Vascular calcification in peritoneal dialysis patients and its association with bone-derived molecules and bone histomorphometry / Calcificación vascular en pacientes en diálisis peritoneal y su asociación con moléculas derivadas de hueso e histomorfometría ósea

Introduction: Data regarding vascular calcification (VC) in contemporary peritoneal dialysis (PD) patients is scarce. Bone–vascular axis has been demonstrated in hemodialysis (HD). However, studies showing the link between bone disease and VC in PD patients are lacking. The role of sclerostin, dickkopf-related protein 1 (DKK-1), receptor activator for nuclear factor kB ligand and osteoprotegerin (OPG) in VC in PD remains to clarify. Materials and methods: Bone biopsy was performed in 47 prevalent PD patients with histomorphometric analysis. Patients were submitted to pelvis and hands X-ray to evaluate VC using the Adragão score (AS). Relevant clinical and biochemical data was collected. Results: Thirteen patients (27.7%) had positive AS (AS≥1). Patients with VC were significantly older (58.9 vs. 50.4 years, p=0.011), had a lower dialysis dose (KT/V 2.0 vs. 2.4, p=0.025) and a higher glycosylated hemoglobin (7.2 vs. 5.4%, p=0.001). There was not any laboratorial parameter of mineral and bone disease used in clinical practice different between patients with or without VC. All diabetic patients had VC but only 8.1% of non-diabetic had VC (p<0.001). Patients with VC showed significantly higher erythrocyte sedimentation rate (ESR) (91.1 vs. 60.0mm/h, p=0.001), sclerostin (2250.0 vs. 1745.8pg/mL, p=0.035), DKK-1 (1451.6 vs. 1042.9pg/mL, p=0.041) and OPG levels (2904.9 vs. 1518.2pg/mL, p=0.002). On multivariate analysis, only ESR remained statistically significant (OR 1.07; 95% CI 1.01–1.14; p=0.022). Bone histomorphometric findings were not different in patients with VC. There was no correlation between bone formation rate and AS (r=−0.039; p=0.796). Conclusion: The presence of VC was not associated with bone turnover and volume evaluated by bone histomorphometry. Inflammation and diabetes seem to play a more relevant role in VC in PD. (AU)

Introducción Los datos sobre calcificación vascular (CV) en pacientes contemporáneos en diálisis peritoneal (DP) son escasos. En pacientes en hemodiálisis, se ha demostrado la existencia de una conexión entre hueso y sistema vascular; sin embargo, faltan estudios que muestren el vínculo entre la enfermedad ósea y la CV en pacientes en DP. Si la esclerostina, la proteína relacionada con Dickkopf 1 (DKK-1), el ligando del receptor activador para el factor nuclear κB (RANKL) y la osteoprotegerina (OPG) tienen un papel en la CV en pacientes en DP aún no está claro. Materiales y métodos Se realizó biopsia ósea en 47 pacientes prevalentes en DP y se analizó mediante histomorfometría. También se tomaron radiografías de pelvis y manos a los pacientes para evaluar la CV mediante el Índice de Adragão (IA). Además, se analizaron datos clínicos y bioquímicos relevantes. Resultados: Trece pacientes (27,7%) tuvieron IA positivo (IA ≥ 1). Los pacientes con CV eran significativamente mayores (58,9 vs 50,4 años, p=0,011) tenían menor dosis de diálisis (KT/V 2,0 vs 2,4, p=0,025) y niveles más elevados de hemoglobina glicosilada (7,2 vs 5,4%, p=0,001). No hubo ningún parámetro de laboratorio de enfermedad mineral y ósea utilizado en la práctica clínica diferente entre pacientes con o sin CV. Todos los pacientes diabéticos mostraron CV, sin embargo, solo el 8,1% de los no diabéticos tenían CV (p <0,001). Además, los pacientes con CV mostraron una velocidad de sedimentación globular más elevada (VSG) (91,1 vs. 60,0mm/h, p=0,001) y mayores concentraciones séricas de esclerostina (2.250,0 vs. 1.745,8 pg/ml, p=0,035), DKK-1 (1451,6 vs 1042,9 pg/ml, p=0,041) y OPG (2.904,9 vs. 1.518,2 pg/ml, p=0,002). En el análisis multivariante, solo la VSG fue estadísticamente significativa (OR 1,07; IC del 95%: 1,01-1,14; p=0,022)... (AU)

Blood, Gut, and Oral Microbiome in Kidney Transplant Recipients.

