Effectiveness and safety of direct oral anticoagulants versus vitamin K antagonists in patients on chronic dialysis: a nationwide registry study.

BACKGROUND AND HYPOTHESIS: Clinical trials of direct oral anticoagulants (DOAC) are scarce and inconclusive in patients who are receiving dialysis, for whom DOAC are not labelled in Europe. In a French nationwide registry study of patients on chronic dialysis, we compared the effectiveness and safety of off-label DOAC use vs. approved vitamin K antagonist (VKA). METHODS: Data on patients on dialysis were extracted from the French Renal Epidemiology and Information Network (REIN) registry and merged with data from the French national healthcare system database (Système National des Données de Santé, SNDS). Patients on dialysis who had initiated treatment with an oral anticoagulant between January 1st, 2012, and December 31st, 2020, were eligible for inclusion. The primary safety outcome was the occurrence of major bleeding events and the primary effectiveness outcome was the occurrence of thrombotic events. Using propensity-score-weighted cause-specific Cox regression, we compared the safety and effectiveness outcomes for DOAC and VKA. RESULTS: 8,954 patients received an oral anticoagulant (483 DOAC and 8,471 VKA) for the first time after the initiation of dialysis. Over a median [interquartile range] follow-up period of 1.7 [0.8-3.2] years, 2,567 patients presented a first thromboembolic event and 1,254 patients had a bleeding event. After propensity score adjustment, the risk of a thromboembolic event was significantly lower in patients treated with a DOAC than in patients treated with a VKA (weighted hazard ratio (wHR) [95% confidence interval (CI)]: 0.66 [0.46; 0.94]. A non-significant trend toward a lower risk of major bleeding events was found in DOAC-treated patients, relative to VKA-treated patients (wHR [95%CI]: 0.68 [0.41; 1.12]). The results were consistent across subgroups and in sensitivity analyses. CONCLUSIONS: In a large group of dialysis patients initiating an oral anticoagulant, the off-label use of DOACs was associated with a significantly lower risk of thromboembolic events and a non-significantly lower risk of bleeding, relative to VKA use. This provides reassurance regarding the off-label use of DOACs in people on dialysis.

Haemoglobin trajectories in chronic kidney disease and risk of major adverse cardiovascular events.

BACKGROUND: The trajectories of haemoglobin in patients with chronic kidney disease (CKD) have been poorly described. In such patients, we aimed to identify typical haemoglobin trajectory profiles and estimate their risks of major adverse cardiovascular events (MACE). METHODS: We used 5-year longitudinal data from the CKD-REIN cohort patients with moderate to severe CKD enrolled from 40 nationally representative nephrology clinics in France. A joint latent class model was used to estimate, in different classes of haemoglobin trajectory, the competing risks of (i) MACE + defined as the first event among cardiovascular death, non-fatal myocardial infarction, stroke or hospitalization for acute heart failure, (ii) initiation of kidney replacement therapy (KRT) and (iii) non-cardiovascular death. RESULTS: During the follow-up, we gathered 33 874 haemoglobin measurements from 3011 subjects (median, 10 per patient). We identified five distinct haemoglobin trajectory profiles. The predominant profile (n = 1885, 62.6%) showed an overall stable trajectory and low risks of events. The four other profiles had nonlinear declining trajectories: early strong decline (n = 257, 8.5%), late strong decline (n = 75, 2.5%), early moderate decline (n = 356, 11.8%) and late moderate decline (n = 438, 14.6%). The four profiles had different risks of MACE, while the risks of KRT and non-cardiovascular death consistently increased from the haemoglobin decline. CONCLUSION: In this study, we observed that two-thirds of patients had a stable haemoglobin trajectory and low risks of adverse events. The other third had a nonlinear trajectory declining at different rates, with increased risks of events. Better attention should be paid to dynamic changes of haemoglobin in CKD.

Indoxyl-sulfate activation of the AhR- NF-κB pathway promotes interleukin-6 secretion and the subsequent osteogenic differentiation of human valvular interstitial cells from the aortic valve.

