[Determination of brain natriuretic peptide in patients undergoing different haemodiafiltration techniques]. / Determinación del péptido natriurético cerebral en pacientes sometidos a diferentes técnicas de hemodiafiltración.

UNLABELLED: IB-type natriuretic peptide is a cardíac neurohormone secreted by the cardíac ventricules in response to ventricular dilatation so plasma BNP level correlate with left ventricular mass and dysfunction. Dialysis patients have much greater levels of BNP due to the volume overload and because of reduced renal clearance. The aim of this study was to mesure and compare the BNP levels in three groups of patients who received different hemodiafiltration techniques: Daily online hemodiafiltration (HDFOLd), on-line hemodiafiltration (HDFOL) and low convective volume hemodiafiltration (HDF). Fifteen patients were included, five in each group. Pre and postdialysis BNP leves were measured during 8 weeks. The measure was done at the beginning of the week (long period), and at the end (short period), in order to study if there were significative differences between techniques and periods. We found significative differences between predialysis BNP levels in the short period (BNPpreC) and the long period (BNPpre-L). We also found significative differences with the posdialysis BNP in both periods; BNPpre- L vs. BNPpos-L (1069+/-1031 vs. 612 +/- 540). After comparing the three techniques the study showed significative differences between BNPpreC in HDF and HDFOL compared with HDFOld. And also after dialysis between BNPpos-C in HDFOLd compared with the other techniques. CONCLUSION: Although previous papers have shown that BNP levels have limited potential for assessment of hydration in hemodialysis patients, in this study our data demonstrate that after dialysis BNP levels decline in a significative way in the long and short period and we have found that patients on daily hemodialysis show lower BNP levels, and maybe this could be explained because daily on-line haemodiafiltration patients had lower weight rise between dialysis sessions and also better haemodynamic tolerance.

[Kinetic of calcium, phosphate, magnesium and PTH variations during hemodiafiltration]. / Cinéica del calcio, fósforo, magnesio y variaciones de la parathormona (PTH) en pacientes en hemodiafiltracion.

Hemodiafiltration (HDF) is a technique resulting from coupling of diffusive and convective transport and thereby increase the elimination of small and middle molecules. However, may induce a convective loss from others substances such as calcium and magnesium. The aim of this study was to evaluate the effects of Ultrafiltration on the kinetics of calcium, phosphate, magnesium and parathyroid hormone. A total of thirteen patients (7 males and 6 females) on hemodialysis, were studied. Each patient was randomly dialyzed with the same dialysate calcium concentration and three different ultrafiltration rate. Schedule A: High flux hemodialysis, schedule B: HDF with 10% of weight body and schedule C: HDF with 20% of weight body. The others parameters were kept identical. Total Ultrafiltration was 2,6+/-0,9 L (9,78+/-3,78 ml/min) in A, 9,3+/-1,7 L (34,54+/-6,22 ml/min) in B and 16,3+/-3,3 L (60,94+/-12,63 ml/min) in C. Replacement fluid during dialysis was 6,85+/-1,42 and 13,65+/-2,9 L. in C and C respectively. Postdialysis total,ionized calcium and magnesium were significantly lower in schedules B and C versus A. PTH levels did not differ significantly. However, PTH changes during dialysis was -36.6+/-38.6%, 6.3+/-69.8% and 32.2+/-63.2% in A, B and C, respectively (p<0.05 A vs. C). A significant inverse correlation was found between total Ultrafiltration and postdialysis levels of total calcium (r:-0.56, p<0.001), ionized calcium (r:-0.65, p<0.001) and magnesium (r:-0.47, p<0.01). No differences were observed in pre and postdialysis phosphate levels, neither mass transfer and clearance of phosphate. We concluded that high ultrafiltration flow rates and substitution fluid without divalent cations induces a negative calcium and magnesium balance. These changes may stimulate PTH secretion during HDF. This technique did not resulted in a higher clearance or phosphate removal.

[Oxidative stress analysis in patients on hemodiafiltration on-line]. / Análisis del estrés oxidativo en pacientes en hemodiafiltración en línea.

