INVESTIGATION OF POSSIBILITIES TO EXTEND FUNCTIONING TIME OF ARTERIOVENOUS FISTULAS FOR HEMODIALYSIS PATIENTS

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1 LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY Sondra Kybartienė INVESTIGATION OF POSSIBILITIES TO EXTEND FUNCTIONING TIME OF ARTERIOVENOUS FISTULAS FOR HEMODIALYSIS PATIENTS Summary of Doctoral Dissertation Biomedical Sciences, Medicine (06B) Kaunas, 2012

2 Dissertation was prepared at the Medical Academy of Lithuanian University of Health Sciences Kaunas during Scientific Supervisor Prof. Dr. Vytautas Kuzminskis (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine 06B) Consultant Prof. Dr. Rytis Rimdeika (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine 06B) The dissertation is defended at the Medical Research Council of the Medical Academy of Lithuanian University of Health Sciences: Chairman Prof. Dr. Antanas Gulbinas (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine 06B) Members: Prof. Dr. Habil. Kęstutis Strupas (Vilnius University, Biomedical Sciences, Medicine 06B) Dr. Rūta Vaičiūnienė (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine 06B) Prof. Dr. Saulius Lukoševičius (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine 06B) Prof. Dr. Aivars Pētersons (Riga Stradins University, Biomedical Sciences, Medicine 06B) Opponents: Assoc. Prof. Dr. Augustina Jankauskienė (Vilnius University, Biomedical Sciences, Medicine 06B) Dr. Vygintas Kaikaris (Lithuanian University of Health Sciences, Medical Academy, Biomedical Sciences, Medicine 06B) The dissertation will be defended at the open session of the Medical Research Council on the 22nd of June, 2012, at 12 a.m. in the Central auditorium of Hospital of Lithuanian University of Health Sciences Kaunas Clinics. Address: Eivenių 2, LT Kaunas, Lithuania. The summary of the doctoral dissertation was sent on the 21th of May, The full text of the doctoral dissertation is available at the Library of Lithuanian University of Health Sciences. Address: Eivenių 6, LT Kaunas, Lithuania. 2

3 LIETUVOS SVEIKATOS MOKSLŲ UNIVERSITETAS MEDICINOS AKADEMIJA Sondra Kybartienė ARTERIOVENINIŲ JUNGČIŲ DIALIZUOJAMIEMS PACIENTAMS FUNKCIONAVIMO PAILGINIMO GALIMYBIŲ TYRIMAS Daktaro disertacijos santrauka Biomedicinos mokslai, medicina (06B) Kaunas,

4 Disertacija rengta metais Lietuvos sveikatos mokslų universitete. Mokslinis vadovas prof. dr. Vytautas Kuzminskis (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina 06B) Konsultantas prof. dr. Rytis Rimdeika (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina 06B) Disertacija ginama Lietuvos sveikatos mokslų universiteto Medicinos akademijos medicinos mokslo krypties taryboje: Pirmininkas prof. dr. Antanas Gulbinas (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina 06B) Nariai: prof. habil. dr. Kęstutis Strupas (Vilniaus universitetas, biomedicinos mokslai, medicina 06B) dr. Rūta Vaičiūnienė (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina 06B) prof. dr. Saulius Lukoševičius (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina 06B) prof. dr. Aivars Petersons (Rygos Stradinio universitetas, biomedicinos mokslai, medicina 06B) Oponentai: doc. dr. Augustina Jankauskienė (Vilniaus universitetas, biomedicinos mokslai, medicina 06B) dr. Vygintas Kaikaris (Lietuvos sveikatos mokslų universitetas, Medicinos akademija, biomedicinos mokslai, medicina 06B) Disertacija ginama viešame Medicinos mokslo krypties tarybos posėdyje 2012 m. birželio 22 d. 12 val. Lietuvos sveikatos mokslų universiteto Kauno klinikų Didžiojoje auditorijoje. Adresas: Eivenių g. 2, LT Kaunas, Lietuva. Disertacijos santrauka išsiuntinėta 2012 m. gegužės 21 d. Disertaciją galima peržiūrėti Lietuvos sveikatos mokslų universiteto bibliotekoje. Adresas: Eivenių 6, LT Kaunas, Lietuva. 4

