Reticulocyte parameters for monitoring anemia in patients with chronic kidney disease on peritoneal dialysis / Parâmetros reticulocitários para monitoramento de anemia em pacientes com doença renal crônica em diálise peritoneal

ABSTRACT Introduction: Anemia is a complication with impact on morbidity and mortality in chronic kidney disease (CKD) patients. Current markers for the diagnosis and monitoring of anemia in CKD are limited by the interrelation between erythropoiesis, iron stores, inflammation, and the resistance to treatment with erythropoiesis stimulant agents (ESA). Objective: The aim of this study was to analyze the role of immature reticulocyte fraction (IRF) and hemoglobin concentration in reticulocytes (RET-He) by the hematology analyser Sysmex XN-5000 in the monitoring of CKD anemia in peritoneal dialysis patients. Methods: This was a prospective, observational multicenter study which compared IRF and RET-He with parameters recommended by the guidelines. Inflammatory biomarkers were analyzed by the Luminex® Multiplexing Instruments system. Thirty-five patients (59 ± 13 years old; 51% men) were included in the analysis. Results: Hemoglobin was 12.2 ± 2 g/dl; 87% had resistance to ESA. Patients with erythropoietin resistance index (ERI) in the upper quartile presented a significantly higher of IRF and a lower percentage of iron deficiency (12%) compared to ferritin (82%) and transferrin saturation index (STI) (51%). Interleukin-6 (IL-6) levels correlated with the percentage of medium fluorescence reticulocyte (MFR) (r = 0.45, p < 0.03). Hemoglobin values after 60 and 180 days were consistently higher in the group of patients with a IRF% lower than 10.5. Conclusion: IRF and RET-He may add value in the iron deficiency investigation, as well as in the identification of patients with ERI. Due to the restricted number of patients analyzed in this study, future studies should be encouraged in larger populations and with prospective follow-up, to validate our findings.

RESUMEN Introducción: La anemia es una complicación con impacto en la morbimortalidad en pacientes con enfermedad renal crónica (ERC). Los biomarcadores usados para el diagnóstico y seguimiento de la anemia en la ERC están limitados por la interrelación entre eritropoyesis, depósitos de hierro, inflamación y resistencia al tratamiento con agentes estimulantes de la eritropoyesis (AEE). Objetivo: El objetivo de este estudio fue analizar el papel de la fracción de reticulocitos inmaduros (IRF) y el equivalente de hemoglobina en reticulocitos (RET-He) mediante el analizador hematológico Sysmex XN-5000 en el seguimiento de la anemia por ERC en pacientes en diálisis peritoneal. Métodos: Estudio prospectivo, observacional multicéntrico que comparó IRF y RET-He con los parámetros recomendados por las guías. Los biomarcadores inflamatorios fueron analizados por el sistema Luminex® Multiplexing Instruments. Este estudio incluyó a 35 pacientes (59 ± 13 años; 51% hombres). Resultados: La hemoglobina fue de 12,2 ± 2 g/dl; el 87% tenía resistencia a AEE. Los pacientes con índice de resistencia a la eritropoyetina (IRE) en el cuartil superior tenían un IRF significativamente más alto y un porcentaje más bajo de deficiencia de hierro (12%) en comparación con la ferritina (82%) y las ITS (51%). Los niveles de interleucina-6 (IL-6) se correlacionaron con el porcentaje de reticulocitos de fluorescencia media (MFR) (r = 0,45, p < 0,03). Los valores de hemoglobina después de 60 y 180 días, fueron consistentemente más altos en el grupo de pacientes con IRF% inferior a 10,5. Conclusión: IRF y RET-He pueden agregar valor en la investigación de ferropenia, así como en la identificación de pacientes con ERI. Debido al número limitado de pacientes analizados en este estudio, se deben impulsar estudios futuros en poblaciones más grandes y con seguimiento prospectivo, para validar nuestros hallazgos.

