Carla Santos-Araújo

Effects of starting hemodialysis with an arteriovenous fistula or central venous catheter compared with peritoneal dialysis: a retrospective cohort study

BackgroundAlthough several studies have demonstrated early survival advantages with peritoneal dialysis (PD) over hemodialysis (HD), the reason for the excess mortality observed among incident HD patients remains to be established, to our knowledge. This study explores the relationship between mortality and dialysis modality, focusing on the role of HD vascular access type at the time of dialysis initiation.MethodsA retrospective cohort study was performed among local adult chronic kidney disease patients who consecutively initiated PD and HD with a tunneled cuffed venous catheter (HD-TCC) or a functional arteriovenous fistula (HD-AVF) in our institution in the year 2008. A total of 152 patients were included in the final analysis (HD-AVF, n = 59; HD-TCC, n = 51; PD, n = 42). All cause and dialysis access-related morbidity/mortality were evaluated at one year. Univariate and multivariate analysis were used to compare the survival of PD patients with those who initiated HD with an AVF or with a TCC.ResultsCompared with PD patients, both HD-AVF and HD-TCC patients were more likely to be older (p<0.001) and to have a higher frequency of diabetes mellitus (p = 0.017) and cardiovascular disease (p = 0.020). Overall, HD-TCC patients were more likely to have clinical visits (p = 0.069), emergency room visits (p<0.001) and hospital admissions (p<0.001). At the end of follow-up, HD-TCC patients had a higher rate of dialysis access-related complications (1.53 vs. 0.93 vs. 0.64, per patient-year; p<0.001) and hospitalizations (0.47 vs. 0.07 vs. 0.14, per patient-year; p = 0.034) than HD-AVF and PD patients, respectively. The survival rates at one year were 96.6%, 74.5% and 97.6% for HD-AVF, HD-TCC and PD groups, respectively (p<0.001). In multivariate analysis, HD-TCC use at the time of dialysis initiation was the important factor associated with death (HR 16.128, 95%CI [1.431-181.778], p = 0.024).ConclusionOur results suggest that HD vascular access type at the time of renal replacement therapy initiation is an important modifier of the relationship between dialysis modality and survival among incident dialysis patients.

Hypertension and angiogenesis in the aging kidney: a review.

With advanced aging, main components of the kidney are altered, including blood vessels, glomeruli and tubulointerstitium. Disruption in these 3 elements is interconnected and associated with several modifications, such as loss of kidney mass and systemic, metabolic and immunologic diseases. In this review we focus on renal blood vessels, the key role of hypertension and angiogenesis in the elderly kidney, the hemodynamic and molecular mechanisms underlying this aging process and the main factors involved. So far, the present data suggests a strong association between renal disease and hypertension and the impairment of regulatory mechanisms, such as angiogenesis in the aging kidney. The endothelium is a key player in vascular control and appears to be also disrupted in many compensatory functions (i.e., vasodilation). Perspectives for the management of the dysfunctional aging kidney are also addressed.

Local modulation of the natriuretic peptide system in the rat remnant kidney

BACKGROUND The natriuretic peptide (NP) system plays a central role in the renal adaptations to acute volume expansion. However, the modulation of the NP system in chronic renal insufficiency (CRI) remains to be elucidated. In the present study, we evaluated cardiac haemodynamics, plasma type-B natriuretic peptide (BNP) levels and the expression of natriuretic peptide receptor A (NPR-A) and NPR-C in the renal cortex (RC) and medulla (RM) of Sham and (3/4) nephrectomized ((3/4)nx) rats, up to 26 weeks after surgery. METHODS Male Wistar-Han rats (190-220 g; n = 49) were randomly assigned to (3/4)nx or Sham surgery. Two, 10 and 26 weeks after surgery, non-invasive blood pressure (BP) and left ventricular (LV) haemodynamics were performed, and urine and blood were collected for metabolic studies and plasma BNP determination. In addition, tissue samples from RC and RM were obtained for NPR-A and NPR-C quantification (RT-PCR and western blotting) as well as NPR-A immunodetection. RESULTS In (3/4)nx rats, the progressive interstitial fibrosis and tubular atrophy were accompanied by a time-dependent increase of BP and impaired natriuretic response to volume expansion (VE). This was accompanied in (3/4)nx rats by an early and time-dependent elevation of BNP circulating levels that was not associated with cardiac dysfunction or increased myocardial BNP gene expression. In (3/4)nx rats, NPR-A expression in the remnant RM was consistently reduced at 2, 10 and 26 weeks, and this was accompanied by an increase in NPR-C expression in the remnant RC from (3/4)nx rats. CONCLUSIONS BP elevation and compromised natriuretic response to VE in (3/4)nx rats is associated with increased circulating BNP levels in the absence of cardiac dysfunction. This is accompanied in (3/4)nx rats by both impaired NPR-A expression in the RM and upregulation of NPR-C in the RC suggesting a novel mechanism for NP resistance in CRI.