5 CONTENT ABBREVIATIONS AND TERMS... 6 INTRODUCTION... 7 Aim and objectives... 7 Scientific novelty of the study MATERIAL AND METHODS Statistical data analysis RESULTS Patient characteristics Results of the monitoring of arteriovenous fistulas Duration of patient's hospitalization when the first HD procedure was done throw central vein catheter Factors influencing duration of fistula function Twelve month survival of arteriovenous fistula Thirty six month survival of arteriovenous fistula in the historical group Preoperative vascular ultrasound examination before arteriovenous fistula creation CONCLUSIONS PRACTICAL RECOMENDATIONS PUBLICATIONS SUMMARY IN LITHUANIAN CURRICULUM VITAE

6 ABBREVIATIONS AND TERMS AVF Catheter sepsis CRF DOPPS Groups examined: historical group partially monitoring group monitoring group HD Kt/V K (liters per hour) t (hours) V n p PTA vs χ 2 arteriovenous fistula a systemic infection, in which the gateway is the central venous catheter case report form Dialysis Outcomes and Practice Patterns Study Patients whose arteriovenous fistulas have not been applied to monitoring patients, who started HD before monitoring program and continued HD during this program new patients who started HD after monitoring program was implemented hemodialysis measure of dialysis adequacy expressed by the treatment-related urea reduction ratio; urea clearance, length of dialysis session, distribution volume of urea (litres) number level of significance percutaneous transluminol angioplasty versus (comparing to) chi-squared test 6

7 INTRODUCTION Patients to be treated with chronic hemodialysis (HD) must have blood vessel connection. There are three types of blood vessel connections: native arteriovenous fistula (AVF), synthetic prosthesis and permanent central venous catheter. Each connection has its strengths and weaknesses. Primary AVF dysfunction occurs in 7.5% of the whole population of patients receiving HD, and in up to 80% of high risk patients (those with diabetes, elderly patients, and women) [Mann et al 2005]. Compared to other blood vessel connections (permanent central venous catheter or synthetic prosthesis) function of properly formed AVF is the longest, and incurs the lowest incidence of infectious and thrombotic complications. All international guidelines on HD procedures recommend native AVF as the method of choice. Formation of blood vessel junctions and treatment of their complications account for up to 20% of all hospitalizations of patients with end stage renal failure in USA [Allon et al 2002], up to 30% in Canada [Mann et al 2005], and up to 25% in Europe [Pissoni et al 2002]. It should be stated that formation of AVF and treatment of their complications are very expensive, and therefore determining the causes of the development of AVF complications and their timely diagnosis and correction are extremely important. Various methods of monitoring of AVF function are used in many European and USA HD centers; however, the most important criterion of early diagnosis of AVF complications has not been established yet [Paulson et al 2012]. Although large scale studies, such as DOPPS, as well as smaller-scale (one country or one centre) studies that are in place in the USA and European countries look into peculiarities of AVF formation, incidence of complications and methods of their correction, no studies of AVF problems have been carried out in Lithuania. Aim and objectives Aim of the study: to determine factors related to the duration of AVF function and to evaluate benefit of monitoring AVF function in order to increase of longevity of AVF functioning. 7

8 Objectives: 1. To evaluate benefits of AVF function monitoring for the increase of longevity of AVF function. 2. To determine relation between the method of the first HD procedure and duration of patient s hospitalization. 3. To determine factors related with the duration of AVF function. 4. To determine significance of presence and site of central venous catheter to the duration of AVF function. 5. To evaluate relation between AVF maturation and duration of AVF function. 6. To evaluate significance of preoperative blood vessel ultrasound examination to the development of primary dysfunctions of fistula and duration of AVF function. Scientific novelty of the study Many nephrologists globally examine issues of AVF formation, function, and complications. However, studies examine mostly only one of above mentioned issues. In our study we analyzed problems starting from formation of AVF and the first HD procedure to AVF thrombosis and formation of new AVF. This is the first study in Lithuania examining problems of AVF formation, function and complications development. For the first time in Lithuania AVF function monitoring and preventive fistula stenosis treatment using percutaneous transluminal angioplasty (PTA) were implemented. 8