RESUMO Introdução: Anemia é uma complicação com impacto na morbidade e na mortalidade de pacientes com doença renal crônica (DRC). Os biomarcadores utilizados no diagnóstico e no monitoramento de anemia na DRC são limitados devido à inter-relação entre eritropoiese, estoque de ferro, inflamação e resistência à terapêutica com agentes estimuladores da eritropoiese (AEE). Objetivo: O objetivo deste estudo foi analisar o papel dos marcadores fração de reticulócitos imaturos (IRF) e concentração de hemoglobina nos reticulócitos (RET-He) do analisador hematológico Sysmex XN 5000 no monitoramento da anemia em pacientes em diálise peritoneal. Métodos: Estudo prospectivo, observacional e multicêntrico que comparou IRF e RET-He com parâmetros laboratoriais recomendados pelos guidelines. Biomarcadores inflamatórios foram analisados pelo sistema Luminex® Multiplexing Instruments. Este estudo incluiu 35 pacientes (59 ± 13 anos; 51% homens). Resultados: Os valores de hemoglobina foram 12,2 ± 2 g/dl; 87% apresentaram resistência a AEE. Pacientes com índice de resistência à eritropoietina (IRE) no quartil superior apresentaram valores significativamente maiores de IRF e menor porcentagem de deficiência de ferro (12%) em comparação com pacientes com ferritina (82%) e índice de saturação de transferrina (IST) (51%). Os níveis de interleucina 6 (IL-6) correlacionaram-se com a porcentagem de reticulócitos de fluorescência média (MFR) (r = 0,45, p < 0,03). Valores de hemoglobina após 60 e 180 dias foram consistentemente mais altos no grupo de pacientes com IRF% menor que 10,5. Conclusão: IRF e RET-He podem agregar valor na investigação da deficiência de ferro, bem como na identificação do índice de existência à eritropoietina (ERI). Devido ao número restrito de pacientes analisados neste trabalho, estudos futuros devem ser estimulados em populações maiores e com acompanhamento prospectivo, para validação dos nossos achados.

Public health investments and mortality risk in Brazilian peritoneal dialysis patients.

BACKGROUND: End-stage kidney disease (ESKD) treatment is very costly and accounts for a significant percentage of public healthcare expenditures. Beyond direct costs, dialysis patients use other healthcare levels, but the impact of public investment on each of these levels is unclear. This study aimed to investigate the association between direct financing at different healthcare levels and overall mortality in peritoneal dialysis (PD) patients. METHODS: We included all adult incident PD patients from a Brazilian prospective, nationwide PD cohort. Overall mortality was the primary outcome of interest. We used a three-level multilevel survival analysis to investigate whether mortality was associated with the investments destined to different levels of healthcare complexity: (i) primary, (ii) medium and high and (iii) professional healthcare training and community awareness. RESULTS: We evaluated 5707 incident PD patients from 78 Brazilian cities, which were divided into four quartiles for each healthcare level (Groups I-IV). After taking the highest quartile (Group IV) as a reference, investment in the primary health level was not associated with patient survival. Otherwise, medium and high complexity levels were associated with higher mortality risk. Also, investment in healthcare manager training and community awareness had an impact on patient survival. CONCLUSIONS: Investments in different levels of the healthcare system have distinct impacts on PD patient survival. Investment in healthcare manager training and community awareness seems to be a promising strategy on which to focus, given the relatively low cost and positive impact on outcome.

APOL1-Associated Kidney Disease in Brazil.