Background and Objective: Recent reports describe the existence of a blood microbiome profile not associated with an infection state. Given the high impact that the dysbiotic human microbiome appears to have in chronic kidney disease and, in particular, in the outcome of kidney transplant recipients (KTRs), we aimed to explore the variations and correlations of the gut, oral, and blood microbiome of recipients, 3 months after kidney transplantation. Materials and Methods: We conducted a cross-sectional study where the microbiome of stool, saliva, and blood collected from recipients 3 months after kidney transplantation (N = 6) was analyzed by polymerase chain reaction (PCR) amplification and sequencing of the V3-V4 hypervariable regions of the 16S rRNA gene using MiSeq Illumina® technology. Results: Blood of KTRs harbors a distinct low-abundance microbiome dominated by Proteobacteria and Firmicutes. Gut and oral microbiome of KTRs also present distinct profiles. The existence of a proportion of shared operational taxonomic units among the different body sites is reported, mainly classified as Proteobacteria and Firmicutes. Conclusions: This study provides evidence of existence a blood microbiome in KTRs, different from the gut and the oral microbiome profiles, with a small number of operational taxonomic units representing a shared microbiome. The clinical relevance of this observation should be further explored in these patients.

Vascular calcification in peritoneal dialysis patients and its association with bone-derived molecules and bone histomorphometry.

INTRODUCTION: Data regarding vascular calcification (VC) in contemporary peritoneal dialysis (PD) patients is scarce. Bone-vascular axis has been demonstrated in hemodialysis (HD). However, studies showing the link between bone disease and VC in PD patients are lacking. The role of sclerostin, dickkopf-related protein 1 (DKK-1), receptor activator for nuclear factor kB ligand and osteoprotegerin (OPG) in VC in PD remains to clarify. MATERIALS AND METHODS: Bone biopsy was performed in 47 prevalent PD patients with histomorphometric analysis. Patients were submitted to pelvis and hands X-ray to evaluate VC using the Adragão score (AS). Relevant clinical and biochemical data was collected. RESULTS: Thirteen patients (27.7%) had positive AS (AS≥1). Patients with VC were significantly older (58.9 vs. 50.4 years, p=0.011), had a lower dialysis dose (KT/V 2.0 vs. 2.4, p=0.025) and a higher glycosylated hemoglobin (7.2 vs. 5.4%, p=0.001). There was not any laboratorial parameter of mineral and bone disease used in clinical practice different between patients with or without VC. All diabetic patients had VC but only 8.1% of non-diabetic had VC (p<0.001). Patients with VC showed significantly higher erythrocyte sedimentation rate (ESR) (91.1 vs. 60.0mm/h, p=0.001), sclerostin (2250.0 vs. 1745.8pg/mL, p=0.035), DKK-1 (1451.6 vs. 1042.9pg/mL, p=0.041) and OPG levels (2904.9 vs. 1518.2pg/mL, p=0.002). On multivariate analysis, only ESR remained statistically significant (OR 1.07; 95% CI 1.01-1.14; p=0.022). Bone histomorphometric findings were not different in patients with VC. There was no correlation between bone formation rate and AS (r=-0.039; p=0.796). CONCLUSION: The presence of VC was not associated with bone turnover and volume evaluated by bone histomorphometry. Inflammation and diabetes seem to play a more relevant role in VC in PD.

Urinary Cysteinyl Leukotrienes as Biomarkers of Endothelial Activation, Inflammation and Oxidative Stress and Their Relationship with Organ Dysfunction in Human Septic Shock.

Cysteinyl leukotrienes (CysLT) are potent vascular leakage-promoting agents but have been scarcely explored in human septic shock (SS). We evaluated CysLT at admission and during hospitalization and their correlation with endothelial dysfunction, inflammation, oxidative stress, the renin-angiotensin-aldosterone system, and cardiac, renal, respiratory, and hepatic parameters in SS patients. Blood and spot-urine samples were collected at days 1-2 (admission), 3-4, and 5-8 in SS patients (n = 13) and at a single time point in controls (n = 22). Urinary CysLT (u-CysLT) and isoprostanes, plasma, and urinary angiotensinogen, serum myeloperoxidase, and IL-10 were quantified by ELISA. Serum intercellular-adhesion molecule-1, vascular cell-adhesion molecule-1, E-selectin, tumor necrosis factor-α, IL-1ß, and IL-6 were measured by multiplex immunoassays. Routine markers were evaluated using automated analyzers. At admission, SS patients had increased u-CysLT, endothelial activation, inflammation, oxidative stress, and plasma and urinary angiotensinogen, as well as cardiac, respiratory, hepatic, and renal injury/dysfunction. There were no changes in u-CysLT during hospitalization. Both correlation and multivariate analyses showed positive relationships of u-CysLT with endothelial activation, inflammation, oxidative stress, proteinuria, and hepatic injury/dysfunction markers. These results suggest that u-CysLT may be potential non-invasive biomarkers for monitoring the pathophysiological mechanisms underlying SS, as well as putative therapeutic targets.