Patients with chronic renal disease have a very high mortality due to cardiovascular disease. However, the traditional risk factors are not the only one explanation. Nowadays, there are new risk factors becoming, and one of these is the oxidative stress. Besides today we know that when these patients receive haemodialysis are being exposed to an additional oxidative stress. The aim of this study was to measure and to compare the degree of oxidative stress in two groups of patients on different dialysis techniques: a) On-Line Haemodiafiltration three times / week (OL-HDF). b) Daily Om-Line haemodiafiltration ( six times / week ) ( dOL-HDF) We studied 9 patients with chronic renal disease stage 5 on hemodialysis. They all were men, with a medium age of 72,5 +/- 6 years. Five patients were on dOL-HDFand four on tOL-HDF. Glutathione (GSH) concentration of patients on dOL-HDF before dialysis was 742+/- 153 nmol/ml and post-dialysis de 878+/- 223. Blood GSSG concentration before and after dialysis was 34+/- 14 nmol/ml y 137+/- 74 nmol/ml (p< 0,03). GSSG/GSH ratio pre-dialysis was 58+/-10 and post-dialysis 169+/-65 ( p < 0,03). In OL-HDF group GSSG concentration and the ratio GSSG/GSH also increased in a significative way from 99+/-45 nmol/ml to 179+/-66 nmol/ml, and from 161+/- 99 to 337+/-143 ( p<0,05). We also found differences in pCR concentrations between both groups; 3+/-1,4 g/l in dOL-HDF and 8,75+/-5,8 g/l in HDF OL. (p< 0,05). We did not find differences between xatine-oxidase activity before and after hemodialysis and between groups. In conclusion, patient with terminal chronic renal disease on OL-HDF receive an additional load of oxidative stress, as the increase in GSSG/GSH ratio in both groups shows. However patients on dHDF-OL shows low ratios GSSG/GSH post-hemodialysis and low pCR concentrations, and maybe this could be explained because daily on line haemodiafiltration improves purification of inflammatory mediators. Clue words: Hemodialysis, oxidative stress, glutathione, gssg/gsh ratio, xantine oxidasa.

[Middle molecules removal. Beyond beta2-microglobulin]. / Depuración de grandes moléculas. Más allá de la beta2-microglobulina.

The uremic toxin removal capacity mainly depends on dialyzer and hemodialysis modes. The low-flux hemodialysis only removes solutes having molecular weights less than 5.000 Da. High-flux hemodyalisis represents a form of low-volume hemodiafiltration because of the internal filtration and back-filtration that can take place within a dialyzer. Hemodiafiltration with large volumes of replacement fluid seems to be the best technique for removing all small, medium-sized and large molecules. The objective of our study was to evaluate the large molecules removal bigger than beta2-microglobuline on high flux haemodialysis and on-line hemodiafiltration with postdilutional infusion, in patients with three times a week dialysis and on short daily dialysis. We studied 24 patients, 15 males and 9 females stable on haemodialysis programme, twelve on standard four to five hours three times a week dialysis and twelve on 2 to 2 1/2 hours six times a week dialysis. All patients were dialysed with Fresenius 4008 monitor, three sessions on high flux haemodialysis (HD) and three sessions on on-line hemodiafiltration (OL-HDF). Two sessions with each filter were performed (polisulfone HF80, polyethersulfone Arylane H9 and new polisulfone APS 900). Pre and postdialysis concentrations of urea, creatinine, (beta2-microglobulin (beta2-m), myoglobin, prolactin and alpha1 microglobulin (alpha1-m) were measured. There was no difference in urea and creatinine small molecules removal. beta2m removal was 68% on HD and 81% on OL-HDF. Myoglobin and prolactin present a similar removal pattern, a higher removal with new filters (60% with Arylane and 59% with APS) in comparison with clasical polisulfone (22% with HF80). The mean alpha1-m reduction rate on HD was 6% and on OL-HDF 22%. OL-HDF with APS 900 filter was the most remove technique (35.4%), significatively higher than the other modes and filters. We can conclude that the new filters generation reach a better uremic toxins removal, specially in large molecules higher than beta2-m and on HD modality.

[Determination of the dose of dialysis with integrated modules in the same monitor]. / Medición de la dosis de diálisis mediante diferentes módulos integrados en un mismo monitor.