9 1. MATERIAL AND METHODS Study was carried out in the Clinic of Nephrology of the Lithuanian University of Health Sciences; permission No. BE-2-20 of the Kaunas Region Ethical Committee was obtained. All patients with end stage renal disease treated with HD procedures in the Department of Detoxication of the Clinic of Nephrology of Kaunas Medical University hospital from January 1, 2000 to December 31, 2010 were involved in to this study. Only patients over 18 years old were involved. Part of data has been collected retrospectively from medical documentation: personal health history (Form No. 025/a), hospital records (Form No. 003/a), and out-patients HD protocols. Other information concerning patients laboratory tests data and HD procedures parameters was collected during the whole study. The CRF were filled by data available for particular variable: Initial HD treatment of patient with end stage renal failure CRF. Patient's demographic data (gender, age, underlying disease causing endstage renal failure, concomitant diseases), method of the initial HD (scheduled beginning of HD through AVF or urgent procedure through central vein catheter), data concerning hospitalization for the beginning of HD procedures were collected using this CRF. Patient s hospitalization due to AVF thrombosis CRF. Data collected using this CRF: duration of hospitalization, time to AVF formation, site of central vein catheter and its complications, site of AVF, its maturation time and data collected during blood vessels preoperative ultrasound examination. Arteriovenous fistula monitoring CRF. This CRF was filled in only for monitored patients. Patient s laboratory blood tests data, HD efficacy marker, HD procedure parameters, and AVF fistula examination data were collected using this questionnaire. Principles of monitoring of arteriovenous fistula Parameters of every HD procedure were recorded in HD procedure protocols (they are filled in by HD center staff during HD procedures). Since January 1, 2009 arterial and venous blood flow resistance was recorded in these protocols; this parameter has been measured 15 minutes 9

10 after the beginning of HD procedure when volume of blood passing through HD apparatus was 200 ml/min. Parameters of the procedure performed during the last week of the month were recorded in the questionnaire. Nurse working in the HD center performed clinical examination of AVF and in case of changes informed investigator on the same day. Indications for fistula ultrasound examination At least one of the following: 1. Kt/V decrease when there are no other objective reasons for decrease % decrease of volume of blood flowing through HD apparatus during procedure when there are no other objective reasons for decrease. 3. >50% increase of arterial and venous blood flow resistance during one month when there are no other objective reasons for increase. 4. All abnormal findings during clinical examination of fistula. During our study all ultrasound examinations were performed by one investigator, radiologist, who had several years experience of AVF examination, the same ultrasound machine was used for ultrasound examinations. Indications for percutaneous transluminal angioplasty of the fistula At least one of the following: 1. Diameter of AVF anastomosis < 2.0 mm; 2. Peripheral stenosis of venous part of AVF with or without partial thrombosis; 3. Partial AVF thrombosis; 4. Volume of blood flowing through brachial artery <300 ml/min irrespective of site of fistula; 5. >25% decrease of blood flow through brachial artery through time. PTA procedures were performed within one week from the establishing of indications for this procedure. All procedures were performed by one physician, invasive radiologist, who had several years experience in the treatment of AVF complications. 10

11 1.1. Statistical data analysis Statistical analysis of study data has been performed using IBM SPSS statistical software package 19.0 version. To test a hypothesis that quantitative values of population are distributed according to Gauss distribution we used modified Kolmogorov- Smirnov test with Lillefors correction. To describe normally distributed (Gauss distribution) quantitative values we used main characteristic of position, mean with standard error (±SE), and standard deviation (s) characterizing dispersion of data. To describe normally distributed rank and qualitative values we calculated median value. Nominal values were described using relative frequencies. To compare means of several normally distributed (Gauss distribution) quantitative values we used parametric criteria (t-test, ANOVA), and in order to test if attributes of not normally distributed rank and qualitative values are uniform we use non-parametric criteria (Mann-Whittney, Cruscal-Wollis rank criteria). Confidence level was P=0.95, and significance level was α=p=0.05. To evaluate statistically significant dependence of two quantitative values and their homogeneity of distribution within comparison group we used χ 2 test for independence (homogeneity). Strength of dependence of two quantitative values within the sample was evaluated by calculating Pearson contingency coefficient. Probability of qualitative value within two analyzed groups was compared using criteria of parity of probabilities (Z-test). Time period from the formation of AVF to its thrombosis or development of critical stenosis when it was necessary to form a new fistula we called AVF survival. In order to present diagram of AVF survival we used Kaplan-Meier method. Log-rank criterion (log-rank test) was used to compare these functions. Influence of single attributes (factors influencing AVF survival) on the fistula life time was evaluated during analysis of AVF survival. Model of proportional risks (Cox model) was used for this purpose. 11