Prevalence and Characterisation of Patients with Asthma According to Disease Severity in Portugal: Findings from the EPI-ASTHMA Pilot Study.

Objective: To assess the feasibility of the procedures of EPI-ASTHMA. EPI-ASTHMA is a population-based multicentre stepwise study about the prevalence and characterisation of patients with asthma based on disease severity in Portugal. Methods: A pilot study of EPI-ASTHMA was conducted with adults from three primary care centres. We followed a stepwise approach comprising 4 stages: stage 0-invitation phone call (n ~1316); stage 1-telephone interview (n ~658); stage 2-clinical assessment with physical examination, diagnostic tests, and patient-reported outcome measures, to confirm the diagnosis of those with possible asthma at stage 1 (n ~160); stage 3-characterization of a subgroup of asthma patients by collecting data through a telephone interview, patient file review and CARATm app (n ~40), after 3-months. The frequency of asthma was calculated in relation to the entire study population (stage 1) and the frequency of difficult-to-treat/severe asthma in relation to the number of asthma patients (stage 3). Results: From 1305 adults invited, 892 (68%) accepted to participate (stage 0) and 574 (64%; 53[42-67] y; 43% male) were interviewed (stage 1). From those, 148 (26%; 60[46-68] y; 43% male) were assessed at stage 2, and 46 (31%; 51[39-67] y; 44% male) were diagnosed with asthma. Half of these patients (n = 23) accepted to install the app. Stage 3 was completed by 41 (93%) patients, of whom 31 (83%) had asthma confirmed by their file review. A total of 8% of participants had asthma, of those 17% had difficult-to-treat and 5% severe asthma. Conclusion: Attained recruitment rates and the quality of the results confirmed the feasibility of the EPI-ASTHMA stepwise approach. This pilot study provided insight into the improvement of the procedures to be generalized across the country.

Endothelitis profile in acute heart failure and cardiogenic shock patients: Endocan as a potential novel biomarker and putative therapeutic target.

Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial dysfunction, but has been scarcely explored in human AHF. We aimed to evaluate serum (S-Endocan) and urinary endocan (U-Endocan) profiles in AHF and CS patients and to correlate them with biomarkers/parameters of inflammation, endothelial activation, cardiovascular dysfunction and prognosis. Methods: Blood and spot urine were collected from patients with AHF (n = 23) or CS (n = 25) at days 1-2 (admission), 3-4 and 5-8 and from controls (blood donors, n = 22) at a single time point. S-Endocan, U-Endocan, serum IL-1ß, IL-6, tumour necrosis factor-α (S-TNF-α), intercellular adhesion molecule-1 (S-ICAM-1), vascular cell adhesion molecule-1 (S-VCAM-1) and E-selectin were determined by ELISA or multiplex immunoassays. Serum C-reactive protein (S-CRP), plasma B-type natriuretic peptide (P-BNP) and high-sensitivity troponin I (P-hs-trop I), lactate, urea, creatinine and urinary proteins, as well as prognostic scores (APACHE II, SAPS II) and echocardiographic left ventricular ejection fraction (LVEF) were also evaluated. Results: Admission S-Endocan was higher in both patient groups, with CS presenting greater values than AHF (AHF and CS vs. Controls, p < 0.001; CS vs. AHF, p < 0.01). Admission U-Endocan was only higher in CS patients (p < 0.01 vs. Controls). At admission, S-VCAM-1, S-IL-6 and S-TNF-α were also higher in both patient groups but there were no differences in S-E-selectin and S-IL-1ß among the groups, nor in P-BNP, S-CRP or renal function between AHF and CS. Neither endocan nor other endothelial and inflammatory markers were reduced during hospitalization (p > 0.05). S-Endocan positively correlated with S-VCAM-1, S-IL-6, S-CRP, APACHE II and SAPS II scores and was positively associated with P-BNP in multivariate analyses. Admission S-Endocan raised in line with LVEF impairment (p = 0.008 for linear trend). Conclusion: Admission endocan significantly increases across AHF spectrum. The lack of reduction in endothelial and inflammatory markers throughout hospitalization suggests a perpetuation of endothelial dysfunction and inflammation. S-Endocan appears to be a biomarker of endothelitis and a putative therapeutic target in AHF and CS, given its association with LVEF impairment and P-BNP and its positive correlation with prognostic scores.

Vascular Calcification and the Gut and Blood Microbiome in Chronic Kidney Disease Patients on Peritoneal Dialysis: A Pilot Study.