BACKGROUND: Calcific aortic stenosis (CAS) is more prevalent, occurs earlier, progresses faster and has worse outcomes in patients with chronic kidney disease (CKD). The uremic toxin indoxyl sulfate (IS) is powerful predictor of cardiovascular mortality in these patients and a strong promoter of ectopic calcification whose role in CAS remains poorly studied. The objective of this study was to evaluate whether IS influences the mineralization of primary human valvular interstitial cells (hVICs) from the aortic valve. METHODS: Primary hVICs were exposed to increasing concentrations of IS in osteogenic medium (OM). The hVICs' osteogenic transition was monitored by qRT-PCRs for BMP2 and RUNX2 mRNA. Cell mineralization was assayed using the o-cresolphthalein complexone method. Inflammation was assessed by monitoring NF-κB activation using Western blots as well as IL-1ß, IL-6 and TNF-α secretion by ELISAs. Small interfering RNA (siRNA) approaches enabled us to determine which signaling pathways were involved. RESULTS: Indoxyl-sulfate increased OM-induced hVICs osteogenic transition and calcification in a concentration-dependent manner. This effect was blocked by silencing the receptor for IS (the aryl hydrocarbon receptor, AhR). Exposure to IS promoted p65 phosphorylation, the blockade of which inhibited IS-induced mineralization. Exposure to IS promoted IL-6 secretion by hVICs, a phenomenon blocked by silencing AhR or p65. Incubation with an anti-IL-6 antibody neutralized IS's pro-calcific effects. CONCLUSION: IS promotes hVIC mineralization through AhR-dependent activation of the NF-κB pathway and the subsequent release of IL-6. Further research should seek to determine whether targeting inflammatory pathways can reduce the onset and progression of CKD-related CAS.

Statin therapy and the incidence of atherosclerotic cardiovascular events after kidney transplantation.

BACKGROUND: Statins are recommended in kidney transplant recipients (KTRs) - a population with a high risk of major cardiovascular (CV) events. However, the literature data on the effectiveness of statins in KTRs are sparse and inconclusive. The present study's objective was to evaluate the association between statin exposure and atherosclerotic CV events in KTRs and the biochemical effectiveness of statins on the lipid profile. METHODS: 318 consecutive KTRs managed at a single center between 2006 and 2019 were retrospectively included. Those exposed to statins after transplantation were incident users. In all users, statins were indicated for primary CV prevention. Lipid profiles, the occurrence of any atherosclerotic CV events (stroke, myocardial infarction, other atherosclerotic CV events, and atherosclerotic CV deaths) were documented comprehensively. We applied Cox models that included statin exposure as a time-dependent covariate fitted with time-varying inverse probability treatment weighting (IPTW) to assess the effectiveness of statins on atherosclerotic CV events and on all CV events. We built linear mixed models to assess the biochemical effectiveness of statins. RESULTS: During a median [interquartile range] follow-up period of 6.0 [3.9-10.0] years, 27 atherosclerotic CV events occurred in 26 patients. In the Cox models fitted with time-varying IPTW, exposure to statins was not associated with a decrease in atherosclerotic CV events; the hazard ratio (HR) [95% confidence interval (CI)] was 1.16 [0.53-2.53] (p=0.700). In the linear mixed models, statin exposure was associated with significant decrease over time in triglyceride and low-density lipoprotein cholesterol concentrations (p < 0.001). These results were consistent when stratified for the intensity of statin therapy. CONCLUSION: Even though the lipid profile improved, statin exposure was not associated with a decrease in CV events in this real-life, single-center, retrospective, long-term follow-up study of a KTR cohort. Larger, controlled studies are needed to confirm or refute these results.

Chronic kidney disease is a key risk factor for aortic stenosis progression.

BACKGROUND: Rapid progression of aortic stenosis (AS) has been observed in patients undergoing dialysis, but existing cross-sectional evidence is contradictory in non-dialysis-dependent chronic kidney disease (CKD). The present study sought to evaluate whether CKD is associated with the progression of AS over time in a large cohort of patients with AS. METHODS: We retrospectively studied all consecutive patients diagnosed with AS [peak aortic jet velocity (Vmax) ≥2.5 m/s] and left ventricular ejection fraction ≥50% in the echocardiography laboratories of two tertiary centers between 2000 and 2018. The estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) was calculated from serum creatinine values. Patients were divided into five CKD stages according to the baseline eGFR. Annual rates of change in the aortic valve area (AVA) were determined by a linear mixed-effects model. RESULTS: Among the 647 patients included, 261 (40%) had CKD. After a median follow-up of 2.9 (interquartile range 1.8-4.8) years, the mean overall rate of change in AVA was -0.077 (95% confidence interval -0.082; -0.073) cm2/year. There was an inverse relationship between the progression rate and kidney function. The more severe the CKD stage, the greater the AVA narrowing (P < .001). By multivariable linear regression analysis, the eGFR was also negatively associated (P < .001) with AS progression. An eGFR strata below 45 mL/min/1.73 m2 was associated with higher odds of rapid progression of AS than normal kidney function. During the clinical follow-up, event-free survival (patients free of aortic valve replacement or death) decreased as CKD progressed. Rapid progression of AS in patients with kidney dysfunction was associated with worse outcomes. CONCLUSIONS: Patients with CKD exhibit more rapid progression of AS over time and require close monitoring. The link between kidney dysfunction and rapid progression of AS is still unknown and requires further research.

