Peritoneal Dialysis Aggravates and Accelerates Atherosclerosis in Uremic ApoE-/- Mice.

BACKGROUND: Atherosclerosis is highly prevalent in people with chronic kidney disease (CKD), including those receiving peritoneal dialysis (PD). Although it is lifesaving, PD induces profound systemic inflammation, which may aggravate atherosclerosis. Therefore, the hypothesis is that this PD-induced inflammation aggravates atherosclerosis via immune cell activation. METHODS AND RESULTS: ApoE-/- mice were subjected to a 5/6 nephrectomy to induce CKD. Three weeks later, mice were fed a high-cholesterol diet. Half of the nephrectomized mice then received daily peritoneal infusions of 3.86% Physioneal for 67 further days (CKD+PD) until the end of the experiment, and were compared with mice without CKD. Sham operated and PD-only mice were additional controls. CKD+PD mice displayed more severe atherosclerotic disease than control mice. Plaque area increased, and plaques were more advanced with a vulnerable phenotype typified by decreased collagen content and decreased fibrous cap thickness. Increased CD3+ T-cell numbers were present in plaques and perivascular adipose tissue of CKD and CKD+PD mice. Plaques of CKD+PD mice contained more iNOS+ immune cells. Spleens of CKD+PD mice showed more CD4+ central memory, terminally differentiated type 1 T-helper (Th1), Th17, and CX3C motif chemokine receptor 1+ (CX3CR1) CD4+ T-cells with less regulatory and effector T-cells. CONCLUSIONS: PD-fluid exposure in uremic mice potentiates systemic and vascular T-cell-driven inflammation and aggravates atherosclerosis. PD polarized CD4+ T-cells toward an inflammatory Th1/Th17 phenotype, and increased CX3CR1+ CD4+ T-cells, which are associated with vascular homing in CKD-associated atherosclerosis. Targeting CD4+ T-cell activation and CX3CR1+ polarization has the potential to attenuate atherosclerosis in PD patients.

Acute kidney injury in Staphylococcus aureus bacteraemia: a recurrent events analysis.

OBJECTIVES: To estimate risk factors for acute kidney injury (AKI) and the effect of AKI on mortality in Staphylococcus aureus bacteraemia, while taking into account recurrent AKI episodes, competing risks, time-varying variables, and time-varying effects. METHODS: We performed an unplanned analysis using data from a multicentre cohort study of patients with Staphylococcus aureus bacteraemia (SAB). The primary outcome was cumulative incidence of AKI, according to Kidney Disease Improving Global Outcomes definitions. RESULTS: We included 453 patients in this study of whom 194 (43%) patients experienced one or more AKI episodes. Age (hazard ratio (HR) 1.013, 95% CI 1.001-1.024), Charlson comorbidity index (HR 1.07, 95% CI 1.01-1.14), prior chronic kidney disease (HR 1.76, 95% CI 1.28-2.42), septic shock (HR 3.28, 95% CI 2.31-4.66), persistent bacteraemia (HR 1.53, 95% CI 1.08-2.17), and vancomycin therapy (HR 1.80, 95% CI 1.05-3.09) were independently associated with AKI, but flucloxacillin, cefazolin, rifampicin, and aminoglycoside therapy were not. After adjustment for confounders and immortal time bias, AKI was associated with an increased risk of 90-day mortality (HR 4.26, 95% CI 2.91-6.23). DISCUSSION: The incidence of AKI in SAB is high and a substantial proportion of patients develop recurrent episodes of AKI after recovery. AKI is specifically linked to the use of vancomycin and not to anti-staphylococcal penicillins. The clinical outcome of patients with SAB complicated by AKI is worse than previously estimated.

Low immunoglobulin G concentrations are not associated with an increased risk of peritoneal dialysis-related peritonitis.