Vascular calcification (VC) is a frequent condition in chronic kidney disease (CKD) and a well-established risk factor for the development of cardiovascular disease (CVD). Gut dysbiosis may contribute to CVD and inflammation in CKD patients. Nonetheless, the role of gut and blood microbiomes in CKD-associated VC remains unknown. Therefore, this pilot study aimed to explore the link between gut and blood microbiomes and VC in CKD patients on peritoneal dialysis (CKD-PD). Our results showed relative changes in specific taxa between CKD-PD patients with and without VC, namely Coprobacter, Coprococcus 3, Lactobacillus, and Eubacterium eligens group in the gut, and Cutibacterium, Pajaroellobacter, Devosia, Hyphomicrobium, and Pelomonas in the blood. An association between VC and all-cause mortality risk in CKD-PD patients was also observed, and patients with higher mortality risk corroborate the changes of Eubacterium eligens in the gut and Devosia genus in the blood. Although we did not find differences in uremic toxins, intestinal translocation markers, and inflammatory parameters among CKD-PD patients with and without VC, soluble CD14 (sCD14), a nonspecific marker of monocyte activation, positively correlated with VC severity. Therefore, gut Eubacterium eligens group, blood Devosia, and circulating sCD14 should be further explored as biomarkers for VC, CVD, and mortality risk in CKD.

Effect of vitamin D sterols on bone histology in pre-dialysis patients: A prospective controlled study.

BACKGROUND: Abnormalities related to mineral and bone metabolism are a common finding in chronic kidney disease (CKD). Vitamin D compounds are often prescribed to CKD patients with the purpose to control secondary hyperparathyroidism and reduce the risk of high-turnover bone disease. However, data on the effect of vitamin D sterols on bone histology in non-dialysis CKD is limited. MATERIALS AND METHODS: A prospective controlled study was conducted on a cohort of 56 patients with CKD stages 3 and 4. 19 patients on calcitriol and 12 patients on cholecalciferol were compared to a group of 25 age- and sex-matched controls. Participants underwent a tetracycline double-labelled transiliac bone biopsy before starting therapy and again 12 months later. Changes from baseline in circulating biomarkers and bone histomorphometric parameters were analyzed. RESULTS: Low-turnover bone disease was the most common pattern of renal osteodystrophy on the initial biopsy. There was no difference in biochemical or histomorphometric values between the three study groups at baseline. Serum intact parathormone (iPTH) and bone formation rate decreased significantly in calcitriol-treated patients, with prevalence of low-turnover bone disease doubling from baseline. In contrast, no significant changes were noted in cholecalciferol-treated and control subjects. CONCLUSION: Calcitriol was effective in preventing secondary hyperparathyroidism and high-turnover bone disease. However, it was associated with an increased risk of developing or aggravating low-turnover bone disease. In the absence of a bone biopsy, calcitriol use in pre-dialysis CKD should be reserved for patients with a progressive rise in iPTH levels, in whom high-turnover bone disease is suspected.

Could Bone Biomarkers Predict Bone Turnover after Kidney Transplantation?-A Proof-of-Concept Study.

AIM: Bone disease after kidney transplant (KT) results from multiple factors, including previous bone and mineral metabolism disturbances and effects of transplant-related medications. New biomolecules have been recently associated with the development and progression of the chronic kidney disease-associated bone and mineral disorder (CKD-MBD). These include sclerostin and the soluble receptor activator of nuclear factor-kB ligand (sRANKL). METHODS: To better understand the role of biomarkers in post-transplant bone disease, this study was designed to prospectively evaluate and correlate results from the histomorphometric analysis of bone biopsies after KT with emerging serum biomarkers of the CKD-MBD: sclerostin, Dickkopf-related protein 1 (Dkk-1), sRANKL and osteo-protegerin (OPG). RESULTS: Our data shows a significant increase in plasma levels of bioactive sclerostin after KT accompanied by a significant reduction in plasma levels of Dkk-1, suggesting a promotion of the inhibition of bone formation by osteoblasts through the activation of these inhibitors of the Wnt signaling pathway. In addition, we found a significant increase in plasma levels of free sRANKL after KT accompanied by a significant reduction in plasma levels of its decoy receptor OPG, suggesting an enhanced bone resorption by osteoclasts mediated by this mechanism. CONCLUSIONS: Taken together, these results suggest that the loss of bone volume observed after KT could be explain mainly by the inhibition of bone formation mediated by sclerostin accompanied by an enhanced bone resorption mediated by sRANKL.

Sclerostin and DKK1 circulating levels associate with low bone turnover in patients with chronic kidney disease Stages 3 and 4.