Fibroblast growth factor 23 is associated with left ventricular hypertrophy, not with uremic vasculopathy in peritoneal dialysis patients.

AIMS Cardiovascular (CV) events are the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD), including those patients on peritoneal dialysis (PD). Fibroblast growth factor 23 (FGF23) has been associated with left ventricular hypertrophy (LVH) and mortality in patients with CKD. However, the role of FGF23 in uremic vasculopathy remains unclear. In this study, we aimed to assess the relationship between FGF23 and LVH, endothelial dysfunction, vascular calcification, and arterial stiffness in 48 stable PD patients. METHODS Left ventricular mass index (LVMI) was assessed using 2-D echocardiography. Intact FGF23 blood levels were evaluated using an ELISA kit (Immutopics, Inc., San Clemente, CA, USA). Reactive hyperemia index (RHI) is a surrogate marker of endothelial dysfunction and the augmentation index (AI) is a surrogate marker of arterial stiffness. Both were assessed using peripheral arterial tonometry (EndoPAT 2000). Vascular calcification (VC) was assessed using the Adragão score. RESULTS In unadjusted analysis; FGF23 was positively correlated with serum Pi (r = 0.487, p < 0.001), serum urea (r = 0.351, p = 0.015), serum creatinine (r = 0.535, p < 0.001), dialysis vintage (r = 0.309, p = 0.033), and LVMI (r = 0.369, p = 0.027) and was negatively correlated with age (r = -0.343, p = 0.017), residual renal function (r = -0.359, p < 0.012), and AI (r = -0.304, p = 0.038). In multivariate adjusted analysis, FGF23 was associated with LVMI (β = 0.298, p = 0.041), serum Pi (β = 0.345, p = 0.018), and age (β = -0.372, p = 0.007) independent of dialysis vintage, gender, residual renal function (RRF), albumin, C-reactive protein and systolic blood pressure. There were no associations found between FGF23 and RHI, AI, or VC in multivariable- adjusted models. CONCLUSIONS Our results show that FGF23 is associated with LVH but not with endothelial dysfunction, arterial stiffness, or vascular calcification in PD patients.

Clinical value of natriuretic peptides in chronic kidney disease

According to several lines of evidence, natriuretic peptides (NP) are the main components of a cardiac-renal axis that operate in clinical conditions of decreased cardiac hemodynamic tolerance to regulate sodium homeostasis, blood pressure and vascular function. Even though it is reasonable to assume that NP may exert a relevant role in the adaptive response to renal mass ablation, evidence gathered so far suggest that this contribution is probably complex and dependent on the type and degree of the functional mass loss. In the last years NP have been increasingly used to diagnose, monitor treatment and define the prognosis of several cardiovascular (CV) diseases. However, in many clinical settings, like chronic kidney disease (CKD), the predictive value of these biomarkers has been questioned. In fact, it is now well established that renal function significantly affects the plasmatic levels of NP and that renal failure is the clinical condition associated with the highest plasmatic levels of these peptides. The complexity of the relation between NP plasmatic levels and CV and renal functions has obvious consequences, as it may limit the predictive value of NP in CV assessment of CKD patients and be a demanding exercise for clinicians involved in the daily management of these patients. This review describes the role of NP in the regulatory response to renal function loss and addresses the main factors involved in the clinical valorization of the peptides in the context of significant renal failure.

PHASE ANGLE PREDICTS ARTERIAL STIFFNESS AND VASCULAR CALCIFICATION IN PERITONEAL DIALYSIS PATIENTS

Objectives: Fluid overload (FO) is frequently present in peritoneal dialysis (PD) patients and is associated with markers of malnutrition, inflammation, and atherosclerosis/calcification (MIAC) syndrome. We examined the relationships in stable PD patients between phase angle (PhA) and the spectrum of uremic vasculopathy including vascular calcification and arterial stiffness and between PhA and changes in serum fetuin-A levels. Methods: Sixty-one stable adult PD patients were evaluated in a cross-sectional study (ST1). Phase angle was measured by multifrequency bioimpedance analysis (InbodyS10, Biospace, Korea) at 50 kHz. Augmentation index (AI), a surrogate marker of arterial stiffness, was assessed by digital pulse amplitude tonometry (Endo PAT, Itamar Medical, Caesarea, Israel). Vascular calcification was assessed by simplified calcification score (SCS). Serum fetuin-A levels were measured by ELISA (Thermo scientific; Waltham, MA, USA). Serum albumin was used as a nutritional marker, and serum C-reactive protein (CRP) was used as an inflammatory marker. The same assessments were carried out longitudinally (ST2) in the first 33 patients who completed 1 year of evaluation in ST1. Results: In ST1, patients with PhA < 6° had higher CRP levels, AI, and SCS and lower serum albumin and fetuin-A levels, in comparison with patients with PhA ≥ 6°. In addition, PhA was a predictor of both AI (β = -0.351, p = 0.023) and SCS ≥ 3 (EXP (B) = 0.243, p = 0.005). In ST2, the increase of PhA over time was associated with decreases in both AI (r = -0.378, p = 0.042) and CRP levels (r = -0.426, p = 0.021), as well as with the increase in serum fetuin-A levels (r = 0.411, p = 0.030). Conclusions: Phase angle predicts both arterial stiffness and vascular calcification in stable PD patients.