Impact of Preformed Donor-Specific Anti-HLA-Cw and Anti-HLA-DP Antibodies on Acute Antibody-Mediated Rejection in Kidney Transplantation.

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA.

Tacrolimus Exposure Before and After a Switch From Twice-Daily Immediate-Release to Once-Daily Prolonged Release Tacrolimus: The ENVARSWITCH Study.

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a switch and the efficiency of the subsequent dose adjustment. Tacrolimus AUC0-24 h was obtained by Bayesian estimation based on three concentrations measured in dried blood spots before (V2), after the switch (V3), and after LCP-tacrolimus dose adjustment intended to reach the pre-switch AUC0-24 h (V4). AUC0-24 h estimates and distributions were compared using the bioequivalence rule for narrow therapeutic range drugs (Westlake 90% CI within 0.90-1.11). Fifty-three KTR and 48 LTR completed the study with no major deviation. AUC0-24 h bioequivalence was met in the entire population and in KTR between V2 and V4 and between V2 and V3. In LTR, the Westlake 90% CI was close to the acceptance limits between V2 and V4 (90% CI = [0.96-1.14]) and between V2 and V3 (90% CI = [0.96-1.15]). The 1:0.7 dose ratio is convenient for KTR but may be adjusted individually for LTR. The combination of DBS and Bayesian estimation for tacrolimus dose adjustment may help with reaching appropriate exposure to tacrolimus rapidly after a switch.

Iron deficiency screening is a key issue in chronic inflammatory diseases: A call to action.

Iron deficiency is frequent in patients with chronic inflammatory conditions (e.g., chronic heart failure, chronic kidney disease, cancers, and bowel inflammatory diseases). Indeed, high concentrations of inflammatory cytokines increase hepcidin concentrations that lead to the sequestration of iron in cells of the reticuloendothelial system (functional iron deficiency). Iron parameters are often assessed only in the context of anemia, but iron deficiency, even without anemia, is present in about half of patients with inflammatory conditions. Iron deficiency worsens underlying chronic diseases and is an independent factor of morbidity and mortality. In daily practice, the most effective biomarkers of iron status are serum ferritin, which reflects iron storage, and transferrin saturation, which reflects the transport of iron. Serum ferritin is increased in an inflammatory context, and there is still no consensus on the threshold to be used in chronic inflammatory conditions. Nevertheless, recent recommendations of international guidelines agreed to define iron deficiency by serum ferritin <100 µg/L and/or transferrin saturation <20%. Iron parameters remain, however, insufficiently assessed in patients with chronic inflammatory conditions. Indeed, clinical symptoms of iron deficiency, such as fatigue, are not specific and often confused with those of the primary disease. Iron repletion, preferably by the intravenous route to bypass tissue sequestration, improves clinical signs and quality of life. Because of the negative impact of iron deficiency on chronic inflammatory diseases and the efficacy of intravenous iron repletion, screening of iron parameters should be part of the routine examination of all patients with chronic inflammatory diseases.

Potential interactions between uraemic toxins and drugs: an application in kidney transplant recipients treated with calcineurin inhibitors.