BACKGROUND: Disordered mineral and bone metabolism is a common complication of chronic kidney disease (CKD). Bone biopsy remains the gold standard tool for evaluating renal osteodystrophy (ROD), but it is an invasive procedure. Despite a growing interest in the ability of newer bone biomarkers to discriminate between different forms of ROD, data on pre-dialysis patients are scarce. METHODS: A cross-sectional study was conducted in a cohort of 56 patients with CKD Stages 3 and 4. Participants underwent a transiliac bone biopsy after a course of double tetracycline labelling. Circulating levels of Wnt signalling inhibitors sclerostin and Dickkopf-1 (DKK1), soluble receptor activator of nuclear factor-κB ligand (sRANKL) and osteoprotegerin were measured and correlated with histomorphometric analysis results. RESULTS: Most patients had abnormal bone histology and low-turnover bone disease was the predominant form of ROD. Characteristics associated with high bone turnover were worse renal function, lower serum calcium and higher intact parathyroid hormone and fibroblast growth factor-23 levels. Patients with low bone turnover, on the other hand, presented with higher sclerostin along with lower DKK1 and sRANKL levels. In the multivariable logistic regression analysis, sclerostin and DKK1 levels were independently associated with low-turnover bone disease. CONCLUSIONS: Our results suggest that circulating levels of Wnt signalling inhibitors sclerostin and DKK1 are predictive of low-turnover bone disease in patients not yet on dialysis. Further research is needed to assess the performance of these bone turnover biomarkers, compared with histomorphometric analysis, in the diagnosis and treatment monitoring of ROD.

Low bone turnover is associated with plain X-ray vascular calcification in predialysis patients.

BACKGROUND: Vascular calcification (VC) is a common finding in chronic kidney disease (CKD) patients and predicts subsequent cardiovascular morbidity and mortality in this population. Vascular calcification is linked to disordered mineral metabolism and has been associated with bone histomorphometry changes in CKD. However, data on predialysis patients is scarce. METHODS: A cross-sectional study was conducted on a cohort of 56 CKD patients not yet on dialysis, who underwent a transiliac bone biopsy for histomorphometric evaluation after double tetracycline labeling. Patients had no previous exposure to calcium salts, vitamin D agents, steroids or bisphosphonates. Vascular calcification was assessed at the time of biopsy, using Kauppila (plain X-ray of the lateral lumbar spine) and Adragão (plain X-ray of the pelvis and hands) scores. RESULTS: Vascular calcification was seen in two-thirds of the cohort. Subjects with VC were more likely to be male and have diabetes, and had significantly higher sclerostin and osteoprotegerin circulating levels than those without VC. The histomorphometric analysis showed that bone formation rate was significantly lower in VC compared to non-VC patients. In the multivariable logistic regression analysis, bone formation rate was independently associated with the presence of VC. CONCLUSIONS: Vascular calcification is highly prevalent in predialysis patients, especially in those with diabetes. The independent association between bone formation rate and VC provides evidence of an important interaction between bone and vessel in CKD. Our results suggest that low bone turnover is a non-traditional risk factor for cardiovascular disease in predialysis patients.

Inflammation in Human Heart Failure: Major Mediators and Therapeutic Targets.

Inflammation has been recognized as a major pathophysiological contributor to the entire spectrum of human heart failure (HF), including HF with reduced ejection fraction, HF with preserved ejection fraction, acute HF and cardiogenic shock. Nevertheless, the results of several trials attempting anti-inflammatory strategies in HF patients have not been consistent or motivating and the clinical implementation of anti-inflammatory treatments for HF still requires larger and longer trials, as well as novel and/or more specific drugs. The present work reviews the different inflammatory mechanisms contributing to each type of HF, the major inflammatory mediators involved, namely tumor necrosis factor alpha, the interleukins 1, 6, 8, 10, 18, and 33, C-reactive protein and the enzymes myeloperoxidase and inducible nitric oxide synthase, and their effects on heart function. Furthermore, several trials targeting these mediators or involving other anti-inflammatory treatments in human HF are also described and analyzed. Future therapeutic advances will likely involve tailored anti-inflammatory treatments according to the patient's inflammatory profile, as well as the development of resolution pharmacology aimed at stimulating resolution of inflammation pathways in HF.

Circulating Renalase as Predictor of Renal and Cardiovascular Outcomes in Pre-Dialysis CKD Patients: A 5-Year Prospective Cohort Study.