The "gold standard" method to measure the mass balance achieved during dialysis for a given solute is based on the total dialysate collection. This procedure is unfeasible and too cumbersome. For this reason, alternative methods have been proposed including the urea kinetic modelling (Kt/V), the measurement of effective ionic dialysance (Diascan), and the continuous spent sampling of dialysate (Quantiscan). The aim of this study was to compare the reliability and agreement of these two methods with the formulas proposed by the urea kinetic modelling for measuring the dialysis dose and others haemodialysis parameters. We studied 20 stable patients (16 men/4 women) dialyzed with a monitor equipped with the modules Diascan (DC) and Quantiscan (QC) (Integra. Hospal). The urea distribution volume (VD) was determined using anthropometric data (Watson equation) and QC data. Kt/V value was calculated according to Daurgidas 2nd generation formula corrected for the rebound (eKt/V), and using DC (Kt/VDC) and QC (Kt/VQC) data. The total mass of urea removed was calculated as 37,93 +/- 16 g/session. The VD calculated using Watson equation was 35.7 +/- 6.6 and the VDQC was 35.06 +/- 9.9. And they showed an significative correlation (r:0,82 p < 0.001). The (VDQC-VDWatson) difference was -0.64 +/- 5.8L (ns). Kt/VDC was equivalent to those of eKt/V (1.64 +/- 0.33 and 1.61 +/- 0.26, mean difference -0.02 +/- 0.29). However, Kt/VQC value was higher than eKt/V (1.67 +/- 0.22 and 1.61 +/- 0.26 mean difference 0.06 +/- 0.07 p < 0.01). Both values correlated highly (R2: 0.92 p < 0.001). Urea generation (C) calculated using UCM was 8.75 +/- 3.4 g/24 h and those calculated using QC was 8.64 +/- 3.21 g/24 h. Mean difference 0.10 +/- 1.14 (ns). G calculated by UCM correlated highly with that derived from QC (R2: 0.88 p < 0.001). In conclusion, Kt/VDC and Kt/VQC should be considered as valid measures for dialysis efficiency. However, the limits of agreement between Kt/VQC and eKt/V were closer than Kt/VDC.

[Estimation of the cost in the farmacologic treatment of chronic renal failure]. / El coste del tratamiento farmacológico en la enfermedad renal crónica.

The prevalence and incidence of end stage renal disease has increased considerably in the past years. We know that the cost of treatment of these patients is high. Limited information exists on care resource utilization for maintenance of patients before the initiation of replacement therapy. The purpose of this study is determine the cost of pharmaceutic treatment during the predialysis phase. Pharmacy cost was analyzed for 200 patients controlled on outpatient nephrology department. The mean age was 72.4 years, 59% were males, and the comorbidity distribution was: hypertension 87%, hyperlipidemia 56% and diabetes 35%. The per-patient-per-month charges were 215.45 Euro, with a continous increase from 84.64 Euro on stage 1 to 352.59 Euro on stage 5 of chronic kidney disease. Erythropoiesis stimulants were reponsible of 46.5% of these cost. The most frequent prescribed medications were antihypertensive drugs, statins and iron preparations. Patients with end stage renal disease generate significant cost during the predialysis period. The limited resources, and the growth of health care expeditures, particulary the spending for prescriptions drugs, are two of the major problems for Health Care Systems. A better knowledge of the associated costs to the treatment of these patients will help us to increase our efficiency.

[Monitoring hemodialysis dose with ionic dialisance in on-line hemodiafiltration]. / Valoración de la medición de la dosis de diálisis con dialisancia iónica en hemodiafiltración on-line.

