Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

Hypomagnesaemia in haemodialysis is associated with increased mortality risk: its relationship with dialysis fluid. / La hipomagnesemia en hemodiálisis se asocia a mayor riesgo de mortalidad: su relación con el líquido de diálisis.

Hypomagnesaemia in haemodialysis (HD) is associated with increased mortality risk: its relationship with dialysis fluid (DF). INTRODUCTION: Low concentrations of magnesium (Mg) in blood have been linked to the development of diabetes, hypertension, arrhythmias, vascular calcifications and an increased risk of death in the general population and in haemodialysis patients. The composition of the dialysis fluid in terms of its magnesium concentration is one of the main determinants of magnesium in haemodialysis patients. OBJECTIVE: To study magnesium concentrations in haemodialysis patients, their predictive mortality rate and what factors are associated with hypomagnesaemia and mortality in haemodialysis. METHODS: Retrospective study of a cohort of prevalent haemodialysis patients followed up for two years. Serum magnesium was measured every six months. The analysis used the initial and average magnesium values for each patient, comparing patients with magnesium below the mean (2.1mg/dl) with those with magnesium above the mean. During the follow-up, three types of dialysis fluid were used: type 1, magnesium 0.5 mmol/l; type 3, magnesium 0.37 mmol/l (both with acetate); and type 2, magnesium 0.5 mmol/l with citrate. RESULTS: We included 137 haemodialysis patients in the study, of which 72 were male and 65 were female, with a mean age of 67 (15) [26-95] years old. Of this group, 57 patients were diabetic, 70 were on online haemodiafiltration (OL-HDF) and 67 were on high-flow haemodialysis (HF-HD). The mean magnesium of the 93 patients with dialysis fluid type 1 was 2.18 (0.37) mg/dl. In the 27 patients with dialysis fluid type 3 it was 2.02 (0.42) mg/dl. And in the 17 with dialysis fluid type 2 it was 1.84 (0.24) mg/dl (p=.01). There was a pronounced direct relationship between Mg and P and albumin. After a mean follow-up of 16.6 (8.9) [3-24] months, 77 remained active, 24 had died and 36 had been transplanted or transferred. Patients with magnesium above than 2.1mg/dl had a longer survival (p=.008). The survival of patients with the three types of dialysis fluid did not differ significantly (Log-Rank, p=.424). Corrected for blood magnesium, patients with dialysis fluid with citrate have better survival (p=.009). The COX regression analysis shows how age, serum albumin, magnesium, dialysis technique and type of dialysis fluid have an independent predictive mortality rate. CONCLUSIONS: Low serum magnesium levels have a greater association with an increased risk of mortality compared to high levels. The type of dialysis fluid affects the magnesium concentration and the risk of death.

Microvesicles from indoxyl sulfate-treated endothelial cells induce vascular calcification in vitro.

Vascular calcification (VC), an unpredictable pathophysiological process and critical event in patients with cardiovascular diseases (CVDs), is the leading cause of morbi-mortality and disability in chronic kidney disease (CKD) patients worldwide. Currently, no diagnostic method is available for identifying patients at risk of VC development; the pathology is detected when the process is irreversible. Extracellular vesicles (EVs) from endothelial cells might promote VC. Therefore, their evaluation and characterization could be useful for designing new diagnostic tools. The aim of the present study is to investigate whether microvesicles (MVs) from endothelial cells damaged by uremic toxin and indoxyl sulfate (IS) could induce calcification in human vascular smooth muscle cells (VMSCs). Besides, we have also analyzed the molecular mechanisms by which these endothelial MVs can promote VC development. Endothelial damage has been evaluated according to the percentage of senescence in endothelial cells, differential microRNAs in endothelial cells, and the amount of MVs released per cell. To identify the role of MVs in VC, VSMCs were treated with MVs from IS-treated endothelial cells. Calcium, inflammatory gene expression, and procalcification mediator levels in VSMCs were determined. IS-treated endothelial cells underwent senescence and exhibited modulated microRNA expression and an increase in the release of MVs. VSMCs exposed to these MVs modulated the expression of pro-inflammatory genes and some mediators involved in calcification progression. MVs produced by IS-treated endothelial cells promoted calcification in VSMCs.