Chronic kidney disease (CKD) is an independent risk factor for adverse cardiovascular and cerebrovascular events (MACCEs), and mortality since the earlier stages. Therefore, it is critical to identify the link between CKD and cardiovascular risk (CVR) through early and reliable biomarkers. Acknowledging that CKD and CKD progression are associated with increased sympathetic tone, which is implicated in CVR, and that renalase metabolizes catecholamines, we aimed to evaluate the relationship between renalase serum levels (RNLS) and cardiovascular and renal outcomes. The study included 40 pre-dialysis CKD patients (19F:21M) with median age of 61 (IQ 45-66) years. At baseline, we measured RNLS as well as routine biomarkers of renal and cardiovascular risk. A prospective analysis was performed to determine whether RNLS are associated with CKD progression, MACCEs, hospitalizations and all-cause mortality. At baseline, the median level of RNLS and median estimated glomerular filtration rate (eGFR) were 63.5 (IQ 48.4-82.7) µg/mL and 47 (IQ 13-119) mL/min/1.73 m2, respectively. In univariate analysis, RNLS were strongly associated with eGFR, age and Charlson Index. Over the course of a mean follow-up of 65 (47 to 70) months, 3 (7.5%) deaths, 2 (5%) fatal MACCEs, 17 (42.5%) hospital admissions occurred, and 16 (40%) patients experienced CKD progression. In univariate analysis, RNLS were associated with CKD progression (p = 0.001), hospitalizations (p = 0.001) and all-cause mortality (p = 0.022) but not with MACCEs (p = 0.094). In adjusted analysis, RNLS predicted CKD progression and hospitalizations regardless of age, Charlson comorbidity index, cardiovascular disease, hypertension, diabetes and dyslipidemia. Our results suggest that RNLS, closely related with renal function, might have a potential role as predictor of renal outcomes, hospitalizations, and mortality in pre-dialysis CKD patients.

Endothelial Dysfunction Is Associated with Cerebrovascular Events in Pre-Dialysis CKD Patients: A Prospective Study.

BACKGROUND: Patients with chronic kidney disease (CKD) have markedly increased rates of end stage renal disease, major adverse cardiovascular/cerebrovascular events (MACCEs), and mortality. Endothelial dysfunction (ED) is an early marker of atherosclerosis that is emerging as an increasingly important non-traditional cardiovascular risk factor in CKD. There is a lack of clinical studies examining the association between ED and both cardiovascular and renal endpoints in patients with CKD. AIMS: We examined the association between reactive hyperemia index (RHI), a validated measure of endothelial function measured by peripheral arterial tonometry (PAT), with traditional cardiovascular risk factors in pre-dialysis CKD patients and prospectively evaluated the role of RHI as predictor of renal and cardiovascular outcomes in this population. METHODS: One hundred and twenty pre-dialysis patients with CKD stages 1 to 5 (CKD group) and 18 healthy kidney donor candidates (control group) were recruited and had a successful RHI measurement by PAT. General demographic and clinical information including traditional cardiovascular risk factors were registered from all participants. Thereafter, patients were prospectively followed-up for a median time of 47 (IQR 19-66) months to determine associations of RHI with renal outcomes, MACCEs, hospitalizations or mortality. RESULTS: In the CKD patient population, the mean age was 57.7 ± 15.5 years, the mean eGFR was 54.9 ± 36.7 mL/min/1.73 m2 (CKD-EPI) and 57 were males (47.5%). At baseline, in univariate analysis, RHI in the CKD group correlated positively with eGFR (r = 0.332, p < 0.0001) and correlated negatively with age (r = -0.469, p < 0.0001), Charlson index (r = -0.399, p < 0.0001), systolic blood pressure (r = -0.256, p = 0.005), and proteinuria (r = 0.211, p = 0.027). Reactive hyperemia index in the control group did not significantly differ from RHI observed in patients with CKD stages 1 to 5 (2.09 ± 0.40 vs. 2.01 ± 0.06, p = 0.493). In adjusted analysis, only age (ß = -0.014, p = 0.003) remained independently associated with RHI at baseline. During follow-up, 8 patients suffered a MACCEs, 33 patients experienced renal function deterioration, 17 patients were hospitalized for medical reasons and 6 patients died. RHI at baseline was not significantly associated with CKD progression (1.94 vs. 2.02, p = 0.584), hospitalizations (1.90 vs. 2.04, p = 0.334), and all-cause mortality (1.65 vs. 2.01, p = 0.208) or MACCEs (1.77 vs. 2.01, p = 0.356), but was significantly associated with cerebrovascular events (1.27 vs. 2.02, p = 0.004) and with a composite cardiovascular outcome (MACCEs, hospital admissions and death; 1.73 vs. 2.07, p = 0.035). Conclusion: Our results suggest that RHI may be a predictor for the development of cerebrovascular events in pre-dialysis CKD patients who may benefit from more aggressive preventive measures.

Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study. / A hiperemia reativa correlaciona-se com presença de sepse e degradação de glicocálix na unidade de terapia intensiva: um estudo de coorte prospectiva.

