Vascular Damage in Kidney Disease: Beyond Hypertension

Chronic kidney disease (CKD) is highly prevalent and a multiplier of cardiovascular disease (CVD) and cannot be completely explained by traditional Framinghan risk factors. Consequently, greater emphasis has been placed in nontraditional risk factors, such as inflammation, endothelial dysfunction, sympathetic overactivation, protein-energy wasting oxidative stress, vascular calcification, and volume overload. The accumulation of uremic toxins (and the involvement of genetic factors) is responsible for many of the clinical consequences of a condition known as uremia. In this brief paper, we discuss mechanisms involved in the vascular damage of CKD patients, aiming to point out that important factors beyond hypertension are largely responsible for endothelial activation and increased CVD risk, with potential impact on risk stratification and development of novel therapeutic options

Modalidades de terapia renal substitutiva: hemodiálise e diálise peritoneal

Neste vídeo, o Dr. Roberto Flávio Pecoits Filho explica as características de cada modalidade do tratamento dialítico, a diálise peritoneal e hemodiálise. A primeira é realizada na casa do paciente, necessitando de treinamento para os familiares, uma adequada comunicação à distância com a equipe médica e armazenamento correto do material. Já a hemodiálise é realizada em uma clínica com equipamento e equipe especializada. Ambas necessitam de atenção redobrada às complicações, que podem culminar em problemas cardiovasculares

Inflammation and the Peritoneal Membrane: Causes and Impact on Structure and Function during Peritoneal Dialysis

Peritoneal dialysis therapy has increased in popularity since the end of the 1970s. This method provides a patient survival rate equivalent to hemodialysis and better preservation of residual renal function. However, technique failure by peritonitis, and ultrafiltration failure, which is a multifactorial complication that can affect up to 40% of patients after 3 years of therapy. Encapsulant peritoneal sclerosis is an extreme and potentially fatal manifestation. Causes of inflammation in peritoneal dialysis range from traditional factors to those related to chronic kidney disease per se, as well as from the peritoneal dialysis treatment, including the peritoneal dialysis catheter, dialysis solution, and infectious peritonitis. Peritoneal inflammation generated causes significant structural alterations including: thickening and cubic transformation of mesothelial cells, fibrin deposition, fibrous capsule formation, perivascular bleeding, and interstitial fibrosis. Structural alterations of the peritoneal membrane described above result in clinical and functional changes. One of these clinical manifestations is ultrafiltration failure and can occur in up to 30% of patients on PD after five years of treatment. An understanding of the mechanisms involved in peritoneal inflammation is fundamental to improve patient survival and provide a better quality of life

Impact of Glucose Exposure on Outcomes of a Nation-Wide Peritoneal Dialysis Cohort – Results of the BRAZPD II Cohort

Background: Data investigating the association of glucose exposure with technique failure and patient survival are limited to retrospective cohorts and was never tested outside Asia and considering the presence of competing risks.Methods: Prospective multicenter cohort study of incident peritoneal dialysis patients where the association of cumulative glucose exposure in 6, 12, and 24 months with patient survival and technique failure was tested using Cox regression analysis and competing risk analysis.Results: We analyzed 4367 incident peritoneal dialysis patients with mean age 59.0 ± 15.8 years, 43.9% were diabetics, 46.7% males and 64.4% Caucasians. Glucose exposure was not associated with patient survival independent of the time of exposure and even after adjustments for confounders. In contrast, higher glucose exposure was associated with more technique failure in the Cox and competing risk models. The higher risk for technique failure was found in the subgroup exposed to the higher amount of glucose to a maximum of 86% in the model analyzing cumulative glucose exposure for 1 year.Conclusion: Glucose exposure was associated with technique failure but not with patient survival

Left ventricular hypertrophy in patients with chronic kidney disease under conservative treatment

Cardiovascular disease (CVD) remains the major cause of death in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) is present in 75% of patients starting dialysis, suggesting that LVH might be present from an early stage of CKD. Few studies have addressed the predialysis prevalence of LVH. This study evaluated 309 clinically stable patients under treatment for at least three months at five Brazilian centers. Biochemical profile and inflammatory markers were assessed. Data were shown as mean ± SD. Left ventricular hypertrophy was present in 53% of the patients, whose mean age was 60 ± 13years. The mean age of those without LVH was 55 ± 14 years. Diabetes mellitus was the underlying disease in 35% of the patients in both groups. Estimated glomerular filtration rate was 30 ± 11 and 32 ± 12 mL/min for patients with and without LVH, respectively (p = 0.19). The distribution of patients showed that 60% of those with LVH were in stage 4. Multivariate logistic regression analysis indicated the following independent determinants for LVH: age (p < 0.001); calcium (p < 0.001); hemoglobin (p < 0.048); and diastolic blood pressure (p < 0.001). Systolic blood pressure, lipids, and inflammatory markers showed no correlation with LVH. In conclusion, the incidence of LVH was high even among patients under conservative treatment, and, except for age, LVH correlated with reversible factors. The need for strictly diagnosing CKD and preventing LVH in the predialysis phase is emphasized to decrease mortality due to CVD in that population.A doença cardiovascular (DCV) permanece sendo uma das maiores causas de morte em pacientes com doença renal crônica (DRC). A hipertrofia ventricular esquerda (HVE) está presente em 75% dos pacientes ao iniciarem diálise, sugerindo que esta deve estar presente precocemente no curso da DRC. Poucos estudos avaliaram a prevalência de HVE na pré-diálise. Foram avaliados 309 pacientes clinicamente estáveis em acompanhamento por pelo menos três meses em cinco Centros no Brasil. Perfil bioquímico e marcadores inflamatórios foram avaliados. Dados são apresentados como media ± DP. Observamos que a HVE esteve presente em 53% dos pacientes, idade = 60 ± 13 anos, e 55 ± 14 anos para aqueles sem HVE. Diabetes mellitus como doença de base esteve presente em 35% dos pacientes em ambos os grupos. Filtração glomerular estimada foi 30 ± 11 e 32 ± 12 mL/min para pacientes com HVE e sem, respectivamente (p = 0,19). A distribuição de pacientes mostrou que 60% com HVE se encontravam no estágio 4. Análise logística multivariada mostrou que eram determinantes independentes para HVE: idade (p < 0,001), cálcio (p < 0,001), hemoglobina (p < 0,048) e pressão arterial diastólica (p < 0,001). Pressão arterial sistólica, lipídeos e marcadores inflamatórios não se correlacionaram com a HVE. Em conclusão, a incidência de HVE foi alta mesmo entre pacientes sob tratamento especializado e com exceção da idade, a HVE se correlacionou com fatores reversíveis. Alertamos para a necessidade do diagnóstico da DRC e prevenção da HVE na pré-diálise de forma rigorosa para diminuir a mortalidade decorrente de DCV nesta população.Universidade do Estado do Rio de JaneiroPontifícia Universidade Católica do Paraná Centro de Ciências Biológicas e da SaúdeUniversidade de São Paulo Facildade de Medicina Hospital das ClínicasUniversidade Federal de São Paulo (UNIFESP)Universidade Federal de Juiz de ForaUNIFESP, EPM, São PauloSciEL