Until now, with the ionic dialysance measurement, it has been possible to determine hemodialysis dose in each session of hemodialysis (HD) and in the conventional hemofiltration (HDF) but not in the modality of on-line HDF. Recently it is possible with a new biosensor that allows to measure the dose in on-line HDF. The aim of this study was to evaluate the value of this biosensor in different dialysis situations comparing the dialysis dose measured in blood in comparison with the values obtained from the sensor. We have analysed 192 hemodialysis sessions performed in 24 patients, 15 male and 9 female, mean age of 70.2 +/- 12 years, included in on-line HDF. All treatments were done using 4008H (Fresenius) monitor equipped with on-line clearance monitoring (OCM), that measure, with non invasive monitoring, the effective ionic dialysance equivalent to urea clearance. Every patient received eight dialysis sessions: one with dialysate flow (Qd) 500 ml/min, two with HD and Qd 800 ml/min and five with on-line HDF. Other habitual haemodialysis parameters were no changed, dialysis time 200 +/- 63 min (135-300) and blood flow 421 +/- 29 ml/min (350-450). Initial and final ionic dialysance values (K), final Kt, Kt/V measured with OCM using V of Watson, and Kt/V determined in blood pre and postdialysis concentrations of urea (Daugirdas second generation), were measured. The mean of initial K was 251 +/- 21 ml/min and the final K was 234 +/- 24 ml/min. The Kt measured with OCM was 50.6 +/- 17 L, 51.2 +/- 17 in men and 49.7 +/- 16 in women. The V (Watson) was 34.5 +/- 6 L. The Kt/V measured with the Kt of OCM and V was 1,499 +/- 0.54 and Kt/V measured in blood samples was 1,742 +/- 0.58. The correlation between both values was 0.956. The Kt was different according to dialysis modality used: in HD and Qd 500 was 44.7 +/- 15 L, in HD and Qd 800 was 50.7 +/- 17 and in on-line HDF (22.1 +/- 7 L of reposition volume), was 51.8 +/- 17 L. The Kt/V from blood samples also shows variation: in HD and QD 500 was 1.60 +/- 0.55, in HD and Qd 800 was 1,726 +/- 0.56 and in on-line HDF was 1,776 +/- 0.59. In this study has been observed a close correlation between the new biosensor OCM with the measures obtained from the blood samples. For this reason this sensor it is useful in all modalities of dialysis treatment, included on-line HDF. The sensor was able to discriminate the efficacy of different dialysis modalities used in this study.

[Acute interstitial nephritis associated with omeprazole therapy]. / Nefritis intersticial aguda por omeprazol.

From 1 to 3% of acute renal failures are due to acute interstitial nephritis (AIN). Most of them are due to drugs. Nonsteroidal antiinflammatory drugs, penicillins and sulfonamides are the most frequently reported. Clinical presentation of drug-induced AIN has changed over time and with the use of new drugs. In fact actually the classic triad of fever, rash and eosinophilia is uncommon. Omeprazole is a drug widely used in the treatment of gastroesophageal reflux disease and peptic ulcer disease. Serious side effects are rare with this drug, but despite of its safety we can see serious adverse effects such as acute renal failure. We describe two cases of acute interstitial nephritis after use of omeprazole and a review of all the cases published in the last years.

[Evaluation of methods to calculate dialysis dose in daily hemodialysis]. / Cuantificación de la dosis de diálisis en hemodiálisis diaria.

UNLABELLED: Daily dialysis has shown excellent clinical results because a higher frequency of dialysis is more physiological. Different methods have been described to calculate dialysis dose which take into consideration change in frequency. The aim of this study was to calculate all dialysis dose possibilities and evaluate the better and practical options. Eight patients, 6 males and 2 females, on standard 4 to 5 hours thrice weekly on-line hemodiafiltration (S-OL-HDF) were switched to daily on-line hemodiafiltration (D-OL-HDF) 2 to 2.5 hours six times per week. Dialysis parameters were identical during both periods and only frequency and dialysis time of each session were changed. Time average concentration (TAC), time average deviation (TAD), normalized protein catabolic rate (nPCR), Kt/V, equilibrated Kt/V (eKt/V), equivalent renal urea clearance (EKR), standard Kt/V (stdKt/V), urea reduction ratio (URR), hemodialysis product and time off dialysis were measured. Daily on-line hemodiafiltration was well accepted and tolerated. Patients maintained the same TAC although TAD decreased from 9.7 +/- 2 in baseline to a 6.2 +/- 2 mg/dl after six months, p < 0.01. No significant changes were observed in weekly Kt/V and eKt/V throughout the study. However EKR, stdKt/V and weekly URR were increased during D-OL-HDF in 24-34%, 46% and 50%, respectively. Hemodialysis product was raised in a 95% and time off dialysis was reduced to half. CONCLUSION: Dialysis frequency is an important urea kinetic parameter which there are to take in consideration. It's necessary to use EKR, stdKt/V or weekly URR to calculate dialysis dose for an adequate comparison between different frequency dialysis schedules.

[Usefulness of the Biofeedback Diacontrol module in the automatic programming of plasmatic conductivity and ionic mass transfer]. / Utilidad del módulo de "Biofeedback" Diacontrol en la programación automática de la conductividad plasmática y la transferencia de masa iónica.