BACKGROUND: Peritonitis is a common and severe complication of peritoneal dialysis (PD) and is associated with high morbidity and sometimes also with mortality. Identification of risk factors, as well as protective mechanisms for peritonitis, is important to reduce peritonitis-induced morbidity. According to the current literature, IgG concentrations might be associated with peritonitis in PD-treated patients. In this study, we aimed to investigate possible associations between dialysate or serum IgG concentration and peritonitis risk in a longitudinal cohort of PD-treated patients. MATERIALS AND METHODS: We analyzed prospectively collected data obtained during the first standard peritoneal permeability analysis (SPA), performed in incident PD patients, aged > 18 years who started PD treatment in our tertiary-care university hospital from January 1, 1994 until December 31, 2008. Patients were divided in groups according to dialysate or serum IgG concentrations and according to peritonitis incidence. A possible association between low dialysate or serum IgG concentrations and time to the first peritonitis episode was investigated using cox proportional hazard models. RESULTS: 120 patients were included in our analyses with a median follow-up time of 36 (16 - 92) months. No significant association between dialysate, nor serum IgG and time to peritonitis was found (HR 0.27 (95% CI 0.65 - 1.62), p = 0.911 and HR 0.87 (95% CI 0.70 - 1.68), p = 0.708, respectively). Moreover, IgG concentrations were not associated with peritonitis incidence, nor with the recurrence of peritonitis. Finally, we found no significant difference in dialysate or serum IgG concentrations between patients who remained peritonitis-free (58.0 ± 35.6 mg/L in dialysate, 11.1 ± 4.4 g/L in serum), and those who experienced a peritonitis episode during follow-up (59.5 ± 41.9 mg/L in dialysate, 10.3 ± 4.3 g/L in serum), respectively. CONCLUSION: Dialysate or serum IgG are not major determinants of local peritoneal defense against peritonitis.

Impact of telehealth interventions added to peritoneal dialysis-care: a systematic review.

BACKGROUND: Telehealth could potentially increase independency and autonomy of patients treated with peritoneal dialysis (PD). Moreover, it might improve clinical and economic outcomes. The demand for telehealth modalities accelerated significantly in the recent COVID-19 pandemic. We evaluated current literature on the impact of telehealth interventions added to PD-care on quality of life (QoL), clinical outcomes and cost-effectiveness. METHODS: An electronic search was performed in Embase, PubMed and the Cochrane Library in order to find studies investigating associations between telehealth interventions and: i. QoL, including patient satisfaction; ii. Standardized Outcomes in Nephrology (SONG)-PD clinical outcomes: PD-related infections, mortality, cardiovascular disease and transfer to hemodialysis (HD); iii. Cost-effectiveness. Studies investigating hospitalizations and healthcare resource utilization were also included as secondary outcomes. Due to the heterogeneity of studies, a meta-analysis could not be performed. RESULTS: Sixteen reports (N = 10,373) were included. Studies varied in terms of: sample size; design; risk of bias, telehealth-intervention and duration; follow-up time; outcomes and assessment tools. Remote patient monitoring (RPM) was the most frequently studied intervention (11 reports; N = 4982). Telehealth interventions added to PD-care, and RPM in particular, might reduce transfer to HD, hospitalization rate and length, as well as the number of in-person visits. It may also improve patient satisfaction. CONCLUSION: There is a need for adequately powered prospective studies to determine which telehealth-modalities might confer clinical and economic benefit to the PD-community.

"It's not lupus". A placental site trophoblastic tumor presenting as a lupus-like paraneoplastic syndrome. A grand round case.