A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients

A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD) patients and there is emerging evidence that genetic factors may contribute to the development of atherosclerosis. Myeloperoxidase (MPO) is an abundant enzyme involved in the production of free radicals. A functional G→A single nucleotide polymorphism (SNP) has been identified at position -463, where the A allele is associated with lower MPO expression. To analyze the association between this SNP and inflammation, oxidative stress, and CVD, we studied a cohort of 155 ESRD patients (52 ± 1 years, 62% males, 22% diabetics) shortly before the initiation of dialysis treatment. CVD was defined by medical history criteria; plasma interleukin-6 (IL-6) was used as a marker of inflammation, and plasma pentosidine as an estimation of oxidative protein damage. DNA from leukocytes was used for genotyping, performed by the pyrosequencing reaction. Only five patients (3%) had the genotype AA at the -463 position, whereas 38 (25%) had the GA and 112 (72%) had the GG genotype. No differences were noted in plasma IL-6 levels between the genotype groups, whereas the pentosidine levels were higher in the GG group (28.4 pmol/mg albumin [range, 8.5 to 123 pmol/mg albumin]) compared to the other two groups (21.4 pmol/mg albumin [range, 7.6 to 384 pmol/mg albumin; P < 0.05]). Patients with the GG genotype had a higher prevalence of positive serology for Chlamydia pneumoniae (51%) when compared to the carriers of the A allele (24%) (P < 0.05). The prevalence of CVD was lower in the AA (0%) and GA genotypes (18%), compared to the GG genotype (35%). The GG genotype was still associated with CVD after correction for age, diabetes, smoking, malnutrition, and inflammation. Our findings suggest that the -463 G→A SNP, which supposedly results in lower MPO activity, is associated with a lower prevalence of CVD in ESRD patients. It could be speculated that this effect is mediated by a decreased oxidative stress due to lower production of free radicals

Contribution of the uremic milieu to an increased pro-inflammatory monocytic phenotype in chronic kidney disease

Intermediate (CD14(++)CD16(+)) monocytes have important pro-inflammatory and atherogenic features and are increased in patients with chronic kidney disease (CKD). The present study aims to elucidate the role of the uremic milieu and of platelet activation in monocyte differentiation. Monocyte subtypes were analyzed in CKD patients (n = 193) and healthy controls (n = 27). Blood from healthy controls (Ctrl; n = 8) and hemodialysis patients (HD; n = 8) was centrifuged, and plasma (pl) was exchanged between Ctrl and HD (Ctrlcells/HDpl and HDcells/Ctrlpl) or reconstituted as original (Ctrlsham and HDsham) and incubated for 24 h (T24). Monocyte differentiation and platelet aggregation to monocytes (MPA) was assessed by flow cytometry. Especially, a higher proportion of CD14(++)CD16(+) monocytes was found in hemodialysis (HD) patients (p < 0.01). In plasma exchange experiments, Ctrl cells/HD pl T24 showed an increased percentage of CD14(++)CD16(+) monocytes versus Ctrl sham (33.7% +/- 15 vs. 15.7% +/- 9.6; P.< 0.005), comparable to the level of CD14(++)CD16(+) monocytes in the HD sham condition. The percentage of CD14(++)CD16(+) monocytes was lowered by suspending HD cells in Ctrl pl (18.4% +/- 7.8 vs. 36.7% +/- 15 in HD sham; P < 0.005) reaching the level of the Ctrl sham condition (15.7% +/- 9.6). A mixture of uremic sulfates increased CD14(++)CD16(+) monocytes compared to control (19.8 +/- 9.6% vs. 15.8 +/- 10.9%; P < 0.05), paralleled by a rise MPA. Blocking MPA by abciximab, a potential therapeutic strategy, or anti-CD62P did not inhibit differentiation towards the CD14(++)CD16(+) monocytes. In conclusion, in the present cohort, CD14(++)CD16(+) monocytes are especially increased in HD patients and this can at least in part be attributed to the presence of the uremic milieu, with uremic sulfates inducing a reversible shift towards pro-inflammatory CD14(++)CD16(+) monocytes