INTRODUCTION: Coding variants in apolipoprotein L-1 (APOL1) are associated with an increased risk of end-stage kidney disease (ESRD) in African American individuals under a recessive model of inheritance. The effect of the APOL1 risk alleles on kidney disease has been observed in studies in African American and African populations. Despite the 130 million individuals of recent African ancestry in South America, the impact of APOL1 has not been explored. METHODS: In this case-control study, we tested APOL1 genotype in 106 Brazilian HD (hemodialysis) patients with African ancestry and compared risk allele frequency with 106 healthy first-degree relatives. The association of risk alleles and ESRD was calculated with a linear mixed model and was adjusted for relatedness and additional confounders. In a broader survey, the age of dialysis initiation and APOL1 variants were analyzed in 274 HD patients. RESULTS: Two APOL1 risk alleles were 10 times more common in patients with ESRD than in controls (9.4% vs. 0.9%; odds ratio [OR]: 10.95, SE = 1.49, P = 0.0017). Carriers of 2 risk alleles initiated dialysis 12 years earlier than patients with zero risk alleles. CONCLUSION: The APOL1 risk variants were less frequent in dialysis patients of African ancestry in Brazil than in the United States. Nonetheless, carriers of 2 risk variants had 10-fold higher odds of ESRD. Age of dialysis initiation was markedly lower in 2-risk allele carriers, suggesting a more aggressive disease phenotype. The Brazilian population represents an opportunity to identify different sets of genetic modifiers or environmental triggers that might be present in more extensively studied populations.

The Impact of Uremic Toxicity Induced Inflammatory Response on the Cardiovascular Burden in Chronic Kidney Disease.

Uremic toxin (UT) retention in chronic kidney disease (CKD) affects biological systems. We aimed to identify the associations between UT, inflammatory biomarkers and biomarkers of the uremic cardiovascular response (BUCVR) and their impact on cardiovascular status as well as their roles as predictors of outcome in CKD patients. CKD patients stages 3, 4 and 5 (n = 67) were recruited and UT (indoxyl sulfate/IS, p-cresil sulfate/pCS and indole-3-acetic acid/IAA); inflammatory biomarkers [Interleukin-6 (IL-6), high sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble Fas (sFas)] and BUCVRs [soluble CD36 (sCD36), soluble receptor for advanced glycation end products (sRAGE), fractalkine] was measured. Patients were followed for 5.2 years and all causes of death was used as the primary outcome. Artery segments collected at the moment of transplantation were used for the immunohistochemistry analysis in a separate cohort. Estimated glomerular filtration rate (eGFR), circulating UT, plasma biomarkers of systemic and vascular inflammation and BUCVR were strongly interrelated. Patients with plaque presented higher signs of UT-induced inflammation and arteries from CKD patients presented higher fractalkine receptor (CX3CR1) tissue expression. Circulating IS (p = 0.03), pCS (p = 0.007), IL-6 (p = 0.026), sFas (p = 0.001), sCD36 (p = 0.01) and fractalkine (p = 0.02) were independent predictors of total mortality risk in CKD patients. Our results reinforce the important role of uremic toxicity in the pathogenesis of cardiovascular disease (CVD) in CKD patients through an inflammatory pathway.

Temporal Trends and Factors Associated with Medication Prescription Patterns in Peritoneal Dialysis Patients.

INTRODUCTION: Patients on peritoneal dialysis (PD) suffer from a high burden of comorbidities, which are managed with multiple medications. Determinants of prescription patterns are largely unknown in this population. This study assesses temporal changes and factors associated with medication prescription in a nationally representative population of patients on PD under the universal coverage healthcare system in Brazil. METHODS: Incident patients recruited in the Brazilian Peritoneal Dialysis Study (BRAZPD) from December 2004 to January 2011, stratified by prior hemodialysis (HD) treatment, were included in the analysis. Multivariable logistic regression was used to assess the association between medication prescription and socioeconomic factors. Yearly prevalent cross-sections were calculated to estimate prescription over time. RESULTS: Medication prescription was in general higher among patients who had previously received HD, compared with those who started renal replacement therapy (RRT) directly on PD. Prescription increased from baseline to 6 months of PD therapy, particularly in those who did not previously receive HD. After accounting for patient characteristics, significant associations were found between socioeconomic factors, geographic region, and medication prescription patterns. Finally, the prescription of all cardioprotective and anemia medications and phosphate binders increased significantly over time. CONCLUSION: In a PD population under universal coverage in a developing country, there was an increase in drug prescription during the first 6 months on PD, and a trend toward more liberal prescription of medications in later years. Independent from patient characteristics and comorbidities, socioeconomic factors influenced drug prescriptions that likely impact patient outcome, calling for public health action to decrease potential inequities in management of comorbidities in PD patients.