Statins and antiplatelet agents are associated with changes in the circulatory markers of endothelial dysfunction in chronic kidney disease. / El uso de estatinas y antiagregantes se asocia con cambios en los marcadores de disfunción endotelial en la enfermedad renal crónica.

BACKGROUNDS AND PURPOSES: Patients with chronic kidney disease (CKD) have higher risk of developing cardiovascular disease. In CKD patients the mechanisms involved in, endothelial damage and the role of different drugs used on these patients are not completely understood. The aim of this work is to analyze the effect of statins and platelet antiaggregant (PA) on endothelial microvesicles (EMVs) and other markers of endothelial dysfunction. EXPERIMENTAL APPROACH: Cross-sectional study of 41 patients with CKD 3b-4 and 8 healthy volunteers. Circulating levels of EMVs, vascular endothelial growth factor (VEGF), and advance oxidized protein products (AOPPS) were quantified and the correlation with different comorbidity variables and therapeutic strategies were evaluated. RESULTS: EMVs are increased in CKD patients as compared with controls (171.1 vs. 68.3/µl, P<.001). It was observed a negative correlation between age and EMVs. Statins and PA were associated with a reduction in EMVs and VEGF levels, independently of the serum total cholesterol levels (TC). The levels of AOPPS and VEGF were not different in CKD vs. controls. CONCLUSION: CKD is associated with a change in EMVs, VEGF and AOPP levels. The treatment with statins and PA normalizes these values to almost the observed in controls and this effect is independently of the prevailing TC level. These findings explain the existence of the pleiotropic effects of statins and PA which deserve further studies.

Unlike Kt, high Kt/V is associated with greater mortality: The importance of low V. / El Kt/V alto, a diferencia del Kt, se asocia a mayor mortalidad: importancia de la V baja.

INTRODUCTION: Kt/V has been used as a synonym for haemodialysis dose. Patient survival improved with a Kt/V>1; this target was subsequently increased to 1.2 and 1.3. The HEMO study revealed no significant relationship between Kt/V and mortality. The relationship between Kt/V and mortality often shows a J-shaped curve. Is V the confounding factor in this relationship? The objective of this study is to determine the relationship between mortality and Kt/V, Kt and body water content (V) and lean mass (bioimpedance). METHODS: We studied a cohort of 127 prevalent haemodialysis patients, who we followed-up for an average of 36 months. Kt was determined by ionic dialysance, and V and nutrition parameters by bioimpedance. Kt/V, Kt corrected for body surface area (Kt/BSA) and target Kt/BSA were calculated. The mean data from 18,998 sessions were used as haemodialysis parameters, with a mean of 155 sessions per patient. RESULTS: Mean age was 70.4±15.3 years and 61% were male; 76 were dialysed via an arteriovenous fistula and 65 were on online haemodiafiltration. Weight was 70.6 (16.8)kg; BSA 1.8 (0.25) m2; total body water (V) 32.2 (7.41) l and lean mass index (LMI) 11.1 (2.7)kg/m2. Mean Kt/V was 1.84 (0.44); Kt 56.1 (7)l and Kt/BSA 52.8 (10.4)l. The mean target Kt/BSA was 49.7 (4.5)l. Mean Kt/BSA-target Kt/BSA +6.4 (7.0)l. Patients with a higher Kt/V had worse survival rates than others; with Kt this is not the case. Higher Kt/V values are due to a lower V, with poorer nutrition parameters. LMI and serum albumin were the parameters that best independently predicted the risk of death and are lower in patients with a higher Kt/V and lower V. CONCLUSION: Kt/V is not useful for determining dialysis doses in patients with low or reduced body water. Kt or the Kt/BSA are proposed as an alternative.

Residual Renal Function in Hemodialysis and Inflammation.