12 2. RESULTS 2.1. Patient characteristics Historical group involved 187 patients; 260 AVF were formed in these patients. These patients were treated at the Department of Detoxication of Lithuanian University of Health Sciences Kaunas Clinics from January 1, 2000 to December 31, When patient continued scheduled HD after December 31, 2008, he was treated as patient of partial monitoring group. 60 patients were involved in this group, and 78 AVF were formed in these patients. New patients, who started chronic HD at the Department of Detoxication of Lithuanian University of Health Sciences Kaunas Clinics from January 1, 2009 to December 31, 2010, were involved in the monitoring group (29 patients with 31 AVF). Gender, age, underlying and concomitant diseases were distributed uniformly both among the patients of historical and combined partial monitoring and monitoring groups, these groups are homogeneous and may be compared. Characteristics of both groups are presented in the Table In the historical group average age of the males was 56.09±1.414 years (median 59.0), and average age of the females was 62.33±1.344 years (median = 62). In the combined partial monitoring and monitoring group average age of the males was 60.46±1.792 years (median 59.0), and average age of the females was 55.24±2.923 years (median = 59.5). Age of males and females did not statistically significantly differ in both groups (Mann-Whitney tests in historical group, p=0.058; in combined partial monitoring and monitoring group, p=0.072). We determined how many AVF were formed in both groups and what was their site. We managed to collect data about all fistulas in monitoring group and about 246 fistulas in historical group. 12

13 Table Comparison of characteristics of AVF of historical and combined partial monitoring and monitoring groups No. 1 Gender male female 2 Age 40 years years 60 years Characteristic 3 Underlying diseases: Chronic glomerulonephritis Chronic pyelonephritis Chronic interstitial nephritis Diabetes mellitus Ischemic nephropathy Hypertensive nephropathy Polycystic kidney disease Other 4 Concomitant diseases Ischemic heart disease Ischemic brain disease Ischemic disease of extremities Diabetes mellitus (as concomitant disease) No concomitant diseases Historical group n (%) 141 (54) 119 (46) 46 (18) 65 (25) 149 (57) 54 (21) 63 (24) 10 (4) 41 (16) 14 (5) 34 (13) 14 (5) 30 (12) 134 (51.5) 9 (3.5) 7 (2.7) 8 (3.1) 102 (39.3) *Characteristic homogeneity criterion χ 2 was used. **Probability parity criterion was used. Combined partial monitoring and monitoring group n (%) 71 (65) 38 (35) 18 (17) 36 (33) 55 (50) 20 (18) 19 (17) 11 (10) 16 (15) 2 (2) 22 (20) 9 (8) 10 (9) 57 (52.3) 4 (4.6) 6 (5.5) 4 (3.7) 38 (33.9) p 0.05* 0.28* 0.064* 0.82** 0.61** 0.18** 0.76** AVF site in both groups is presented in Fig and Fig There were no statistically significant differences between AVF site within groups (p>0.05). There was no statistically significant differences between groups in right-hand or left-hand AVF (p=0.273). 13

14 Fig Site of arteriovenous fistula in the historical group, n (%) Fig Site of arteriovenous fistula in the combined partial monitoring and monitoring group, n (%) 14

15 2.2. Results of the monitoring of arteriovenous fistulas Average duration of monitoring was 16.26±0.732 months (median = 19). Cumulative analysis of monitoring of arteriovenous fistulas is presented in Fig Fig Cumulative analysis of duration of monitoring of arteriovenous fistulas Ninety four fistulas (87.03%) were monitored longer than 6 months, 73 fistulas (67.59%) were monitored longer than 12 months, and 57 fistulas (52.7%) were monitored longer than 18 months. Twenty nine fistulas (26.8%) were monitored through the whole monitoring period of 24 months. Frequency of ultrasound examination and PTA of arteriovenous fistulas in the monitoring group: fistula function parameters were recorded during the whole period of monitoring, and when indication occurred fistula ultrasound examination was performed. Doppler ultrasound examination was used in 34 AVF (30.9%). Ultrasound examination was not performed in 76 fistulas (60.1%) because of absence of indications during monitoring period. Twenty fistulas were further monitored without additional procedures after ultrasound examination. Angiography and angioplasty (PTA) was recommended in 14 cases. Two PTA procedures 15

16 were performed without ultrasound examination. In both these cases indications were established based on clinical criteria. Pathological changes were found in all 16 PTA cases, and angioplasty was performed to these patients. Distribution of lesion sites presented in Fig Fig Sites of stenosis found during PTA Balloon angioplasty was applied in all cases except multiple stenoses. PTA was efficient in 14 (87.5%) cases, and repeated procedures or surgical reconstructions were not applied. AVF correction failed in 1 patient (6.25%). Due to failure in formation of new fistula central venous catheter was inserted. Complications were observed in 1 case (6.25%) out of 16 PTA. Pseudoaneurism was diagnosed after PTA examination; it was corrected using conservative treatment methods. No surgical intervention was applied, fistula function was normal. Twelve months survival of arteriovenous fistulas in groups examined: Group I: historical group (n=233); Group II: monitoring group (n=31); Group III: partially monitoring group (n=77). It was found out that one year survival in Group I was 73.0±3.1%; in group II 92.9±4.9%; and in Group III 96.1±2.2% (Group I vs Group II, p=0.03; Group I vs Group III, p<0.001; Group II vs Group III, p=0.554) (Fig ). 16

