José Portolés

Factors that condition the response to erythropoietin in patients on hemodialysis and their relation to mortality

The response to erythropoietin-stimulating agents (ESA) can vary among different patients and according to the different circumstances over time within a given individual. The aim of this study was to analyze the factors that can modify the response to epoetin in patients on hemodialysis (HD) and its influence on early mortality. Prospective and observational study including 1710 patients from 119 HD units in Spain with a follow-up of 12 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI), calculated as the weekly weight-adjusted dose of EPO divided by the hemoglobin level. Patients were stratified in three groups according to ERI: group A, ERI <5; group B, ERI=5-15; group C, ERI>15 U/kg/week/g per 100 ml. Mean ERI for the entire group was 10.2+/-7.3 U/kg/week/g per 100 ml. ERI was directly related with incident comorbidity (Charlson Index), age, female gender and low body mass index with no relationship with etiology of chronic kidney disease. Patients with antecedents of heart failure, acute infection or malignant neoplasm had significantly higher ERI than those without. Transferrin saturation index, but not serum ferritin, was inversely related with ERI. Serum levels of albumin and cholesterol were related with lower ERI, but no relation was found with normalized protein catabolic rate. Patients with a permanent catheter for HD had significant higher values of ERI than those with native fistula (P=0.012). One year survival in all three groups of patients according to ERI was 0.916 in group A, 0.877 in group B and 0.788 in group C (log-rank=20.7, P<0.001). The resistance to ESA is directly related with incident comorbidity in patients on hemodialysis and it can be interpreted as a useful marker of early mortality.

Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in spain: the MERENA observational cohort study

BackgroundTo obtain information on cardiovascular morbidity, hypertension control, anemia and mineral metabolism based on the analysis of the baseline characteristics of a large cohort of Spanish patients enrolled in an ongoing prospective, observational, multicenter study of patients with stages 3 and 4 chronic kidney diseases (CKD).MethodsMulticenter study from Spanish government hospital-based Nephrology outpatient clinics involving 1129 patients with CKD stages 3 (n = 434) and 4 (n = 695) defined by GFR calculated by the MDRD formula. Additional analysis was performed with GFR calculated using the CKD-EPI and Cockcroft-Gault formula.ResultsIn the cohort as a whole, median age 70.9 years, morbidity from all cardiovascular disease (CVD) was very high (39.1%). In CKD stage 4, CVD prevalence was higher than in stage 3 (42.2 vs 35.6% p < 0.024). Subdividing stage 3 in 3a and 3b and after adjusting for age, CVD increased with declining GFR with the hierarchy (stage 3a < stage 3b < stage 4) when calculated by CKD-EPI (31.8, 35.4, 42.1%, p 0.039) and Cockcroft-Gault formula (30.9, 35.6, 43.4%, p 0.010) and MDRD formula (32.5, 36.2, 42.2%,) but with the latter, it did not reach statistical significance (p 0.882). Hypertension was almost universal among those with stages 3 and 4 CKD (91.2% and 94.1%, respectively) despite the use of more than 3 anti-hypertensive agents including widespread use of RAS blockers. Proteinuria (> 300 mg/day) was present in more than 60% of patients and there was no significant differences between stages 3 and 4 CKD (1.2 ± 1.8 and 1.3 ± 1.8 g/day, respectively). A majority of the patients had hemoglobin levels greater than 11 g/dL (91.1 and 85.5% in stages 3 and 4 CKD respectively p < 0.001) while the use of erythropoiesis-stimulating agents (ESA) was limited to 16 and 34.1% in stages 3 and 4 CKD respectively. Intact parathyroid hormone (i-PTH) was elevated in stage 3 and stage 4 CKD patients (121 ± 99 and 166 ± 125 pg/mL p 0.001) despite good control of calcium-phosphorus levels.ConclusionThis study provides an overview of key clinical parameters in patients with CKD Stages 3 and 4 where delivery or care was largely by nephrologists working in a network of hospital-based clinics of the Spanish National Healthcare System.