Programmed variable sodium in the dialysate can improve hypotension during hemodialysis but may also alter sodium balance and thus resulting in a increase of water intake and weight gain between dialysis sessions. The aim of this study was to evaluate the changes on plasma volume (PV), Ionic Mass Transfer (IMT) and plasma conductivity (PC) with two different hemodialysis techniques. We studied 10 patients during a four-period protocol (one week each: PF1-DC1-DC2PF2): 120 dialysis sessions. During periods PF1 and PF2, the dialysis procedure was as usual, with exponential decrease of dialysate conductivity (DC) profile (15.7 mS/cm at start, 14.4 mS/cm at middle and 13.8 mS/cm at the end of the session) and UF profile (1.7 1/h at start and 0.1 1/h at the end). During periods DC1 and DC2, DC was automatically determined by a biofeedback modulae (Diacontrol) in order to reach a plasma water conductivity fixed at 14 mS/cm. All hemodialysis parameters were the same for the four periods: duration, blood and dialysate flow rates, dialysis membrane. A lower reduction of PV was evident on PF1 and PF2 (104 +/- 3.26% and -4.36 +/- 2.7%) compared with DC 1 and DC2 (-6.53 +/- 3.31% and -6.67 +/- 3.12%) (p < 0.001). No significant differences were seen in systolic, mean and diastolic blood pressure pre-HD or post-HD, UF, and weight gain, between the four periods. Hypotensive episodes were seen in 33.3% of PF1, 20% of DC1, 23.3% of DC2 and 26.6% of PF2 sessions (NS). PF1 and PF2 periods resulted in a significantly higher 30', mid and post-dialysis PC as compared to DC1 and DC2 periods (p < 0.001). The mean difference between the actual value and the prescribed value of PC at the end of the session was -0.01 +/- 0.07 mS/cm (n: 60). There was a negative correlation between the mean DC during session and the PC at 30' of session. IMT was 420.73 +/- 126.9 mEq in PF1, 311.96 +/- 161.75 in DC1, 278.34 +/- 153.14 in DC2 and 417.66 +/- 152.17 in PF2 (p > 0.001 PF1 and PF2 vs. DC1 and DC2). Diacontrol determines automatically an individualized DC profile for each patient, and accurately reaches the prescribed PC target. By reaching both the dry weight and PC settings, the water and sodium pool is maintained lower in the hemodialysis session using a biofeedback module. Clinical tolerance was similar in the two different dialysis procedures.

[Improvement of nutritional status in patients with short daily on-line hemodiafiltration]. / Mejoría del estado nutricional con hemodiafiltración en línea diaria.

Daily dialysis have showed excellent results because a higher frequency of dialysis is more physiological and it decreases the fluctuation of liquid, solutes and electrolytes. Improvement of certain causes of anorexia such as postdialysis fatigue, reduction in fluid overload, uremic milieu, medium and large-sized molecule removal could be observed with daily dialysis. The aim of this study was to evaluate nutritional parameters when thrice weekly on-line hemodiafiltration (OL-HDF) were switched to daily OL-HDF. 24 patients have been studied. Eight patients, 6 males and 2 females, mean age of 65.9 +/- 14 years, on thrice weekly 4 to 5 hours OL-HDF were switched to 2 to 2.5 hours six times per week. Dialysis parameters were the same in both periods and only frequency and dialysis time were changed. Other sixteen patients, mean age of 68.4 +/- 14 years, were a control group which dialysis parameters were maintained. Clinical and biochemical outcome were carried out over twelve months. Daily OL-HDF group: Dry weight increased from 67.8 +/- 8 kg at baseline to 68.5 +/- 8 kg after three months, 69.3 +/- 8 kg after six months (NS), 69.5 +/- 8 kg after nine months (p < 0.05) and 70.8 +/- 8 (p < 0.01) after one year. Mean nPCR increased from 0.93 +/- 0.2 g/kg/d on baseline to 1.18 +/- 0.3 after three moths (P < 0.0-5), 1.13 +/- 0.2 after six months (NS), 1.06 +/- 0.2 after nine months (NS) and 1.10 +/- 0.2 after twelve months (NS). There were no significant changes in serum protein, albumin, prealbumin, transferrin, total cholesterol, HDL-c, LDL-c and triglycerides (TG). There were no changes in control group. Mean dry weight was 62.3 +/- 9 kg at baseline and 62.1 +/- 10 kg after one year. Mean nPCR was 0.97 +/- 0.2 g/kg/d on baseline and 1.03 +/- 0.2 g/kg/d after one year. Neither there were changes in serum protein, albumin, transferrin, total cholesterol, HDL-c, LDL-c and TG. Improvement in nutrition status has been observed with the change from thrice weekly OL-HDF to short daily OL-HDF. Increased appetite and protein intake was accompanied by a dry body weight increase of three kg after twelve months.