BACKGROUND: The uraemic toxins that accumulate as renal function deteriorates can potentially affect drug pharmacokinetics. This study's objective was to determine whether plasma concentrations of certain uraemic toxins are correlated with blood concentrations of two immunosuppressants. METHODS: DRUGTOX was a cross-sectional study of 403 adult patients followed up after kidney transplantation and who had undergone therapeutic drug monitoring (TDM) of calcineurin inhibitors (tacrolimus or cyclosporin) between August 2019 and March 2020. For each patient, immunosuppressant trough concentrations (C0) were measured in whole blood samples and then normalized against the total daily dose (C0:D ratio). The sample was assayed for five uraemic toxins [urea, trimethylamine N-oxide (TMAO), indole acetic acid (IAA), p-cresylsulphate (PCS) and indoxylsulphate (IxS)] using liquid chromatography-tandem mass spectrometry. RESULTS: The median age was 56 years [interquartile range (IQR) 48-66] and the median estimated glomerular filtration rate was 41 mL/min/1.73 m2 (IQR 30-57). Age, sex, body mass index (BMI), urea, IxS and PCS were significantly associated with an increment in the tacrolimus C0:D ratio. A multivariate analysis revealed an independent association with IxS [odds ratio 1.36 (95% confidence interval 1.00-1.85)] after adjustment for sex, age and BMI, whereas adjustment for age weakened the association for PCS and urea. In a univariate logistic analysis, age, sex, BMI and the TMAO level (but not PCS, IxS, IAA or urea) were significantly associated with an increment in the cyclosporine C0:D ratio. CONCLUSIONS: Even though TDM and dose adaptation of immunosuppressants keep levels within the therapeutic window, increased exposure to tacrolimus (but not cyclosporine) is associated with an accumulation of PCS, IxS and urea.

Impact of pre-graft serology on risk of BKPyV infection post-renal transplantation.

OBJECTIVES: BK polyomavirus-associated nephropathy is a troublesome disease caused by BK polyomavirus (BKPyV) infection in immunocompromised renal graft recipients. There are no effective treatments available, making immunosuppression reduction the only management option. Thus, pre-graft predictive BKPyV replication markers are needed for identification of patients at high risk of viraemia. METHODS: We conducted a retrospective study to assess the correlation between pre-transplantation BKPyV serostatus and post-transplantation incidence of BKPyV infection. Sera from 329 recipients and 222 matched donors were tested for anti-BKPyV antibodies against BKPyV serotypes I and IV by using a virus-like particle-based immunoglobulin G enzyme-linked immunosorbent assay, and BKPyV DNA load was monitored for at least 1 year post-transplantation. RESULTS: Eighty recipients were viruric and 59 recipients were viraemic post-transplantation. In the post-transplantation period, the probability of developing viraemia for serotype I increased from 4.3% for the D-/R+ group to 12.1% for the D+/R+ group, climbing to 37.5% for the D+/R- group (P < 0.05). When calculating recipient mean titres for serotypes I and IV, we observed a clear difference in the proportions of viraemia, decreasing from 50% for mean titres <400 to 13.5% for titres ≥400 (P < 0.001), as well as a higher proportion of presumptive nephropathy (50% versus 23.1%, respectively; P < 0.05). In univariate analysis, this parameter had an odds ratio of 6.41 for the risk of developing post-transplantation BKPyV viraemia (95% confidence interval 3.16-13.07; P < 0.0001). CONCLUSIONS: Determination of both donor and recipient BKPyV seropositivity before transplantation and antibody titre measurements may serve as a predictive tool to manage clinical BKPyV infection by identification of patients at high risk.

Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017.

We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

Decreased monocyte calcium sensing receptor expression in patients with chronic kidney disease is associated with impaired monocyte ability to reduce vascular calcification.

In chronic kidney disease (CKD), calcium-sensing receptor (CaSR) expression and function have been extensively studied in parathyroid tissue and vascular tissues. To examine whether similar changes occurred in other tissues, we measured total and surface CaSR expression in monocytes of patients with various stages of CKD and healthy volunteers respectively in cross-sectional studies. We further explored in vitro the impact of uremic serum on CaSR expression in monocytes (U937 and THP-1 cell lines), and whether human peripheral blood mononuclear cells or U937 and THP-1 monocytes might modify vascular calcium deposition in rat carotid arteries in vitro. CKD was associated with a decrease in peripheral blood mononuclear cell CaSR expression both in total and at the monocyte surface alone (43% and 34%, respectively in CKD stages 4-5). This decrease was associated with a reduction in the ability of monocytes to inhibit vascular calcification in vitro. Pretreatment with the calcimimetic NPSR568 of peripheral blood mononuclear cells isolated from patients with CKD significantly improved monocyte capacity to reduce carotid calcification in vitro. The fewer peripheral blood mononuclear cells expressing cell surface CaSR, the more calcimimetic treatment enhanced the decrease of carotid calcium content. Thus, we demonstrate that monocyte CaSR expression is decreased in patients with CKD and provide in vitro evidence for a potential role of this decrease in the promotion of vascular calcification. Hence, targeting this alteration or following monocyte CaSR expression as an accessible marker might represent a promising therapeutic strategy in CKD-associated arterial calcification.

HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.

Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.

Syndecan-1 and Free Indoxyl Sulfate Levels Are Associated with miR-126 in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major cause of death worldwide and is associated with a high risk for cardiovascular and all-cause mortality. In CKD, endothelial dysfunction occurs and uremic toxins accumulate in the blood. miR-126 is a regulator of endothelial dysfunction and its blood level is decreased in CKD patients. In order to obtain a better understanding of the physiopathology of the disease, we correlated the levels of miR-126 with several markers of endothelial dysfunction, as well as the representative uremic toxins, in a large cohort of CKD patients at all stages of the disease. Using a univariate analysis, we found a correlation between eGFR and most markers of endothelial dysfunction markers evaluated in this study. An association of miR-126 with all the evaluated uremic toxins was also found, while uremic toxins were not associated with the internal control, specifically cel-miR-39. The correlation between the expression of endothelial dysfunction biomarker Syndecan-1, free indoxyl sulfate, and total p-cresyl glucuronide on one side, and miR-126 on the other side was confirmed using multivariate analysis. As CKD is associated with reduced endothelial glycocalyx (eGC), our results justify further evaluation of the role of correlated parameters in the pathophysiology of CKD.

Impact of the dialysate acid component on haemodialysis mortality rates.

BACKGROUND: No prospective study has evaluated the long-term effect on mortality of the new acid concentrates added to bicarbonate dialysate. The aim of this pharmacoepidemiological study was to evaluate the association between hydrochloric or citric acid-based dialysate and mortality on haemodialysis (HD). METHODS: This study included 117 796 patients with 3 723 887 months on HD recorded in the national French Renal Epidemiology and Information Network registry. Dialysate acid components were retrospectively reconstructed for each facility. All patients on HD were associated each month with an exposure based on that at their facility of treatment. We took each patient's time-varying exposure into account to calculate the monthly mortality rates for each exposure. Incidence rate ratios (IRRs) for mortality were calculated with a Poisson regression, with acetic acid as the reference. Regressions were adjusted for initial clinical characteristics (age, gender, previous cardiovascular events, active malignancy, diabetes, pulmonary disease, mobility), dialysis technique and location (in-centre, outpatient centre, self-care unit) and ESRD vintage, updated monthly. RESULTS: The crude mortality rate per 1000 patient-months with citric acid {11.5 [95% confidence interval (CI) 11.1-12.0]} was lower than with either acetic acid [12.9 (95% CI 12.8-13.1)] or hydrochloric acid [12.8 (95% CI 12.2-13.5)]. For the 2014-17 period, the IRR for mortality with citric acid [adjusted IRR 0.94 (95% CI 0.90-0.99)] and with hydrochloric acid [adjusted IRR 0.86 (95% CI 0.79-0.94)] were significantly lower than with acetic acid. CONCLUSION: This post-marketing study of long-term exposure to dialysate acidifiers at the patient level found the use of citric and hydrochloric acid-based dialysates, compared with acetic acid, was associated with lower mortality.

Difference in Profiles of the Gut-Derived Tryptophan Metabolite Indole Acetic Acid between Transplanted and Non-Transplanted Patients with Chronic Kidney Disease.

BACKGROUND: Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts. METHODS: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss). RESULTS: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio [95% confidence interval]: 2.5 [1.2-5.1] and 2.5 [1.3-4.8], respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. CONCLUSION: We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but-at least in our study setting-not in transplanted patients.

Epitope load identifies kidney transplant recipients at risk of allosensitization following minimization of immunosuppression.

