigate CKD in mice. We assessed the effect of nicotinamide riboside (NR) supplementation on AKI and CKD in animal models. RESULTS: RNA sequencing analysis of human kidney allograft biopsies during the reperfusion phase showed that the NAD+de novo synthesis is impaired in the immediate post-transplantation period, whereas the salvage pathway is stimulated. This decrease in de novo NAD+ synthesis was confirmed in two mouse models of IRI where NR supplementation prevented plasma urea and creatinine elevation and tubular injury. In human biopsies from CKD patients, the NAD+de novo synthesis pathway was impaired according to CKD stage, with better preservation of the salvage pathway. Similar alterations in gene expression were observed in mice with UUO or chronic proteinuric glomerular disease. NR supplementation did not prevent CKD progression, in contrast to its efficacy in AKI. CONCLUSION: Impairment of NAD+ synthesis is a hallmark of AKI and CKD. NR supplementation is beneficial in ischaemic AKI but not in CKD models.

Severe restless legs syndrome in a family with Alport syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a common sleep-related movement disorder characterized by an urge to move the legs during inactivity, especially at evening-night. RLS is highly prevalent in patients with kidney failure and have an impact on quality of life, mood, sleep quality and overall on compliance to the dialysis. Alport syndrome (AS) is a rare inherited disease, predominantly X-linked, secondary to mutations in genes encoding α3, α4 or α5 chains of type IV collagen, and characterized by hematuria, chronic kidney disease, neurosensory deafness, and lenticonus. CASE PRESENTATION: Here we describe a family with a combination of X-linked AS and severe RLS accompanied by periodic limb movements during sleep (PLMS). In the first patient we identified, RLS was complicated by a paradoxical response to dopamine agonists named "augmentation", leading to sleep disruption, hallucinations and five peritoneal perforations during the peritoneal dialysis due to the difficulty to rest still. Therapeutic adjustments and renal transplantation improved RLS and PLMS. In two brothers, severe RLS prevented a compliance with hemodialysis. Female family members carrying the mutation were also affected by RLS, while those without the mutations were RLS-free. CONCLUSIONS: RLS has not been reported earlier in association with AS, but the peculiar combinations observed in this family will stimulate further clinical studies and motivate nephrologists to seek for RLS symptoms and sleep disturbances in AS patients.

Renoprotective and Immunomodulatory Effects of GDF15 following AKI Invoked by Ischemia-Reperfusion Injury.

BACKGROUND: Gdf15 encodes a TGF-ß superfamily member that is rapidly activated in response to stress in multiple organ systems, including the kidney. However, there has been a lack of information about Gdf15 activity and effects in normal kidney and in AKI. METHODS: We used genome editing to generate a Gdf15nuGFP-CE mouse line, removing Gdf15 at the targeted allele, and enabling direct visualization and genetic modification of Gdf15-expressing cells. We extensively mapped Gdf15 expression in the normal kidney and following bilateral ischemia-reperfusion injury, and quantified and compared renal responses to ischemia-reperfusion injury in the presence and absence of GDF15. In addition, we analyzed single nucleotide polymorphism association data for GDF15 for associations with patient kidney transplant outcomes. RESULTS: Gdf15 is normally expressed within aquaporin 1-positive cells of the S3 segment of the proximal tubule, aquaporin 1-negative cells of the thin descending limb of the loop of Henle, and principal cells of the collecting system. Gdf15 is rapidly upregulated within a few hours of bilateral ischemia-reperfusion injury at these sites and new sites of proximal tubule injury. Deficiency of Gdf15 exacerbated acute tubular injury and enhanced inflammatory responses. Analysis of clinical transplantation data linked low circulating levels of GDF15 to an increased incidence of biopsy-proven acute rejection. CONCLUSIONS: Gdf15 contributes to an early acting, renoprotective injury response, modifying immune cell actions. The data support further investigation in clinical model systems of the potential benefit from GDF15 administration in situations in which some level of tubular injury is inevitable, such as following a kidney transplant.

Soluble CD146 and B-type natriuretic peptide dissect overhydration into functional components of prognostic relevance in haemodialysis patients.