[Secondary amyloidosis (AA) and renal disease]. / Amiloidosis secundaria (AA) y afectación renal.

Amyloidosis is a disease resulting from extracellular deposition of fibrillar protein in various organs. AA amyloidosis may complicate chronic inflammatory diseases, chronic infections and another chronic diseases. We review 31 patients (13 males and 18 females) with biopsy proven renal or rectal AA amyloidosis, referred to out hospital between january 1999 and november 2002. Renal failure was defined as serum creatinine > or = 1.5 mg/dl. Mean age was 58.4 +/- 15.7 years. The causes of AA amyloidosis were an underlying chronic rheumatologic disease (51.6%), chronic infection (41.9%) and a chronic inflammatory intestinal disorder (6.5%). Renal failure (RF) was detected in 20 patients (61.2%) and proteinuria and hematuria were found in 90.3% and 45.5 respectively. Proteinuria at diagnosis was 5.2 +/- 3.9 g/24 h and mean serum creatinine 3.5 +/- 3.7 mg/dl. Survival of patients without dialysis was 66.8 (51.1% RF, 90.9% non-RF) and 53.4% (38.2 RF, 77.9% non-RF) at 12 and 24 months respectively (p = 0.017). End-stage renal disease developed in 13 patients (41.9%). Ten patients were maintained on hemodialysis and 3 on CAD. Survival in dialysis at 6 and 12 months was 68.3% and 42.7% respectively. Fifteen patients died and the main causes of death were: infections (46.6) haemorrhagic complications (33.3%), cardiovascular events (13.3%) and cachexia (6.6%).

[Intradialysis hemolysis secondary to hypophosphatemia]. / Hemólisis intradiálisis secundaria a hipofosforemia.

We report a 76-year-old man, stable on a thrice-weekly hemodialysis program over a period of 3 years, who developed acute intradialysis hemolysis secondary to hypophosphatemia, an unusual cause of hemolysis. During the dialysis session we monitored the starting point, the severity and duration of intradialysis hemolysis. Severe hyphosphatemia is a rare cause of intradialysis hemolysis. It is important to think of his possibility to make an adequate diagnosis and treatment. The patient was treated with a phosphorus-enriched acid concentrate, bicarbonate-buffered dialysate, with biochemical and clinical improvement.

[Outcome of tunneled hemodialysis catheters as permanent vascular access]. / Seguimiento a largo plazo de catéteres permanentes en pacientes con dificultad en la obtención de un acceso vascular definitivo.

UNLABELLED: Tunneled cuffed hemodialysis catheters (THC) are developed as a means of short hemodialysis access while a more permanent form of access are maturing. The aim of this study is to investigate the effectiveness, survival and complications of the THC used for long-term vascular access. METHODS: In a retrospective study we looked at 42 THC inserted between November 2000 and October 2003, in 40 elderly patients, with systemic disease or when other vascular access was not possible. RESULTS: Procedural complications occurred in 5 cases (11.9%), which included: local haemorrhage (3), hemothorax (1) and one fatal venous tear. 6 catheters (14.2%) were removed due to complications (non-function 3 and bacteraemia 3). The total incidence of THC related infections was 0.18 episodes/1,000 catheters-days. Patients were followed up for a mean 379 days (range 1-1,140) and a total of 15,946 catheter-days. Qb and KT/V achieved at one month were 278.3 +/- 34.1 ml/min and 1.48 +/- 0.27 respectively. At the end of the follow-up, 23 patients (54.7%) were alive with catheter functioning. One, three and twelve months survival was 90.4%, 73.1% and 59.5% respectively. CONCLUSION: The THC may be a useful alternative permanent vascular access for hemodialysis patients when others vascular access are not possible.