IntroductionSide effects of calcineurin inhibitors (CNI) comprise hypertension, diabetes and nephrotoxicity, and endothelial dysfunction (ED) has often been implicated. Belatacept, a co-stimulation blocker, may offer a more favourable vascular profile.MethodsWe investigated markers of endothelial function in blood samples from kidney transplant recipients (KTR) that were converted from CNI to belatacept. We assessed established markers of ED including soluble thrombomodulin, P-selectin and angiopoietin 1 and 2. In addition, we assessed expression levels of microRNAs (miRNAs), which have been identified as discriminative markers for ED, rejection and renal fibrosis in the setting of transplantation. Lastly, we used patient samples and CNI-dilution series in a validated model of ED in which changes in morphological characteristics of endothelial cells were evaluated.ResultsUnexpectedly, we found no differences in our assays between both groups. We did observe dose-related effects of CNI on endothelial cell (EC) morphology upon direct exposure of EC to tacrolimus and ciclosporin A, but a similar effect was not seen when plasma samples of KTR who were converted to belatacept were compared with samples from KTR on CNI's.DiscussionThese data suggest that CNI-side-effects bundled under the term “CNI-toxicity” are not derived from a significant clinical effect of CNI on endothelial function.

Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio. In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's C -index; added value by the fraction of new information (FNI). Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61–94) and eGFRcr 79 (IQR: 65–91) mL/min/1.73 m 2 . Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49–2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68–0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80–2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70–2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13–1.46, FNI 5%). In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.

Immunoglobulin A nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN) are inflammatory diseases that frequently progress to end-stage kidney disease (ESKD). Biomarkers for early detection and monitoring of disease progression or interventions are needed. Inflammation-related proteins, including cytokines and chemokines, play a crucial role in the initiation and maintenance of kidney inflammation and have been implicated in IgAN development. We aimed to detect potential new serum biomarkers for the prediction of disease progression and treatment response in IgAN and IgAVN. A Swedish single center cohort with biopsy-proven IgAN or IgAVN was studied. Serum samples were collected at the time of kidney biopsy and during the follow-up period (1994–2019), with sample collection completed by 2015. The median clinical follow-up time was 10.7 years, and the median eGFR slope was −1.6 mL/min per year. Samples were analyzed using the OLINK Proximity Extension Assay (PEA) Inflammation panel, a multiplex immunoassay technology designed to detect and quantify 96 inflammation-related proteins. We used linear mixed-effect models to determine yearly change of GFR (eGFR slope) and adjusted linear regression models, Random Forest and Boruta to evaluate associations between detected proteins and markers of disease severity and progression: eGFR, eGFR slope, 24-hour albuminuria at the time of kidney biopsy (U-alb/24 h) and during follow up (time average albuminuria, TAA). Variables were also tested for correlation with the predicted 5-year risk of 50% eGFR decline or ESKD using the International IgAN Prediction Tool (IIgAN-PT). U-alb/24 h, TAA and IIgAN-PT-risk were log2 transformed due to skewed distribution in the cohort. To adjust for multiplicity the significance level was set at 0.05/92. A total of 92 patients with IgAN (n = 63) or IgAVN (n = 29) were included in this study. eGFR at the time of diagnosis was strongly negatively associated with serum levels of CCL23, CCL25, CD40, CSF-1, CX3CL1, IL10, IL-10RB, IL-15RA, IL-17C, PD-L1, TNFRSF9 (all P < 0.05/92). IL-10RB was also strongly associated with U-alb/24h at the time of diagnosis and TAA during follow-up (P < 0.05/92). The results for eGFR slope and the 5-year IIgAN-PT-risk were inconclusive, as no markers exceeded the Bonferroni-corrected significance threshold. However, the association between uPA, IL-10RB, SCF, and IL-15-RA and eGFR slope was confirmed by the Boruta algorithm. Similarly, CCL23, CCL25, CCL3, CD40, CD5, CSF-1, CX3CL1, IL10, IL-10RB, IL-15RA, IL-17C, PD-L1, SCF, TNFRSF9, and VEGFA were associated with IIgAN-PT-risk, as indicated by the Boruta analysis. Notably, IL-10RB was highly ranked both for eGFR slope and the IIgAN-PT-risk. Several inflammation-related proteins in serum were linked to kidney function, with IL-10RB also showing an association with both initial and persistent albuminuria in patients with IgAN or IgAVN. IL-10RB may serve as a marker of disease severity and could also indicate disease progression. Further research is needed to validate these findings.

Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries. Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.

BACKGROUND:Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio. METHODS:In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's C-index; added value by the fraction of new information (FNI). RESULTS:Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61-94) and eGFRcr 79 (IQR: 65-91) mL/min/1.73 m2. Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49-2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68-0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80-2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70-2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13-1.46, FNI 5%). CONCLUSION:In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.

Background Patients with end-stage kidney disease (ESKD) undergoing haemodialysis (HD) have a high risk of cardiovascular (CV) events. This study evaluated troponin I (hs-cTnI) as a predictor of major adverse cardiac events (MACEs), CV death and all-cause death. Methods The AURORA trial, a multicentre, randomized, double-blind trial involved 2776 HD patients comparing rosuvastatin with placebo. No significant effect was found on the composite primary endpoint of CV death, non-fatal myocardial infarction or non-fatal stroke. In this post hoc analysis, we analysed the association between baseline hs-cTnI and outcomes using Cox regression analyses. We adjusted for multiple background factors and available biomarkers. Hs-cTnI was log2-transformed and modelled using a four-knot restricted cubic spline. Variables were ordered by their importance in the models using chi 2 value minus degrees of freedom. Results Baseline median hs-cTnI was 17.3 pg/mL. During follow-up, 734 MACEs, 598 CV deaths, and 1094 total deaths occurred. Patients in the upper quartile of hs-cTnI (>32.6 pg/mL) had significantly higher risk of MACEs [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.57-2.35], CV death (HR 2.12; 95% CI 1.69-2.66), all-cause death (HR 1.84; 95% CI 1.55-2.17) and non-CV death (HR 1.59; 95% CI 1.23-2.05) after full adjustment compared with those in the lowest quartile (<10.1 pg/mL). Hs-cTnI was identified as the strongest predictor for MACEs, CV death, and all-cause death, but not for non-CV death. Conclusions Baseline hs-cTnI is a strong and independent predictor for MACEs and death in patients with ESKD undergoing haemodialysis.

Cystatin C was identified as a marker of glomerular filtration rate (GFR) in 1979, and the parallel analysis of cystatin C and creatinine led to the identification of shrunken pore syndrome (SPS) - a new kidney disorder - in 2015. Since then, it has been shown that cystatin C in many aspects is superior to creatinine as a marker of GFR and cardiovascular risk. SPS, an entity within the selective glomerular hypofiltration syndromes (SGHS), has been demonstrated to be associated with a strong increase in morbidity and mortality in several populations. Despite the seriousness of SPS and SGHS, and the availability of potential treatments, many patients with these conditions remain undiagnosed, due to the limitations of the international Kidney Disease Improving Global Outcomes Organization (KDIGO) guidelines. Given the significant clinical advantages of cystatin C in diagnosing and treating kidney disorders, there is a need to expand the KDIGO guidelines to include cystatin C measurements alongside creatinine at least in the initial patient evaluation but also in follow-up evaluations. This would improve the early detection and management of patients with kidney diseases, ultimately enhancing patient outcomes. The present discourse summarizes the development of this understanding from the original observations in 1979 and 2015 to the latest findings.