Oral Yeast Colonization and Fungal Infections in Peritoneal Dialysis Patients: A Pilot Study

Peritonitis and exit-site infections are important complications in peritoneal dialysis (PD) patients that are occasionally caused by opportunistic fungi inhabiting distant body sites. In this study, the oral yeast colonization of PD patients and the antifungal susceptibility profile of the isolated yeasts were accessed and correlated with fungal infection episodes in the following 4 years. Saliva yeast colonization was accessed in 21 PD patients and 27 healthy controls by growth in CHROMagar-Candida® and 18S rRNA/ITS sequencing. PD patients presented a lower oral yeast prevalence when compared to controls, namely, Candida albicans. Other species were also isolated, Candida glabrata and Candida carpophila. The antifungal susceptibility profiles of these isolates revealed resistance to itraconazole, variable susceptibility to caspofungin, and higher MIC values of posaconazole compared to previous reports. The 4-year longitudinal evaluation of these patients revealed Candida parapsilosis and Candida zeylanoides as PD-related exit-site infectious agents, but no correlation was found with oral yeast colonization. This pilot study suggests that oral yeast colonization may represent a limited risk for fungal infection development in PD patients. Oral yeast isolates presented a variable antifungal susceptibility profile, which may suggest resistance to some second-line drugs, highlighting the importance of antifungal susceptibility assessment in the clinical practice.

Asymptomatic Effluent Protozoa Colonization in Peritoneal Dialysis Patients.

Currently, chronic kidney disease (CKD) is a global health problem. Considering the impaired immunity of CKD patients, the relevance of infection in peritoneal dialysis (PD), and the increased prevalence of parasites in CKD patients, protozoa colonization was evaluated in PD effluent from CKD patients undergoing PD. Overnight PD effluent was obtained from 49 asymptomatic stable PD patients. Protozoa analysis was performed microscopically by searching cysts and trophozoites in direct wet mount of PD effluent and after staining smears. Protozoa were found in PD effluent of 10.2% of evaluated PD patients, namely Blastocystis hominis, in 2 patients, and Entamoeba sp., Giardia sp., and Endolimax nana in the other 3 patients, respectively. None of these patients presented clinical signs or symptoms of peritonitis at the time of protozoa screening. Our results demonstrate that PD effluent may be susceptible to asymptomatic protozoa colonization. The clinical impact of this finding should be further investigated.

Oral Colonization of Staphylococcus Species in a Peritoneal Dialysis Population: A Possible Reservoir for PD-Related Infections?

Peritoneal dialysis-related infections are important morbidity/mortality causes, being staphylococci the most prevalent agents. Since Staphylococcus aureus nasopharynx carriage is a known risk factor for PD infections and the oral cavity is a starting point for systemic diseases development, we aimed at comparing the oral staphylococci colonization between PD patients and controls and studying the association with PD-related infections. Saliva samples were plated in Mannitol salt, and isolates were identified by DnaJ gene sequencing. Staphylococci PD-related infections were recorded throughout the 4-year period following sample collection. Staphylococcus colonization was present in >90% of the samples from both groups (a total of nine species identified). PD patients presented less diversity and less prevalence of multispecies Staphylococcus colonization. Although all patients presenting Staphylococcus epidermidis PD-related infections were also colonized in the oral cavity by the same agent, only 1 out of 7 patients with ESI caused by S. aureus presented S. aureus oral colonization. Staphylococci are highly prevalent in the oral cavity of both groups, although PD patients presented less species diversity. The association between oral Staphylococcus carriage and PD-related infections was present for S. epidermidis but was almost inexistent for S. aureus, so, further studies are still necessary to evaluate the infectious potential of oral Staphylococcus carriage in PD.

Direct downregulation of Toll-like receptors by anti-IL-2 alpha chain-receptor antibody in cadaver kidney transplant recipients.