OBJECTIVE: To investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness. METHODS: A prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection. RESULTS: Fifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m. CONCLUSION: Reactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

OBJETIVO: Investigar se a hiperemia reativa correlaciona-se com marcadores de disfunção endotelial e pode ser utilizada para identificar sepse na doença crítica. MÉTODOS: Trata-se de estudo prospectivo em uma coorte de pacientes críticos. A disfunção endotelial foi avaliada quando da admissão, por meio da quantificação de hiperemia por tonometria arterial periférica e níveis plasmáticos de endotelina 1, E-selectina solúvel, endocana e sindecano 1. Os pacientes sépticos foram comparados com pacientes sem evidência de infecção. RESULTADOS: Cinquenta e oito pacientes sépticos foram comparados com 28 controle. O logaritmo natural da tonometria arterial periférica teve correlação negativa com comorbidades cardiovasculares, severidade da doença e níveis plasmáticos de E-selectina solúvel (p = 0,024) e sindecano 1 (p < 0,001). O logaritmo natural da tonometria arterial periférica foi mais baixo nos pacientes sépticos quando comparado com os de pacientes controle (0,53 ± 0,48 versus 0,69 ± 0,42, respectivamente) e, quando ajustado à idade, o modelo multivariado predisse que cada 0,1 de diminuição em unidades de logaritmo natural da tonometria arterial periférica levou a aumento de 14,6% na probabilidade de infecção. CONCLUSÃO: A hiperemia reativa avaliada por tonometria arterial periférica tem estreita relação com E-selectina solúvel e sindecano 1, o que sugere associação entre ativação endotelial, degradação de glicocálix e reatividade vascular. A hiperemia reativa por tonometria arterial periférica parece estar comprometida em pacientes críticos, especialmente os com sepse.

A hiperemia reativa correlaciona-se com presença de sepse e degradação de glicocálix na unidade de terapia intensiva: um estudo de coorte prospectiva / Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study

RESUMO Objetivo: Investigar se a hiperemia reativa correlaciona-se com marcadores de disfunção endotelial e pode ser utilizada para identificar sepse na doença crítica. Métodos: Trata-se de estudo prospectivo em uma coorte de pacientes críticos. A disfunção endotelial foi avaliada quando da admissão, por meio da quantificação de hiperemia por tonometria arterial periférica e níveis plasmáticos de endotelina 1, E-selectina solúvel, endocana e sindecano 1. Os pacientes sépticos foram comparados com pacientes sem evidência de infecção. Resultados: Cinquenta e oito pacientes sépticos foram comparados com 28 controle. O logaritmo natural da tonometria arterial periférica teve correlação negativa com comorbidades cardiovasculares, severidade da doença e níveis plasmáticos de E-selectina solúvel (p = 0,024) e sindecano 1 (p < 0,001). O logaritmo natural da tonometria arterial periférica foi mais baixo nos pacientes sépticos quando comparado com os de pacientes controle (0,53 ± 0,48 versus 0,69 ± 0,42, respectivamente) e, quando ajustado à idade, o modelo multivariado predisse que cada 0,1 de diminuição em unidades de logaritmo natural da tonometria arterial periférica levou a aumento de 14,6% na probabilidade de infecção. Conclusão: A hiperemia reativa avaliada por tonometria arterial periférica tem estreita relação com E-selectina solúvel e sindecano 1, o que sugere associação entre ativação endotelial, degradação de glicocálix e reatividade vascular. A hiperemia reativa por tonometria arterial periférica parece estar comprometida em pacientes críticos, especialmente os com sepse.

Abstract Objective: To investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness. Methods: A prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection. Results: Fifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m. Conclusion: Reactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

Renalase regulates peripheral and central dopaminergic activities.

Renalase is a recently identified FAD/NADH-dependent amine oxidase mainly expressed in kidney that is secreted into blood and urine where it was suggested to metabolize catecholamines. The present study evaluated central and peripheral dopaminergic activities in the renalase knockout (KO) mouse model and examined the changes induced by recombinant renalase (RR) administration on plasma and urine catecholamine levels. Compared with wild-type (WT) mice, KO mice presented increased plasma levels of epinephrine (Epi), norepinephrine (NE), and dopamine (DA) that were accompanied by increases in the urinary excretion of Epi, NE, DA. In addition, the KO mice presented an increase in urinary DA-to-l-3,4-dihydroxyphenylalanine (l-DOPA) ratios without changes in renal tubular aromatic-l-amino acid decarboxylase (AADC) activity. By contrast, the in vivo administration of RR (1.5 mg/kg sc) to KO mice was accompanied by significant decreases in plasma levels of Epi, DA, and l-DOPA as well as in urinary excretion of Epi, DA, and DA-to-l-DOPA ratios notwithstanding the accompanied increase in renal AADC activity. In addition, the increase in renal DA output observed in renalase KO mice was accompanied by an increase in the expression of the L-type amino acid transporter like (LAT) 1 that is reversed by the administration of RR in these animals. These results suggest that the overexpression of LAT1 in the renal cortex of the renalase KO mice might contribute to the enhanced l-DOPA availability/uptake and consequently to the activation of the renal dopaminergic system in the presence of renalase deficiency.