Introduction: Placental site trophoblastic tumor (PSTT) is a rare subtype of gestational trophoblastic disease. Association of PSTT and nephrotic syndrome is exceedingly rare and has been described in 8 cases thus far. In all cases hysterectomy was performed within months after onset of symptoms, leading to immediate remission of nephrotic syndrome, except for one patient who died of complications of PSTT. Case: We describe the history of a woman in which PSTT was discovered years after onset of nephrotic syndrome. Kidney biopsy revealed lupus-like mesangiocapillary nephritis and over time the patient developed additional symptoms mimicking systemic lupus erythematosus (SLE). Discussion: We provide an overview of the literature on this clinical entity and elaborate on its pathophysiology. In addition, we reflect on the phenomenon of anchoring bias, that led physicians to assume the patient had SLE without questioning this diagnosis in the light of the unexplained finding of increased tumor markers.

Recovery of kidney function in patients treated with maintenance dialysis-a report from the ERA-EDTA Registry.

BACKGROUND: Literature on recovery of kidney function (RKF) in patients with end-stage kidney disease treated with maintenance dialysis (i.e. >90 days) is limited. We assessed the incidence of RKF and its associated characteristics in a European cohort of dialysis patients. METHODS: We included adult patients from the European Renal Association-European Dialysis and Transplant Association Registry who started maintenance dialysis in 1997-2016. Sustained RKF was defined as permanent discontinuation of dialysis. Temporary discontinuation of ≥30 days (non-sustained RKF) was also evaluated. Factors associated with RKF adjusted for potential confounders were studied using Cox regression analyses. RESULTS: RKF occurred in 7657 (1.8%) of 440 996 patients, of whom 71% experienced sustained RKF. Approximately 90% of all recoveries occurred within the first 2 years after Day 91 of dialysis. Of patients with non-sustained RKF, 39% restarted kidney replacement therapy within 1 year. Sustained RKF was strongly associated with the following underlying kidney diseases (as registered by the treating physician): tubular necrosis (irreversible) or cortical necrosis {adjusted hazard ratio [aHR] 20.4 [95% confidence interval (CI) 17.9-23.1]}, systemic sclerosis [aHR 18.5 (95% CI 13.8-24.7)] and haemolytic uremic syndrome [aHR 17.3 (95% CI 13.9-21.6)]. Weaker associations were found for haemodialysis as a first dialysis modality [aHR 1.5 (95% CI 1.4-1.6)] and dialysis initiation at an older age [aHR 1.8 (95% CI 1.6-2.0)] or in a more recent time period [aHR 2.4 (95% CI 2.1-2.7)]. CONCLUSIONS: Definitive discontinuation of maintenance dialysis is a rare and not necessarily an early event. Certain clinical characteristics, but mostly the type of underlying kidney disease, are associated with a higher likelihood of RKF.

Dosage reduction of low weight heparin in patients with renal dysfunction: Effects on anti-Xa levels and clinical outcomes.

BACKGROUND: To prevent bio-accumulation of low molecular weight heparins (LMWHs) in patients with decreased kidney function, dosage reduction and anti-Xa monitoring has been suggested. The aim of this study was to investigate the effect of pre-emptive dosage reduction of LMWH on anti-Xa levels. Furthermore, we investigated the association between anti-Xa levels and bleeding, thrombotic events and mortality. METHODS: In this single center study, we followed 499 patients with decreased renal function in whom anti-Xa levels were measured. We observed how many patients had anti-Xa levels that fell within the reference range, with a standard protocol of a pre-emptive dosage reduction of LMWH (25% reduction in patients with an estimated glomerular filtration rate (eGFR) between 30 and 60 ml/min/1.73m2 and a reduction of 50% in patients with an eGFR below the 30 ml/min/1.73m2). Furthermore, Cox proportional hazard analyses were used to estimate hazard ratios to investigate the association between anti-Xa levels and major bleeding, thrombotic events and mortality within three months of follow-up. RESULTS: In a cohort of 499 patients (445 dalteparin and 54 nadroparin users), a pre-emptive dosage reduction of LMWH led to adequate levels of anti-Xa in only 19% of the patients (12% for the dalteparin users and 50% for nadroparin users). We did not find an association between anti-Xa levels and bleeding, thrombosis or mortality. CONCLUSION: Pre-emptive dosage reduction of LMWH leads to low anti-Xa levels in a large proportion, but this was not associated with bleeding, thrombosis or mortality.