Human leukocyte antigen (HLA) mismatching and minimization of immunosuppression are two major risk factors for the development of de novo donor-specific antibodies, which are associated with reduced kidney graft survival. Antibodies do not recognize whole HLA antigens but rather individual epitopes, which are short sequences of amino acids in accessible positions. However, compatibility is still assessed by the simple count of mismatched HLA antigens. We hypothesized that the number of mismatched epitopes, or ("epitope load") would identify patients at the highest risk of developing donor specific antibodies following minimization of immunosuppression. We determined epitope load in 89 clinical trial participants who converted from cyclosporine to everolimus 3 months after kidney transplantation. Twenty-nine participants (32.6%) developed de novo donor specific antibodies. Compared to the number of HLA mismatches, epitope load was more strongly associated with the development of donor specific antibodies. Participants with an epitope load greater than 27 had a 12-fold relative risk of developing donor-specific antibodies compared to those with an epitope load below that threshold. Using that threshold, epitope load would have missed only one participant who subsequently developed donor specific antibodies, compared to 8 missed cases based on a 6-antigen mismatch. DQ7 was the most frequent antigenic target of donor specific antibodies in our population, and some DQ7 epitopes appeared to be more frequently involved than others. Assessing epitope load before minimizing immunosuppression may be a more efficient tool to identify patients at the highest risk of allosensitization.

Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.

The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; P = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.

Endothelial cells exposed to phosphate and indoxyl sulphate promote vascular calcification through interleukin-8 secretion.

BACKGROUND: Vascular calcification (VC) is amplified during chronic kidney disease, partly due to uraemic toxins such as inorganic phosphate (Pi) and indoxyl sulphate (IS) that trigger osteogenic differentiation of vascular smooth muscle cells (VSMCs). These toxins also alter endothelial cell (EC) functions but whether this contributes to VC is unknown. Here, we hypothesized that ECs exposed to Pi and IS promote VSMC calcification. METHODS: Human umbilical vein ECs were treated with Pi, IS or both, and then the conditioned media [endothelial cell conditioned medium (EC-CM)] was collected. Human aortic SMCs (HASMCs) were exposed to the same toxins, with or without EC-CM, and then calcification and osteogenic differentiation were evaluated. Procalcifying factors secreted from ECs in response to Pi and IS were screened. Rat aortic rings were isolated to assess Pi+IS-induced calcification at the tissue level. RESULTS: Pi and Pi+IS induced HASMCs calcification, which was significantly exacerbated by EC-CM. Pi+IS induced the expression and secretion of interleukin-8 (IL-8) from ECs. While IL-8 treatment of HASMCs stimulated the Pi+IS-induced calcification in a concentration-dependent manner, IL-8 neutralizing antibody, IL-8 receptors antagonist or silencing IL-8 gene expression in ECs before collecting EC-CM significantly prevented the EC-CM procalcifying effect. IL-8 did not promote the Pi+IS-induced osteogenic differentiation of HASMCs but prevented the induction of osteopontin (OPN), a potent calcification inhibitor. In rat aortic rings, IS also promoted Pi-induced calcification and stimulated the expression of IL-8 homologues. Interestingly, in the Pi+IS condition, IL-8 receptor antagonist lifted the inhibition of OPN expression and partially prevented aortic calcification. CONCLUSION: These results highlight a novel role of IL-8, whose contribution to VC in the uraemic state results at least from interaction between ECs and VSMCs.

Cognitive Impairments and Dysexecutive Behavioral Disorders in Chronic Kidney Disease.

The purpose of this study was to characterize cognitive impairments and behavioral disorders in a sample of patients with chronic kidney disease (CKD). A total of 52 patients with CKD were prospectively recruited over a 344-day period. Cognitive functions (memory, action speed, executive function, and language) and behavioral characteristics were assessed with a standardized comprehensive battery. The patients' performances were interpreted with a validated method on the basis of normative data from 1,003 healthy control subjects. Brain MRI and biological data were collected. Multivariable linear regression models and bootstrap analyses were used to identify risk factors for cognitive impairment. Cognitive impairment was observed in 32.5% (95% confidence interval: 17%-48%) of the 40 included patients with full data sets. Action speed and executive functions were the most frequently impaired domains. Dysexecutive behavioral disorders were observed in 27% of patients, and depression was observed in 32.5%. Cognitive impairment was independently associated with stroke volume, high serum parathyroid hormone and uric acid levels, and low serum glucose levels (adjusted R2=0.54, p<0.001 One-third of patients with CKD had cognitive impairments (action speed and executive functions), behavioral dysexecutive disorders (hypoactivity with apathy, irritability, or anosognosia), or depression.