Background: Accurate volume status evaluation and differentiation of cardiac and non-cardiac components of overhydration (OH) are fundaments of optimal haemodialysis (HD) management. Methods: This study, by combining bioimpedance measurements, cardiovascular biomarkers and echocardiography, aimed at dissecting OH into its major functional components, and prospectively tested the association between cardiac and non-cardiac components of OH with mortality. In the first part, we validated soluble CD146 (sCD146) as a non-cardiac biomarker of systemic congestion in a cohort of 30 HD patients. In the second part, we performed a prospective 1-year follow-up study in an independent cohort of 144 HD patients. Results: sCD146 incrementally increased after the short and long intervals after HD (+53 ng/mL, P = 0.006 and +91 ng/mL, P < 0.001), correlated with OH as determined by bioimpedance and well-diagnosed OH (area under the receiver operating characteristics curve 0.72, P = 0.005). The prevalence of OH was lower for low-sCD146 and low-BNP patients (B-type natriuretic peptide, 29%) compared with subjects with either one or both biomarkers elevated (65-74%, P < 0.001). Notably, most low-BNP but high-sCD146 subjects were overhydrated. Systolic dysfunction was 2- to 3-fold more prevalent among high-BNP compared with low-BNP patients (44-68% versus 21-23%, chi-square P < 0.001), regardless of sCD146. One-year all-cause mortality was markedly higher in patients with high-BNP (P = 0.001) but not with high-sCD146. In multivariate analysis, systolic dysfunction and BNP, but not OH, were associated with lower survival. Conclusions: The combination of BNP and sCD146 dissects OH into functional components of prognostic value. OH in HD patients is associated with higher mortality only if resulting from cardiac dysfunction.

High accuracy of proximity extension assay technology for the quantification of plasma brain natriuretic peptide.

BACKGROUND: Novel multiplex assays allow the simultaneous identification of a large number of plasma proteins. While these new technologies have been shown to be highly sensitive and accurate for the identification of plasma proteins, the use of this technology to quantify those proteins has not been properly investigated. In this pilot study, we tested the accuracy of the proximity extension assay (PEA) for the quantification of the cardiac biomarker brain natriuretic peptide (BNP) compared to a standard clinically approved method. METHODS: Concentrations of BNP were assessed in 120 plasma samples from 30 patients with PEA and compared to chemiluminescent microparticle immunoassay (CMIA). Venous blood samples were collected from in tubes containing ethylenediaminetetraacetic acid, centrifuged within 6 hours at 3,500 rpm for 15 minutes at 4°C, frozen and stored at -80°C until analyzed. Correlation between the CMIA and PEA techniques was tested using the Spearman's rank correlation coefficient (rho) and the agreement was described with a Bland-Altman plot. RESULTS: Brain natriuretic peptide values obtained by CMIA and PEA were highly correlated (Spearman's rho = 0.865, P < .0001). In two patients, PEA consistently overestimated resp. underestimated BNP values compared to CMIA. After removal of those two patients, a very high correlation between the two techniques was shown (rho = 0.966, P < .0001). A high agreement between the two techniques over the whole range of tested concentrations was shown. CONCLUSION: This pilot study showed for the first time an excellent correlation between a clinically approved method and the PEA-based approach for quantification of circulating plasma BNP.

Cardiorenal Interactions Revisited: How to Improve Heart Failure Outcomes in Patients With Chronic Kidney Disease.

PURPOSE OF THE REVIEW: To summarize current advances in the understanding and management of heart failure (HF) in patients with advanced chronic kidney disease (CKD). RECENT FINDINGS: Diagnosis of HF and treatment of congestion are crucial in the management of patients with advanced CKD to reduce symptoms, preserve organ function, and improve outcomes. Echocardiography and cardiovascular biomarkers may help to differentiate cardiac from non-cardiac components of overhydration. Renal replacement therapy or ultrafiltration may be required to treat congestion. Furthermore, patients with advanced CKD are frequently undertreated with disease-modifying HF therapies, but the use of beta-blockers and ACEi should be considered under close monitoring of kidney function and serum potassium. The use of the new oral potassium binders may translate into improved outcomes. The treatment of HF in patients with advanced CKD requires a multi-disciplinary approach. New diagnostic and therapeutic strategies are under evaluation and may contribute to improved outcomes.