Transintestinal Cholesterol Transport Is Active in Mice and Humans and Controls Ezetimibe-Induced Fecal Neutral Sterol Excretion.

Except for conversion to bile salts, there is no major cholesterol degradation pathway in mammals. Efficient excretion from the body is therefore a crucial element in cholesterol homeostasis. Yet, the existence and importance of cholesterol degradation pathways in humans is a matter of debate. We quantified cholesterol fluxes in 15 male volunteers using a cholesterol balance approach. Ten participants repeated the protocol after 4 weeks of treatment with ezetimibe, an inhibitor of intestinal and biliary cholesterol absorption. Under basal conditions, about 65% of daily fecal neutral sterol excretion was bile derived, with the remainder being contributed by direct transintestinal cholesterol excretion (TICE). Surprisingly, ezetimibe induced a 4-fold increase in cholesterol elimination via TICE. Mouse studies revealed that most of ezetimibe-induced TICE flux is mediated by the cholesterol transporter Abcg5/Abcg8. In conclusion, TICE is active in humans and may serve as a novel target to stimulate cholesterol elimination in patients at risk for cardiovascular disease.

Intraperitoneal Meropenem for Polymicrobial Peritoneal Dialysis-Related Peritonitis.

With the current rise in multiresistant gram-negative bacteria, carbapenems are more frequently used. Surprisingly, limited data exist on the pharmacokinetics of meropenem in peritoneal dialysis (PD)-related peritonitis. We report on the pharmacokinetics of repeated intraperitoneal (IP) meropenem during 21 days as treatment for polymicrobial multiresistent PD-related peritonitis.Our current report supports daily doses of 125 mg/L intraperitoneal meropenem in all bags as an effective and safe modality in the treatment of PD-associated peritonitis with multiresistant microorganisms. No signs of over- or underdosing were found based on serial drug concentration measurements at fixed time points up to 21 days.

In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1.

Atheroprotection by high density lipoprotein (HDL) is considered to be mediated through reverse cholesterol transport (RCT) from peripheral tissues. We investigated in vivo cholesterol fluxes through the RCT pathway in patients with low plasma high density lipoprotein cholesterol (HDL-c) due to mutations in APOA1. Seven carriers of the L202P mutation in APOA1 (mean HDL-c: 20 ± 19 mg/dl) and seven unaffected controls (mean HDL-c: 54 ± 11 mg/dl, P < 0.0001) received a 20 h infusion of (13)C2-cholesterol ((13)C-C). Enrichment of plasma and erythrocyte free cholesterol and plasma cholesterol esters was measured. With a three-compartment SAAM-II model, tissue cholesterol efflux (TCE) was calculated. TCE was reduced by 19% in carriers (4.6 ± 0.8 mg/kg/h versus 5.7 ± 0.7 mg/kg/h in controls, P = 0.02). Fecal (13)C recovery and sterol excretion 7 days postinfusion did not differ significantly between carriers and controls: 21.3 ± 20% versus 13.3 ± 6.3% (P = 0.33), and 2,015 ± 1,431 mg/day versus 1456 ± 404 mg/day (P = 0.43), respectively. TCE is reduced in carriers of mutations in APOA1, suggesting that HDL contributes to efflux of tissue cholesterol in humans. The residual TCE and unaffected fecal sterol excretion in our severely affected carriers suggest, however, that non-HDL pathways contribute to RCT significantly.

Plasma plant sterols serve as poor markers of cholesterol absorption in man.