Residual renal function (RRF) has an important effect on uremic toxin clearance, on volume control, on quality of life, and on mortality. In patients with chronic kidney disease (CKD), microinflammation with an increased percentage of CD14+ /CD16++ inflammatory monocytes has been reported, even with no clinical evidence of inflammation. No correlation has been established between these and RRF in hemodialysis (HD) patients. Our objective was to assess the relationship between RRF and the inflammatory parameters in HD patients. Cross-sectional observational study was carried out on 69 adult patients on chronic HD for at least 6 months, from which demographic, analytic and HD-technique data were collected and the following were measured: (i) RRF with average urea and creatinine clearance ((CCr + CU)/2) in 24-h urine (if >1 mL/min and diuresis >100 mL/day, RRF was considered); (ii) Inflammation through biochemical parameters (C-reactive protein, ß2 microglobulin, albumin) and monocyte subpopulations in peripheral blood. The average age was 70.9 [40-88] years old; 38 (55.1%) were male; and 25 (36.2%) were diabetic. 43.5% (30/69) presented RRF, with an average of ((CCr + CU)/2): 1.8 (2.6) mL/min and diuresis: 454.5 (569) mL /24 h. Patients with RRF presented lower concentrations of C-reactive protein (6.2 vs 21.4 mg/L) (P = 0.038) and a lower percentage of non-classical CD14+ /CD16++ monocytes (14.6 vs. 28.3%, P = 0.02). In our study, patients with RRF present lower concentrations of inflammatory parameters, which is another reason why its preservation is an essential objective in HD.

Follow a recipe to prescribe phosphate during hemodialysis. / Receta para prescribir fósforo durante hemodiálisis.

The addition of phosphorus (P) to the dialysate (LD) in the form of enema Casen® is common practice in patients with hypophosphatemia. The estimation of the amount to be used and the identification of the problems that may can occur are not well defined. As a result of our work we propose a practical approach of how to proceed to increase phosphate concentration in the hemodialysate. We present a reasoned formula to calculate how much enema has to be added and the problems that may arise.

Serratia marcescens bacteraemia outbreak in haemodialysis patients with tunnelled catheters due to colonisation of antiseptic solution. Experience at 4 hospitals. / Brote de bacteriemia por Serratia marcescens en pacientes portadores de catéteres tunelizados en hemodiálisis secundario a colonización de la solución antiséptica. Experiencia en 4 centros.

INTRODUCTION: The application of antiseptic solution for handling tunnelled catheters is recommended in patients undergoing haemodialysis. These routine antiseptic procedures in handling catheters are crucial to avoid complications. We report an outbreak of Serratia marcescens (S. marcescens) bacteraemia in numerous haemodialysis units of the Community of Madrid. MATERIAL AND METHODS: The first cases of bacteraemia due to S. marcescens were isolated in December 2014. The Preventive Medicine Services were informed of the detection of an atypical pathogen in several patients, suspecting a probable nosocomial outbreak. Information from 4 centres with similar S. marcescens bacteraemia was analysed. RESULTS: Twenty-one cases of bacteraemia related to S. marcescens were identified. The mean age of affected patients was 72±10 years. The mean time on haemodialysis of affected patients was 33±13 months (range: 3-83 months), the median time of tunnelled catheter was 22±13 months. In 11 cases the clinical picture was similar, with hypotension and general malaise during the haemodialysis session. Fever was present in a further 7 cases. In 3 cases the presentation was asymptomatic and was detected by blood cultures. All patients had tunnelled catheters (12 patients with catheter in the right jugular vein, 5 in the left jugular, 2 in the right femoral artery and 2 in the left subclavian artery). Gentamicin intravenous doses (1mg/kg) with catheter lock solution with ciprofloxacin post-dialysis were administered for 3 weeks in 6 patients. In 12 patients the treatment was ceftazidime (2g IV) plus catheter lock solution with the same antibiotic, for 2 weeks. Four patients received oral ciprofloxacin for 2 weeks, in one case together with IV vancomycin. The patients were asymptomatic and without new episodes 48hours after the treatment. No major complications were observed. The teams informed the health authorities of the situation, which then reported the presence of batches of antiseptic (chlorhexidine 0.05 and 2%) colonised by S. marcescens. Given the routine application of this antiseptic in handling catheters at these units, this was considered the source of contagion and new cases were not observed after the removal of the batches. CONCLUSIONS: The presence of bacteraemia due to unconventional germs should alert us to a potential outbreak. The application of a solution contaminated by S. marcescens in haemodialysis catheters was the source of bacteraemia. The intravenous antibiotic treatment and the catheter lock solution allowed an excellent survival of patients and catheters.