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) and haemodialysis treatment (HD) have a high risk of cardiovascular (CV) events. The underlying pathophysiology is complex and multifactorial. This study aimed to explore the role of high-sensitivity cardiac Troponin I (hs-cTnI) as a predictor of major adverse cardiac events (MACE), CV- and all-cause mortality. Method A retrospective analysis using data from the AURORA study (CT00240331). Association with baseline hs-cTnI and MACE, CV- and all-cause mortality were assessed using Cox-regression analyses. The analyses were adjusted for multiple background factors and available biomarkers. hs-cTnI was log2 transformed and modelled using a four knot restricted cubic spline. The hazard ratio [HR] estimates are presented for the upper quartile (32.6 pg/mL) vs the lower quartile (10.1 pg/mL) of the distribution of hs-cTnI. Variables were ordered by variable importance in the models using χ2 value minus degrees of freedom. Results During the follow-up, there were 1094 total deaths of which 598 were CV deaths, and 734 MACE in patients with hsTnI measurements available at baseline. Baseline hs-cTnI was associated with an increased risk for MACE (HR 1.92; 95% Confidence interval [CI] 1.57-2.35), CV mortality (HR 2.12; 95% CI 1.69-2.66), all-cause mortality (HR 1.84; 95% CI 1.55-2.17) and non-CV mortality (HR 1.59; 95% CI 1.23-2.05) after adjustments for age, ethnicity, sex, smoking status, diabetes status, history of coronary heart disease, atrial fibrillation, blood pressure, heart rate, height, weight, years on HD, hemoglobin, cholesterol, LDL-C, HDL-C, triglycerides, hs-CRP, creatinine, albumin, phosphate, erythropoietin treatment, ACE -inhibitor use, anticoagulation treatment, treatment with rosuvastatin, sevelamer use, iron supplements, ferritin, transferrin, galectin-3, pro-BNP, CICP and SCF. When ranking variables by variable importance, hs-cTnI was the strongest predictor for MACE (Fig. 1), CV- and all-cause mortality. For non-CV mortality age was the most important variable. Conclusion Baseline hs-cTnI, is a strong and independent risk marker for MACE and all-cause mortality in patients with haemodialysis treatment.

Abstract Background and Aims Unfractionated heparin (UFH) and low molecular-weight heparin (LMWH) are the most commonly used anticoagulants in haemodialysis (HD). While effective in preventing clotting, they are also associated with complications including increased risk of bleeding and heparin induced thrombocytopenia. The contact activation system is commonly assumed to be the main trigger of coagulation during HD, through autoactivation of factor (F)XII upon contact with the dialyser. FXII deficient individuals do not have an increased risk of bleeding which makes activated FXII (FXIIa) an attractive drug target as it has the potential to inhibit clotting without disrupting haemostasis. The aim of the study was to evaluate the efficacy of CSL312, a monoclonal, humanized IgG4 antibody against activated FXII (FXIIa), in preventing intradialytic coagulation. Method An ex vivo haemodialysisis model was used to test the efficacy of CSL312 as an anticoagulant. CSL312 (400 µg/mL) was compared to standard doses of UFH, LMWH and citrate anticoagulation. The antibody was provided by CSL Limited. Anticoagulant-free haemodialysisis was used as control. Whole-blood was collected from 12 healthy adult donors in blood-transfer bags containing citrate to prevent clotting before dialysis. Each donor provided blood for two HD-sessions, using different anticoagulants. The blood was dialyzed for one hour through paediatric polysulfone high-flux dialysers. Right before the start of HD, calcium was added to reverse the anticoagulant effect of citrate, except in the citrate group. Blood was sampled before and at 5, 15, 30 and 60 minutes after HD start. To quantify the activity of the contact system, the concentrations of enzyme-inhibitor complexes of antithrombin (AT) or C1-inhibitor (C1INH) in conjunction with FXIIa, FXIa, kallikrein, MASP-1, MASP-2 and thrombin were measured in plasma using enzyme-linked immunosorbent assays. Results Using CSL312 to inhibit FXIIa protease activity (n = 5), clotting occurred in all tests (at 30, 31, 36, 49 and 50 minutes) with a mean clotting time of 39.2 minutes compared to 17 and 30 minutes using no anticoagulation (n = 2). No clotting was evident with other anticoagulants. Using CSL312, the plasma concentration of FXIIa-C1INH at 15 minutes was significantly higher than at baseline (mean 26.2 (SD 9.08) vs mean 17.6 (SD 10.6) µg/mL, p = 0.011). Conclusion FXIIa inhibition using a monoclonal antibody does not provide sufficient anticoagulation during HD. This suggests that the contact system may not be solely responsible for clotting during HD.