The validation of the use of plasma plant sterols as a marker of cholesterol absorption is frail. Nevertheless, plant sterol concentrations are routinely used to describe treatment-induced changes in cholesterol absorption. Their use has also been advocated as a clinical tool to tailor cholesterol-lowering therapy. Prior to wider implementation, however, the validity of plant sterols as absorption markers needs solid evaluation. Therefore, we compared plasma plant sterol concentrations to gold-standard stable isotope-determined cholesterol absorption. Plasma campesterol/TC concentrations (camp/TC) were measured in a population of 175 mildly hypercholesterolemic individuals (age: 59.7 ± 5.6 years; BMI: 25.5 ± 2.9 kg/m(2); LDL-C: 4.01 ± 0.56 mmol/l). We compared cholesterol absorption according to the plasma dual-isotope method in subjects with the highest camp/TC concentrations (N = 41, camp/TC: 2.14 ± 0.68 µg/mg) and the lowest camp/TC concentrations (N = 39, camp/TC: 0.97 ± 0.22 µg/mg). Fractional cholesterol absorption did not differ between the groups (24 ± 12% versus 25 ± 16%, P = 0.60), nor was it associated with plasma camp/TC concentrations in the total population of 80 individuals (ß = 0.13; P = 0.30, adjusted for BMI and plasma triglycerides). Our findings do not support a relation between plasma plant sterol concentrations and true cholesterol absorption and, therefore, do not favor the use of these sterols as markers of cholesterol absorption. This bears direct consequences for the interpretation of earlier studies, as well as for future studies targeting intestinal regulation of cholesterol metabolism.

Ezetimibe stimulates faecal neutral sterol excretion depending on abcg8 function in mice.

Ezetimibe stimulates faecal neutral sterol (FNS) excretion in mice, which cannot be explained by cholesterol absorption inhibition alone. We investigated whether these effects are mediated via the sterol exporter ATP binding cassette transporter G8 (abcg8). Ezetimibe increased FNS excretion 2.7-fold in WT mice and 1.5-fold in abcg8(-/-) mice, without affecting biliary cholesterol secretion. Daily FNS excretion exceeded the sum of dietary cholesterol intake and biliary secretion by about 60%. Ezetimibe enhanced this 'extra' FNS excretion by 3.5-fold and 1.5-fold in wildtype (WT) and abcg8(-/-) mice, respectively. Ezetimibe stimulates fecal sterol excretion of non-biliary and non-dietary origin, probably through stimulation of trans-intestinal cholesterol excretion. We show that this effect depends on intact abcg8 function.

ABCG5/G8 polymorphisms and markers of cholesterol metabolism: systematic review and meta-analysis.

Genetic variation at the ABCG5/G8 locus has been associated with markers of cholesterol homeostasis. As data originate from small-scale studies, we performed a meta-analysis to study these associations in a large dataset. We first investigated associations between five common ABCG5/G8 polymorphisms (p.Q604E, p.D19H, p.Y54C, p.T400K, and p.A632V) and plasma sterol levels in 245 hypercholesterolaemic individuals. No significant associations were found. Subsequently, our data were pooled into a meta-analysis that comprised 3,364 subjects from 16 studies (weighted mean age, 46.7 ± 10.5 years; BMI, 23.9 ± 3.5 kg/m(2)). Presence of the minor 632V allele correlated with reduced LDL-C concentrations (n = 367) compared with homozygosity for the 632A variant [n = 614; -0.11 mmol/l (95% CI, range: -0.20 to -0.02 mmol/l); P = 0.01]. The remaining polymorphisms were not associated with plasma lipid levels. Carriers of the 19H allele exhibited lower campesterol/TC (n = 83; P < 0.001), sitosterol/TC (P < 0.00001), and cholestanol/TC (P < 0.00001), and increased lathosterol/TC ratios (P = 0.001) compared with homozygous 19D allele carriers (n = 591). The ABCG8 632V variant was associated with a clinically irrelevant LDL-C reduction, whereas the 19H allele correlated with decreased cholesterol absorption and increased synthesis without affecting the lipid profile. Hence, associations between frequently studied missense ABCG5/G8 polymorphisms and markers of cholesterol homeostasis are modest at best.