Plasma and urine renalase levels and activity during the recovery of renal function in kidney transplant recipients.

Renalase is a recently described enzyme secreted by the kidney into both plasma and urine, where it was suggested to degrade catecholamines contributing to blood pressure control. While there is a controversy regarding the relationship between renal function and plasma renalase levels, there is virtually no data in humans on plasma renalase activity as well as on both urine renalase levels and activity. We prospectively examined the time course of plasma and urine renalase levels and activity in 26 end-stage renal disease (ESRD) patients receiving a cadaver kidney transplant (cadaver kidney recipients [CKR]) before surgery and during the recovery of renal function up to day 90 post transplant. The relationship with sympathetic and renal dopaminergic activities was also evaluated. The recovery of renal function in CKR closely predicted decreases in plasma renalase levels (r = 0.88; P < 0.0001), urine renalase levels (r = 0.75; P < 0.0001) and urine renalase activity (r = 0.56; P < 0.03), but did not predict changes in plasma renalase activity (r = -0.02; NS). Plasma norepinephrine levels positively correlated with plasma renalase levels (r = 0.64, P < 0.002) as well as with urine renalase levels and activity (r = 0.47 P < 0.02; r = 0.71, P < 0.0005, respectively) and negatively correlated with plasma renalase activity (r = -0.57, P < 0.002). By contrast, plasma epinephrine levels positively correlated with plasma renalase activity (r = 0.67, P < 0.0001) and negatively correlated with plasma renalase levels (r = -0.62, P < 0.003). A significant negative relationship was observed between urine dopamine output and urine renalase levels (r = -0.48; P < 0.03) but not with urine renalase activity (r = -0.33, NS). We conclude that plasma and urine renalase levels closely depend on renal function and sympathetic nervous system activity. It is suggested that epinephrine-mediated activation of circulating renalase may occur in renal transplant recipients with good recovery of renal function. The increase in plasma renalase activity observed in ESRD patients and renal transplant recipients can be explained on the basis of reduced inhibition of the circulating enzyme.

Plasma renalase in chronic kidney disease: differences and similarities between humans and rats.

Renalase was described in 2005 as a new flavoprotein expressed mainly in the kidney that functions as a flavin adenine dinucleotide (FAD)- and nicotinamide adenine dinucleotide (NADH)-dependent amine oxidase. In contrast to other monoamine oxidases, renalase can be secreted into both plasma and urine where it has been suggested to metabolise catecholamines and contribute to blood pressure control. Renalase was first reported to be undetectable in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), suggesting a causal link between the reduced plasma renalase levels, increased plasma catecholamine, and heightened cardiovascular risk that are well documented in this population. Plasma renalase deficiency has been consistently reported in studies using animal models of CKD. However, in studies with 3/4 nephrectomised (3/4nx) rats, the reduced circulating renalase levels were accompanied by increased plasma renalase activity that appeared to be related to decreased inhibition of circulating enzyme. By contrast, a series of recent studies in human subjects provides evidence suggesting that plasma renalase levels are negatively correlated with renal function. Though, similar to that found in the rat remnant kidney, the increased plasma renalase activity in patients with ESRD was associated with decreased inhibition of the circulating enzyme.

Concerted action of ANP and dopamine D1-receptor to regulate sodium homeostasis in nephrotic syndrome.

The edema formation in nephrotic syndrome (NS) is associated with a blunted response to atrial natriuretic peptide (ANP). The natriuretic effects of ANP have been related to renal dopamine D1-receptors (D1R). We examined the interaction between ANP and renal D1R in rats with puromycin aminonucleoside-induced NS (PAN-NS). Urinary sodium, cyclic guanosine monophosphate (cGMP) excretion, and D1R protein expression and localization in renal tubules were evaluated in PAN-NS and control rats before and during volume expansion (VE). The effects of zaprinast (phosphodiesterase type 5 inhibitor), alone or in combination with Sch-23390 (D1R antagonist), were examined in both groups. The increased natriuresis and urinary cGMP excretion evoked by acute VE were blunted in PAN-NS despite increased levels of circulating ANP. This was accompanied in PAN-NS by a marked decrease of D1R expression in the renal tubules. Infusion of zaprinast in PAN-NS resulted in increased urinary excretion of cGMP and sodium to similar levels of control rats and increased expression of D1R in the plasma membrane of renal tubular cells. Combined administration of Sch-23390 and zaprinast prevented natriuresis and increased cGMP excretion induced by zaprinast alone. We conclude that D1R may play a major role in the ANP resistance observed in PAN-NS.