Effect of Different Dialysis Modalities on Microinflammatory Status and Endothelial Damage

BACKGROUND AND OBJECTIVES We studied the relationship between microinflammation and endothelial damage in chronic kidney disease (CKD) patients on different dialysis modalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Four groups of CKD stage 5 patients were studied: 1) 14 nondialysis CKD patients (CKD-NonD); 2) 15 hemodialysis patients (HD); 3) 12 peritoneal dialysis patients with residual renal function >1 ml/min (PD-RRF >1); and 4) 13 peritoneal dialysis patients with residual renal function <or=1 ml/min (PD-RRF <or=1). Ten healthy subjects served as controls. CD14(+)CD16(+) cells and apoptotic endothelial microparticles (EMPs) were measured by flow cytometry. Serum vascular endothelial growth factor (VEGF) was measured by ELISA. RESULTS CKD-NonD and HD patients had a higher percentage of CD14(+)CD16(+) monocytes than PD groups and controls. CD14(+)CD16(+) was similar in the PD groups, regardless of their RRF, and controls. The four uremic groups displayed a marked increase in apoptotic EMPs and VEGF compared with controls. Apoptotic EMPs and VEGF were significantly higher in HD patients than in CKD-NonD and both PD groups. However, there were no significant differences between CKD-NonD and the two PD groups. There was a correlation between CD14(+)CD16(+) and endothelial damage in CKD-NonD and HD patients, but not in PD and controls. CONCLUSIONS There was an increase in CD14(+)CD16(+) only in CKD-NonD and HD patients. In these patients, there was a relationship between increased CD14(+)CD16(+) and endothelial damage. These results strongly suggest that other factors unrelated to the microinflammatory status mediated by CD14(+)CD16(+) are promoting the endothelial damage in PD, regardless of their RRF.

The development of anemia is associated to poor prognosis in NKF/KDOQI stage 3 chronic kidney disease

BackgroundAnemia is a common condition in CKD that has been identified as a cardiovascular (CV) risk factor in end-stage renal disease, constituting a predictor of low survival. The aim of this study was to define the onset of anemia of renal origin and its association with the evolution of kidney disease and clinical outcomes in stage 3 CKD (CKD-3).MethodsThis epidemiological, prospective, multicenter, 3-year study included 439 CKD-3 patients. The origin of nephropathy and comorbidity (Charlson score: 3.2) were recorded. The clinical characteristics of patients that developed anemia according to EBPG guidelines were compared with those that did not, followed by multivariate logistic regression, Kaplan-Meier curves and ROC curves to investigate factors associated with the development of renal anemia.ResultsDuring the 36-month follow-up period, 50% reached CKD-4 or 5, and approximately 35% were diagnosed with anemia (85% of renal origin). The probability of developing renal anemia was 0.12, 0.20 and 0.25 at 1, 2 and 3 years, respectively. Patients that developed anemia were mainly men (72% anemic vs. 69% non-anemic). The mean age was 68 vs. 65.5 years and baseline proteinuria was 0.94 vs. 0.62 g/24h (anemic vs. non anemic, respectively). Baseline MDRD values were 36 vs. 40 mL/min and albumin 4.1 vs. 4.3 g/dL; reduction in MDRD was greater in those that developed anemia (6.8 vs. 1.6 mL/min/1.73 m2/3 years). These patients progressed earlier to CKD-4 or 5 (18 vs. 28 months), with a higher proportion of hospitalizations (31 vs. 16%), major CV events (16 vs. 7%), and higher mortality (10 vs. 6.6%) than those without anemia. Multivariate logistic regression indicated a significant association between baseline hemoglobin (OR=0.35; 95% CI: 0.24-0.28), glomerular filtration rate (OR=0.96; 95% CI: 0.93-0.99), female (OR=0.19; 95% CI: 0.10-0.40) and the development of renal anemia.ConclusionsRenal anemia is associated with a more rapid evolution to CKD-4, and a higher risk of CV events and hospitalization in non-dialysis-dependent CKD patients. This suggests that special attention should be paid to anemic CKD-3 patients.