LDL-C-lowering therapy: current and future therapeutic targets.

Recent trials have emphasized that more intensive low-density lipoprotein cholesterol (LDL-C) lowering results in a further reduction in cardiovascular disease risk. Uptitration of statins has limited incremental LDL-C-lowering effects and leads to an increased incidence of side effects. Therefore, attention has shifted toward alternative LDL-C-lowering modalities. Several promising compounds have entered the clinical trial arena, although with mixed results. Acyl-coenzyme A: cholesterol O-acyltransferase (ACAT) inhibitors failed to show benefit. Microsomal triglyceride transfer protein and squalene synthase inhibitors, in spite of beneficial lipid profile changes, have shown adverse event profiles. In contrast, inhibitors of intestinal cholesterol absorption have shown LDL-C-lowering efficacy associated with few side effects. The inhibition of apolipoprotein B100 synthesis by antisense oligonucleotides has now been tested in phase 2 clinical trials, with promising results. Finally, compounds modifying protein convertase subtilisin/kexin type 9 levels are currently in the preclinical phase. In the present article, we discuss these LDL-C-lowering strategies.

Plant stanols do not restore endothelial function in pre-pubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels.

OBJECTIVE: To examine the effect of plant stanols on lipids and endothelial function in pre-pubertal children with familial hypercholesterolemia (FH). STUDY DESIGN: Children with FH (n=42), aged 7-12 years, were enrolled in a double-blind crossover trial, in which they consumed 500 mL of a low-fat yogurt enriched with 2.0 g of plant stanols and 500 mL of a low-fat placebo yogurt for 4 weeks, separated by a 6-week washout period. Lipid profiles and endothelial function were assessed after both consumption periods. Endothelial function was measured as flow-mediated dilation (FMD) of the brachial artery. RESULTS: This daily intake of 2.0 g of stanols significantly decreased the levels of total cholesterol (TC) by 7.5% and low-density lipoprotein cholesterol (LDL-C) by 9.2% as compared with placebo. High-density lipoprotein cholesterol and triglyceride levels remained unaltered. The reduction of LDL-C levels did not improve FMD, which was 10.5%+/-5.1% after plant stanol consumption and 10.6%+/-5.0% after placebo consumption, respectively (P=.852). CONCLUSION: This study demonstrates that plant stanols reduce LDL-C levels in children with FH without improving endothelial function.

Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels.

Consumption of plant sterols and treatment with ezetimibe both reduce cholesterol absorption in the intestine. However, the mechanism of action differs between the two treatments, and the consequences of combination treatment are unknown. Therefore, we performed a double-blind, placebo-controlled, crossover study for the plant sterol component with open-label ezetimibe treatment. Forty mildly hypercholesterolemic subjects were randomized to the following treatments for 4 weeks each: 10 mg/day ezetimibe combined with 25 g/day control spread; 10 mg/day ezetimibe combined with 25 g/day spread containing 2.0 g of plant sterols; 25 g/day spread containing 2.0 g of plant sterols; and placebo treatment consisting of 25 g/day control spread. Combination treatment of plant sterols and ezetimibe reduced low density lipoprotein cholesterol (LDL-C) by 1.06 mmol/l (25.2%; P < 0.001) compared with 0.23 mmol/l (4.7%; P = 0.006) with plant sterols and 0.94 mmol/l (22.2%; P < 0.001) with ezetimibe monotherapy. LDL-C reduction conferred by the combination treatment did not differ significantly from ezetimibe monotherapy (-0.12 mmol/l or -3.5%; P = 0.13). Additionally, the plasma lathosterol-to-cholesterol ratio increased with all treatments. Sitosterol and campesterol ratios increased after plant sterol treatment and decreased upon ezetimibe and combination therapy. Our results indicate that the combination of plant sterols and ezetimibe has no therapeutic benefit over ezetimibe monotherapy in subjects with mild hypercholesterolemia.