Is it useful to increase dialysate flow rate to improve the delivered Kt?

BACKGROUND: Increasing dialysate flow rates (Qd) from 500 to 800 ml/min has been recommended to increase dialysis efficiency. A few publications show that increasing Qd no longer led to an increase in mass transfer area coefficient (KoA) or Kt/V measurement. Our objectives were: 1) Studying the effect in Kt of using a Qd of 400, 500, 700 ml/min and autoflow (AF) with different modern dialysers. 2) Comparing the effect on Kt of water consumption vs. dialysis time to obtain an individual objective of Kt (Ktobj) adjusted to body surface. METHODS: This is a prospective single-centre study with crossover design. Thirty-one patients were studied and six sessions with each Qd were performed. HD parameters were acquired directly from the monitor display: effective blood flow rate (Qbe), Qd, effective dialysis time (Te) and measured by conductivity monitoring, final Kt. RESULTS: We studied a total of 637 sessions: 178 with 500 ml/min, 173 with 700 ml/min, 160 with AF and 126 with 400 ml/min. Kt rose a 4% comparing 400 with 500 ml/min, and 3% comparing 500 with 700 ml/min. Ktobj was reached in 82.4, 88.2, 88.2 and 94.1% of patients with 400, AF, 500 and 700 ml/min, respectively. We did not find statistical differences between dialysers. The difference between programmed time and Te was 8' when Qd was 400 and 500 ml/min and 8.8' with Qd = 700 ml/min. Calculating an average time loss of eight minutes/session, we can say that a patient loses 24' weekly, 312' monthly and 62.4 hours yearly. Identical Kt could be obtained with Qd of 400 and 500 ml/min, increasing dialysis time 9.1' and saving 20% of dialysate. CONCLUSIONS: Our data suggest that increasing Qd over 400 ml/min for these dialysers offers a limited benefit. Increasing time is a better alternative with demonstrated benefits to the patient and also less water consumption.

Psychosocial factors and adherence to drug treatment in patients on chronic haemodialysis.

BACKGROUND: The daily pill burden in hemodialysis patients is one of the highest reported to date in any chronic disease. The adherence to prescribed treatment has implications on the quality of life, the survival of patients, and the economic cost of their treatment, this being a priority public health issue. OBJECTIVE: To evaluate the adherence to pharmacological treatment examining, among the possible causes of non-adherence, psychosocial factors such as depression, anxiety, cognitive impairment and social support. METHOD: Transversal-observational study of thirty five patients that suffer from chronic renal disease and who are on manteinance hemodialysis, evaluated by self-reported measures. RESULTS: Non-adherent patients have significant higher depression index than adherent patients. Anxiety, cognitive impairment and social support do not show a significant relation with the degree of adherence or compliance with farmacological treatment. CONCLUSIONS: These results suggest that psychological intervention in chronic haemodialysis patients with a severe depression index could increase the degree of fulfillment and general well-being of renal patients.

A comparison of the effectiveness of two online haemodiafiltration modalities: mixed versus post-dilution.