Maintenance of target hemoglobin level in stable hemodialysis patients constitutes a theoretical task: a historical prospective study

Maintenance of target hemoglobin (Hb) values in hemodialysis patients treated with erythropoiesis-stimulating agents (ESAs) remains difficult. We examined Hb variability in the clinical setting in hemodialysis patients. Hemodialysis patients treated with ESAs who maintained the recommended Hb range of 11-13 g per 100 ml over 3 months and were not admitted to hospital, did not require transfusion, and did not experience any major clinical event during this period were followed prospectively for 1 year. Anemia events, Hb variation events (any value out of +/-1.5 g per 100 ml of the median Hb level in the total follow-up period for the individual patient), risk factors for anemia, and Hb variation events were assessed. We studied 420 patients (63% males, mean age 61 years), 222 received short-acting erythropoietin (EPO) and 198 long-acting darbepoetin. A total of 4654 blood samples (mean 11.1 per patient-year) were analyzed. Only 3.8% of patients were maintained within the target Hb levels (11-13 g per 100 ml) during 1 year. Hb variation events occurred in 20.8% of laboratory values and anemia events in 14.7%, with a median time to the first event of 3 months. Treatment with short-acting EPO (vs long-acting darbepoetin), change of ESA dose in the previous visit, resistance index, and hospitalization were significant risk factors for both anemia events and Hb variation events. Our results show that Hb values are rarely maintained within the recommended guidelines even in more stable hemodialysis patients. Hb variability is frequently associated with clinical events or ESA dose changes. Long-acting darbepoetin achieved better Hb stability than short-acting EPO.

Eculizumab in secondary atypical haemolytic uraemic syndrome

Background. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab. Methods. We identified 29 patients with so‐called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration. Results. Twenty‐nine patients with secondary aHUS (15 drug‐induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer‐related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow‐up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses. Conclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA‐inducing condition.

Peritoneal Dialysis Can Be an Option for Dominant Polycystic Kidney Disease: an Observational Study

♦ Background: Autosomal dominant polycystic kidney disease (ADPKD) has been considered a relative contraindication for peritoneal dialysis (PD), although there are few specific studies available. ♦ Methods: A multicenter historical prospective matched-cohort study was conducted to describe the outcome of ADPKD patients who have chosen PD. All ADPKD patients starting PD (n = 106) between January 2003 and December 2010 and a control group (2 consecutive patients without ADPKD) were studied. Mortality, PD-technique failure, peritonitis, abdominal wall leaks and cyst infections were compared. ♦ Results: Patients with ADPKD had similar age but less comorbidity at PD inclusion: Charlson comorbidity index (CCI) 4.3 (standard deviation [SD] 1.6) vs 5.3 (SD 2.5) p < 0.001, diabetes mellitus 5.7% vs 29.2%, p < 0.001 and previous cardiovascular events 10.4% vs 27.8%, p < 0.001. No differences were observed in clinical events that required transient transfer to hemodialysis, nor in peritoneal leakage episodes or delivered dialysis dose. The cyst infection rate was low (0.09 episodes per patient-year) and cyst infections were not associated to peritonitis episodes. Overall technique survival was similar in both groups. Permanent transfer to hemodialysis because of surgery or peritoneal leakage was more frequent in ADPKD. More ADPKD patients were included in the transplant waiting list (69.8 vs 58%, p = 0.04) but mean time to transplantation was similar (2.08 [1.69 – 2.47] years). The mortality rate was lower (2.5 vs 7.6 deaths/100 patient-year, p = 0.02) and the median patient survival was longer in ADPKD patients (6.04 [5.39 – 6.69] vs 5.57 [4.95 – 6.18] years, p = 0.024). ♦ Conclusion: Peritoneal dialysis is a suitable renal replacement therapy option for ADPKD patients.