Peritonitis as a risk factor for long-term cardiovascular mortality in peritoneal dialysis patients: The case of a friendly fire?

AIM: Since the impact of peritonitis on long-term non-infectious mortality has not been investigated until the present, the aim of this study was to analyze the impact of peritonitis on long-term cardiovascular (CV) mortality in a large peritoneal dialysis (PD) cohort. METHODS: The analysis was based on BRAZPD II, a national prospective cohort study that recruited patients in Brazilian centres from December 2004 to January 2011. Incident adult PD patients with at least 90 days on treatment were included in the analysis. Cardiovascular death occurring after a minimum of 30 days after a peritonitis episode was considered the primary endpoint. Cox regression analysis for time-dependent variables was used for the adjustments. RESULTS: There were 2405 episodes of peritonitis in 5707 patients (48% males, 44% diabetes, 73% hypertensive). Patients with one episode of peritonitis presented a 22% increase in the hazard ratio of late CV mortality compared to those who never experienced peritonitis (HR1.22; CI95%1.01-1.47). Adjusted hazard for CV mortality showed a stepwise negative effect on survival for each additional peritonitis episode of infection: two episodes (HR1.78; CI95%1.31-2.42), three episodes (HR2.81; CI95%1.83-4.32) and four episodes (HR3.84; CI95%2.01-7.32). CONCLUSION: Peritonitis was an independent predictor of CV mortality and the frequency of peritonitis was strongly associated with an increase in this risk. This is the first study to demonstrate the impact of peritonitis on late cardiovascular mortality of PD patients, suggesting a link between acute inflammation and cardiovascular outcomes.

Impact of Pre-Dialysis Care on Clinical Outcomes in Peritoneal Dialysis Patients.

BACKGROUND: Structured pre-dialysis care is associated with an increase in peritoneal dialysis (PD) utilization, but not with peritonitis risk, technical and patient survival. This study aimed at analyzing the impact of pre-dialysis care on these outcomes. METHODS: All incident patients starting PD between 2004 and 2011 in a Brazilian prospective cohort were included in this analysis. Patients were divided into 2 groups: early pre-dialysis care (90 days of follow-up by a nephrology team); and late pre-dialysis care (absent or less than 90 days follow-up). The socio-demographic, clinical and biochemical characteristics between the 2 groups were compared. Risk factors for the time to the first peritonitis episode, technique failure and mortality based on Cox proportional hazards models. RESULTS: Four thousand one hundred seven patients were included. Patients with early pre-dialysis care presented differences in gender (female - 47.0 vs. 51.1%, p = 0.01); race (white - 63.8 vs. 71.7%, p < 0.01); education (<4 years - 61.9 vs. 71.0%, p < 0.01), respectively, compared to late care. Patients with early pre-dialysis care presented a higher prevalence of comorbidities, lower levels of creatinine, phosphorus, and glucose with a significantly better control of hemoglobin and potassium serum levels. There was no impact of pre-dialysis care on peritonitis rates (hazard ratio (HR) 0.88; 95% CI 0.77-1.01) and technique survival (HR 1.12; 95% CI 0.92-1.36). Patient survival (HR 1.20; 95% CI 1.03-1.41) was better in the early pre-dialysis care group. CONCLUSION: Earlier pre-dialysis care was associated with improved patient survival, but did not influence time to the first peritonitis nor technique survival in this national PD cohort.

Dialysis: Systemic IL-6 levels predict survival after peritoneal dialysis.

In a recent study, Lambie and colleagues suggest that systemic and local intraperitoneal inflammation, evidenced by elevated levels of interleukin-6, are independent processes and have different consequences for patients undergoing peritoneal dialysis. Prevention of inflammation in these patients will, therefore, require different therapeutic approaches.

Lack of adequate predialyis care and previous hemodialysis, but not hemoglobin variability, are independent predictors of anemia-associated mortality in incident Brazilian peritoneal dialysis patients: results from the BRAZPD study.