INTRODUCTION: Haemodiafiltration (HDF) with high reinfusion volumes is the most effective technique for clearing uraemic toxins. There are various modalities depending on the location where the replacement volume is administered in the extracorporeal circuit: pre-dilution, mixed or mid-dilution and post-dilution, in which the infusion is carried out pre-dilution, pre- and post-dilution simultaneously and post-dilution, respectively. OBJECTIVE: Compare the clearance of small, medium-sized and protein-bound molecules and the convective volume administered in online HDF (OL-HDF) in post-dilution and mixed (pre-post-dilution) infusion. MATERIAL AND METHOD: A prospective, randomised, crossover study comparing post-dilution and mixed OL-HDF. Patients (n=8) were randomly assigned to receive 6 sessions in each technique. We conducted 89 sessions, of which 68 were at a scheduled time (ST) and 21 at an effective time (ET). We determined the reduction rate (RR) percentages for various substances and the infusion volumes. The RR study was performed using ET. RESULTS: The KT value obtained was greater with post-dilution OL-HDF [68 (8.1) compared to 64.9 (8.8) litres] (P=.009) when patients were dialysed at ST. This difference disappeared when dialysis was performed at ET. The difference between ST and ET was greater in mixed HDF than in post-dilution HDF [10.3 (7.4) compared to 6.5 (3.1) minutes, P=.02]. We found no differences in the RR of the substances analysed. CONCLUSION: Mixed OL-HDF is not inferior to post-dilution OL-HDF either in the clearance of small and medium-sized molecules or in the clearance of protein-bound molecules at the same ET.

On-line haemodiafiltration improves response to calcifediol treatment.

INTRODUCTION: 25-hydroxy vitamin D (25-OH-vit D) levels in the blood are associated with multiple pathologies. "Normal" values have been defined based on cardiovascular risk, and under this framework, patients with chronic kidney disease often have a deficit. 25-OH-vit D replacement in patients on haemodialysis (HD), in which dosage has not yet been clearly established, is becoming a constant in our daily practice. OBJECTIVE: To assess whether dialysis technique influences the baseline concentration of 25-OH-vitamin D and the response to supplements. METHOD: Prospective observational study of two cohorts of patients, those patients treated with calcifediol and those untreated (controls). Blood levels of Ca, P, PTH, and 25-OH-vit D were measured in 59 prevalent patients on HD (35 male; mean age: 65.2 (15.7) years) in November 2010. Thirty-six patients with 25-OH-vit D<10 ng/ml were treated with weekly calcifediol (Hidroferol®, 1 ampoule: 266 µg) since January 2011, which was administered after HD by a nurse. They received 6 doses, and blood levels were measured again in March 2011. We compared the response based on the technique of HD (online haemodiafiltration [OL-HDF] vs HD). RESULTS: Mean baseline values (n=59): 25-OH-vit D: 9.8 (7.0)ng/ml, Ca: 9.3 (0.5)mg/dl, P: 4.5 (1.4)mg/dl, and iPTH: 299 (224)pg/ml. There were no differences by age, sex, or dialysis technique (HD vs OL-HDF). Treated patients (n=36): 25-OH-vit D levels rose from 6.2 (3.4)ng/ml to 51 (22.9)ng/ml (P<.0001), without significant changes in Ca. Serum phosphate increased an average of 0.6 (1.4)mg/dl, from 4.4 mg/dl to 5mg/dl, (P=.015). PTH decreased an average of 85 (208)pg/ml (P=.023). In these patients, the indication for phosphate binders increased by an average dose equivalent of 0.47 (0.82)mg/dl (P<.001). The 13 patients under treatment with OL-HDF reached 25-OH-vit D levels significantly higher than the 23 treated on HD: 63 (21)ng/ml vs 43 (21)ng/ml (P=.011). Dual treatment with native and active Vit D was associated with significantly increased levels of P (P=.043). Untreated patients (n=23): 25-OH-vit D levels decreased from 15.3 (7.5)ng/ml in November to 11.1 (6.8)ng/ml in March (P<.01), without significant changes in P or PTH and without differences according to age. 25-OH-vit D levels declined in patients on HD (15) but not in patients on OL-HDF. CONCLUSION: The patients on haemodialysis have low or very low baseline values for 25-OH-vit D. The response to treatment with calcifediol is good, with the most marked improvement occurring in patients on OL-HDF. Furthermore, 25-OH-vit D levels decreased in untreated patients, which was probably correlated with the lower sun exposure in winter. Some patients experienced an increase in phosphataemia despite increasing the dosage of phosphate binders, mainly in those receiving treatment with active vitamin D.