Antibodies against the chain of IL-2 receptor (IL-2R Ab) seems to act by preventing signaling after IL-2 receptor ligation by IL-2 (1), an adaptive immune reaction-associated cytokine. However, as the effect of IL-2R Ab seems to be stronger when delayed graft function supervenes (2), we explored whether IL-2R Ab modulates innate inflammatory reaction by looking at tolllike receptors (TLR)-2, -4, and -9. The first 20 cadaver kidney graft recipients with original renal diseases, not deviated from the pattern observed in a white European population and treated with calcineurin inhibitors, mycophenolate mofetil, and prednisolone, were divided into group I (n 13), no further immunosuppressive therapy, and group II (n 7), which received IL2R Ab. Every case remained rejection free. No differences were observed by comparing demographic data of donorrecipient pairs of both groups and neither serum creatinine nor calcineurin inhibitors levels were different on days 7 and 30 postsurgery between groups. Fine-needle aspiration biopsy (FNAB) were performed on days 7 and 30, and total mRNA samples were extracted using Quiagen Rneasy. Experiments were performed in duplicate for each gene, and mRNA quantification results were expressed in an arbitrary unit set as the average value of the no antibody treatment group. Specific polymerase chain reaction primers were TLR-2-fw 5 -TGG CCA CAC CGG AAT AAG-3 and rev 5 -CAA GCC AGG ATG AGG ACT-3 ; TLR-4-fw 5 CTA AAC CAG CCA GAC CTT GAA-3 and rev 5 -ACC TGT CCC TGA ACC CTA TGA-3 ; and TLR-9-fw 5 -GCC CGG ACT GCC ACA CTT-3 and rev 5 -GAT GTA AGC GCC AAC CCT CTG-3 . Four milliliters of the FNAB sample was used for the culture process, which followed the procedures we published previously (3). Immunocytochemistry of every FNAB sample was studied using avidinbiotin methodology. TLR-2, -4, and -9 monoclonal antibodies at 40 g/mL were purchased from Santa Cruz Biotechnology. This study was approved by the local ethics committee, and informed consent was obtained in all cases On day 7 post-KTX, both TLR-2 and -9 mRNAs were significantly reduced in group II compared with group I, P 0.026, and 0.027, respectively. A close to significant downregulation for mRNA of TLR-4 was observed among II, P 0.091. TLR-2 and -4 mRNA expression displayed a significant positive correlation within group II (R 0.75, P 0.01). TLR-9 mRNA values were negatively correlated with the number of DR mismatches in groups I and II (R 0.52, P 0.038). On day 30 post-KTX, no mRNA amplification was observed for TLR-4 and -9 from both groups in 70% of samples. In the remaining cases, only minor amounts were observed and no significant differences were found between groups. As for TLR-2, a significant downregulation within group II persisted, P 0.03. In immunocytochemistry of FNAB samples, each positive cell and the number of renal cells, lymphocytes, and monocytes was counted to calculate the ratios. Only seven samples were positive for TLR-2 and -4, always less than five cells. TLR-9 was significantly higher in group I, whether for absolute number of cells (P 0.000), or ratio of positive over renal cells (P 0.0001) and ratio of positive ones over lymphocytes plus monocytes (P 0.0001). Day 30 samples were negative for TLR-9. FNAB samples cultures displayed a significantly higher cell proliferation when comparing group I versus groups II on day 7 post-KTX, P 0.039, and a significantly lower proliferation result was found when comparing day 30 with day 7 samples from group I, P 0.016. We tested whether IL-2R Ab directly modulates TLR-4 and -9 expression. Eleven healthy blood donors provided the mononuclear cells separated by Lymphoprep, with cultures manipulated through lipopolysaccharide (LPS; for TLR-4) and CpG oligodeoxynucteotide (ODN) from Coley (for TLR-9). The immunocytochemistry studies for TLR-4 and -9 were performed as described for FNAB samples. LPS significantly enhanced TLR-4 expression (P 0.004) and IL-2R antibody significantly down-regulated TLR-4 expression (P 0.004), whereas a preincubation with IL-2R antibody significantly decreased the ability of LPS to upregulate TLR (P 0.012). CPG ODN close to significant rise of TLR-9 expression (P 0.09), and again IL-2R antibody was able to significantly suppress the CPG ODN promoted TLR expression when both added simultaneously (P 0.015) or when CPG ODN provision was delayed by 48 hr (P 0.049). As far as we are aware, this is the first report of a significant downregulation in FNAB samples of TLR-2 and -9 in KTX treated with IL-2R Ab (with a close to significant downregulation of TLR-4). IL-2R antibody is able by itself, without the concourse of other immunosuppressive drugs, to modulate TLR-4 and -9 upregulation by LPS and CPG ODN, respectively. Our data may be of clinical significance as TLR are a powerful link of innate to adaptive immunity.