BACKGROUND/AIMS: The objective of this study was to analyze the prevalence of anemia and variability of hemoglobin (Hb) values in peritoneal dialysis (PD) patients, to establish its associated factors and their impact on clinical outcomes in a large cohort of patients starting PD treatment. METHODS: Data were collected monthly in incident patients, who were followed until the primary endpoint (death from all causes) or until leaving the study. RESULTS: 2,156 patients starting PD were included. The prevalence of Hb lower than 11 g/dl was 57% at baseline and decreased to 38% at the 4th month. Lack of adequate predialysis care and previous treatment with hemodialysis were the most important factors associated with anemia. Anemia was an independent predictor of mortality. There were no differences in patient survival throughout the different groups of Hb variability. CONCLUSION: Our data point to the need of identifying other risk factors for anemia and aggressively interfere with the modifiable ones in order to correct anemia and decrease mortality in this group of high-risk patients.

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.

Similar outcomes of catheters implanted by nephrologists and surgeons: analysis of the Brazilian peritoneal dialysis multicentric study.

A good catheter implantation technique is important to allow for effective peritoneal access function and long-term technique survival. Studies regarding results obtained by nephrologists in comparison with surgeons have been limited to small single-center experiences. Thus, the objective of this study was to explore the impact of the peritoneal dialysis (PD) catheter insertion operator on early catheter complications and on technique survival in a large national multicentric cohort study (Brazilian Peritoneal Dialysis Multicentric Study, BRAZPD). Adult incident patients recruited in the BRAZPD from December 2004 to October 2007 having undergone first PD catheter implantation were included in the analysis. Mechanical and infectious early complication rates were defined as time to the first event occurring up to 3 months after catheter insertion and adjusted for comorbidities. Valid data of 736 patients (mean age of 59 ± 16 years old, 52% women, 61% white) were analyzed. Mechanical (HR 0.99 [CI 0.56-1.76]; p = 0.98) and infectious (HR 0.63 [CI 0.32-1.23]; p = 0.17) early complication rates were similar between groups. Long-term catheter survival was also similar between groups. Early complications rates and catheter survival were similar between groups defined by operator profile (nephrologist or surgeon), supporting the role of interventional nephrology in the placement of PD catheters.

Peritoneal dialysis in Brazil: twenty-five years of experience in a single center.

OBJECTIVES: To evaluate patient and technique survival and to provide an analysis of peritoneal dialysis (PD)-related peritonitis in 25 years of experience in a single center. STUDY DESIGN: Retrospective study of incident patients on PD from July 1980 to July 2005. SETTING: Single, university based, Brazilian dialysis program. PATIENTS: 680 patients were analyzed in our study from July 1980 to July 2005, with a cumulative experience of 15 303 patient-months. All patients over 15 years of age entering the dialysis program were included in the study. Patients with less than 30 days of follow-up were excluded. Biochemical and demographic variables, peritonitis episodes, and patient and technique survival were analyzed. RESULTS: Mean age at start of PD was 53 +/- 16 years; diabetic nephropathy was the main cause of chronic kidney disease. Cardiovascular disease was the main cause of death (44%); peritonitis was responsible for 16% of fatal events. The predictors of death in our study were diabetes [relative risk (RR) 1.23, p < 0.01], advanced age (RR 1.58, p < 0.001), low serum albumin level (RR 1.25, p < 0.01), and low serum phosphate level (RR 1.39, p < 0.001) upon starting PD. There were 1048 cases of peritonitis over the 25-year period, with a significant reduction in incidence after the introduction of the double-bag system. The number of incident PD patients originating from hemodialysis increased threefold over the observation period (p < 0.001), with a similar increase in comorbidities over time. CONCLUSION: In the largest single-center report of PD experience in Latin America, we describe the overall rate and trends over time of peritonitis as well as patient and technique survival, which are similar to previous reports. Significant changes in peritonitis rates and causative organisms as well as a significant time-dependent increase in high-risk patients starting PD were observed.