Rationale & Objective: In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs.Study Design: Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial.Setting & Participants: KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion.Intervention: Continuation with a CNI-based regimen or switch to belatacept for 12 months.Outcomes: Comparison of the change in the esti-mated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness.Results: Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pres-sure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss.Limitations: The heterogeneous baseline esti-mated glomerular filtration rate and time from transplantation to trial enrollment in the partici-pants. A limited study duration of 1 year.Conclusions: We found no effects on the calculated CV risk by switching to the belata-cept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate.Funding: The trial has received a financial grant from Bristol-Myers Squibb.Trial Registration: EudraCT no. 2013-001178-20.

Abstract In renal transplant recipients (RTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. The aim of this randomized, multi-national trial was to compare calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a valdidated model developed for RTRs. From 9 transplant centers, RTRs from 3 to 60 months post-transplantation were recruited to either continue treatment with a CNI-based regimen or switch to belatacept. We compared the change in estimated 7-year risk of major adverse cardiovascular events (MACE) and all-cause mortality after 12 months of treatment. In the 105 RTRs randomized, we found no differences between the treatment groups in predicted risk for MACE or mortality. Diastolic blood pressure was lower after belatacept treatment compared with CNI. The mean changes in traditional CV risk factors, including renal transplant function, were otherwise similar in both treatment groups. The belatacept group had four acute rejection episodes; two were severe rejections, of which one led to graft loss. In conclusion, we found no effects on calculated CV risk by switching to belatacept treatment.

End-stage kidney disease increases mortality and the risk of cardiovascular (CV) disease. It is crucial to explore novel biomarkers to predict CV disease in the complex setting of patients receiving hemodialysis (HD). This study investigated the association between 92 targeted proteins with all-cause death, CV death, and composite vascular events (CVEs) in HD patients. From December 2010 to March 2011, 331 HD patients were included and followed prospectively for 5 years. Serum was analyzed for 92 CV-related proteins using Proseek Multiplex Cardiovascular I panel, a high-sensitivity assay based on proximity extension assay (PEA) technology. The association between biomarkers and all-cause death, CV death, and CVEs was evaluated using Cox-regression analyses. Of the PEA-based proteins, we identified 20 proteins associated with risk of all-cause death, 7 proteins associated with risk of CV death, and 17 proteins associated with risk of CVEs, independent of established risk factors. Interleukin-8 (IL-8), T-cell immunoglobulin and mucin domain 1 (TIM-1), and C-C motif chemokine 20 (CCL20) were associated with increased risk of all-cause death, CV death, and CVE in multivariable-adjusted models. Stem cell factor (SCF) and Galanin peptides (GAL) were associated with both decreased risk of all-cause death and CV death. In conclusion, IL-8, TIM-1, and CCL20 predicted death and CV outcomes in HD patients. Novel findings were that SCF and GAL were associated with a lower risk of all-cause death and CV death. The SCF warrants further study with regard to its possible biological effect in HD patients.

Aims:End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine.Methods and results:The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths.Conclusions:Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.

Background The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treat-ment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis.& nbsp;Methods An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR < 15 ml/min per 1.73m(2). All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months.& nbsp;Results At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m(2). The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P < 0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug.& nbsp;Conclusions In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.

The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.

There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1α, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.