A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome

Pregnancy-associated atypical hemolytic uremic syndrome (aHUS) refers to the thrombotic microangiopathy resulting from uncontrolled complement activation during pregnancy or the postpartum period. Pregnancy-associated aHUS is a devastating disease for which there is a limited clinical understanding and treatment experience. Here we report a retrospective study to analyze the clinical and prognostic data of 22 cases of pregnancy-associated aHUS from the Spanish aHUS Registry under different treatments. Sixteen patients presented during the first pregnancy and as many as nine patients required hemodialysis at diagnosis. Identification of inherited complement abnormalities explained nine of the 22 cases, with CFH mutations and CFH to CFHR1 gene conversion events being the most prevalent genetic alterations associated with this disorder (66%). In thirteen of the cases, pregnancy complications were sufficient to trigger a thrombotic microangiopathy in the absence of genetic or acquired complement alterations. The postpartum period was the time with highest risk to develop the disease and the group shows an association of cesarean section with pregnancy-associated aHUS. Seventeen patients underwent plasma treatments with a positive renal response in only three cases. In contrast, ten patients received eculizumab with an excellent renal response in all, independent of carrying or not inherited complement abnormalities. Although the cohort is relatively small, the data suggest that pregnancy-associated aHUS is not different from other types of aHUS and suggest the efficacy of eculizumab treatment over plasma therapies. This study may be useful to improve prognosis in this group of aHUS patients.

Course of vascular access and relationship with treatment of anemia.

BACKGROUND AND OBJECTIVES Maintenance of the vascular access is a crucial factor in hemodialysis, but large studies of factors that are predictive of thrombosis are lacking. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This prospective, multicenter study investigated a cohort to describe the management of vascular access and establish the influence of anemia as a risk factor. The cohort included 1710 patients (aged 64.4 yr; 60% men) who were followed every 3 mo at 119 centers during 12 mo. On inclusion, 9.6% had a catheter, 80.3% had a native arteriovenous fistula, and 10.1% had a polytetrafluoroethylene graft. RESULTS Low baseline hemoglobin increased the risk for vascular access events. The risk was higher with a polytetrafluoroethylene graft and a catheter versus arteriovenous fistula. The multivariate model included type of vascular access, previous cardiovascular events, and noncorrected anemia. The likelihood of remaining free of vascular access events 12 mo later was 0.727 (baseline hemoglobin <10.0 g/dl), 0.801 (10.01 to 11.0 g/dl), 0.814 (11.01 to 12.0 g/dl), and 0.833 (>12.0 g/dl), figures similar to those obtained with hemoglobin from the trimester before the event. The Cox model included type of vascular access. CONCLUSIONS Correcting anemia did not increase the risk for vascular access-related events, and anemia that was resistant to treatment identified a subgroup of patients with higher comorbidity and higher likelihood of a vascular access event.

Definición de procesos e indicadores para la gestión de accesos vasculares para hemodiálisis

Resumen Introduccion La prevalencia del tratamiento renal sustitutivo ha aumentado hasta 885 pacientes por millon de habitantes. Mas del 50% de estos pacientes necesitan hemodialisis (HD) con acceso vascular (AVH) permanente. En nuestro centro se organizo un grupo multidisciplinar para gestionar los procesos relacionados con el AVH. Objetivos Definicion y evaluacion de procesos para gestionar los AVH. Material y metodo Ambito: hospital de tercer nivel de la Comunidad de Madrid, referencia para 550.000 habitantes. Periodo de estudio: 2002-2004. Metodo: se constituyo un grupo de trabajo multidisplinario. Definicion y descripcion de los 3 procesos mas frecuentes. Se utilizaron flujogramas para representacion grafica. Se definieron criterios e indicadores de calidad, con monitorizacion prospectiva en la historia clinica electronica, diseno de protocolo quirurgico especifico y analisis retrospectivo. Resultados Comparacion de resultados con los de la literatura: Primer acceso vascular: porcentaje de pacientes con fistulas arteriovenosas (FAV) desarrollado al comenzar HD; porcentaje de pacientes prevalentes con AVH autologo/protesico/cateter. Mantenimiento del acceso: tasa de trombosis FAV autologa-protesica, porcentaje de AVH rescatadas tras trombosis, tasa de cateteres temporales. Gestion de recursos: porcentaje de intervenciones ambulatorias, tasa de ingresos relacionados con AVH. Conclusiones Los AVH son la fuente de morbilidad e ingresos hospitalarios principal de los pacientes con insuficiencia renal cronica en programas de HD. La gestion multidisciplinar ha permitido conseguir resultados por encima de los estandares descritos en la bibliografia. No parece que haya otros factores determinantes de estos resultados, ya que los procedimientos tecnicos realizados no difieren de los descritos en la bibliografia.