17 Fig One year survival of all arteriovenous fistulas in studied groups It was found out that AVF one year survival in monitoring group is statistically significantly higher compared to non-monitored arteriovenous fistulas. Proportional hazard model or Cox regression model showed that AVF thrombosis risk in monitoring group is times lower (95% CI 0.06; 1.001) compared to Group I (historical group) AVF. Comparison of risk of AVF thrombosis of Group I (historical group) and Group III (partially monitored patients) showed that AVF thrombosis risk in Group III patients is times lower (95% CI 0.041; 0.421). Comparison of only two groups, historical and combined partial monitoring plus monitoring group showed that when patient switches from historic group to monitoring group, fistula thrombosis risk decrease times (95% CI 0.065; 0.403). 17

18 2.3. Duration of patient's hospitalization when the first HD procedure was done through central vein catheter When AVF had not been formed previously the first HD procedure is being performed urgently through central vein catheter. During patients started their HD treatment through central venous catheter in our center. Catheter was inserted into 122 (62.2%) males and 74 (37.8% females). Males statistically significantly more often started their HD treatment urgently through central vein catheter (p=0.036). There was no statistically significant difference between age groups (p=0.617). Hospital stay length was statistically significantly longer in patients who started their treatment urgently through central venous catheter (average length of stay in the hospital was 33.15±1.557 days; median = 30) if compared to the patients who started HD treatment through AVF (average length of stay in the hospital was 18.12±1.150 days; median = 15) (p<0.001). Complications of central venous catheter significantly increased the duration of hospital stay. Fig Dependence of duration of hospital stays on complications (related with catheter) presence and type in patients starting hemodialysis treatment through central venous catheter Difference in the duration of hospital stay between the patients without complications or with any of central venous catheter complications is 18

19 statistically significant (p<0.05). Duration of hospital stay in case of central venous catheter complication is presented in Fig There were 46 episodes of catheter sepsis. In 37 cases catheter was inserted into jugular vein, in 8 cases into subclavian vein, and in 1 case into femoral vein. Attribute homogeneity criteria (χ 2 ) did not show statistically reliable relation between the site of central venous catheter insertionand development of catheter sepsis (p=0.162) Factors influencing duration of fistula function Influence of the duration of arteriovenous fistula maturation on fistula function duration: we grouped all AVF by duration of their maturation according to results obtained during DOPPS study (<14 days and 14 days) and earlier recommendations (<90 days and 90 days). We analyzed relation between duration of maturation period and duration of fistula function. Two AVF groups were analyzed: Group I maturation duration <14 days (n=100), and group II maturation duration 14 days (n=178). It was found that median duration of fistula function in group I was 35.81±3.27 months (median = 28.0) and in group II 28.21±2.061 months (median = 19.0). Analysis of influence of <14 days maturation only on first AVF in the historical group (n=163) did not present any statistically significant evidence of longer functioning of AVF when its maturation period is 14 days was found (group I (n=64): average function duration 39.2±4.41 months (median = 32.0); group II (n=99): average function duration 29.44±2.30 months (median = 20.5) (p=0.087). Analysis of maturation groups by AVF site did not reveal statistically significant data confirming that maturation of fistula formed in upper forearm or brachium were matured longer than low radiocephalic fistulas (p=0.051). Analysis of all AVF showed relationship between gender and duration of maturation. In males duration of fistula maturation was statistically significantly shorter (p=0.03). Distribution of AVF maturation by gender is presented in Fig

20 Fig All arteriovenous fistulas matured <14 or 14 days by gender (%) Analysis of all AVF showed relations between duration of maturation and age groups (p=0.041). Only in 14 percent of patients younger than 40 years AVF were matured for 14 days (p=0.0003). Underlying disease causing endstage renal failure did not influence AVF distribution by groups neither in the group of first fistulas (p=0.703), no in the group of all fistulas (p=0.254). The first fistulas formed to the patients were allocated in two groups according to the duration of maturation: group I involved patients with duration of AVF maturation in 90 days (n=38), and group II involved patients with duration of AVF maturation in <90 days (n=24). Gender, age and underlying disease were distributed uniformly. It was found out that when AVF was matured for 90 days, duration of its functioning was statistically significantly longer (44.14±5.44 months; median 20.0) compared to group where duration of maturation was <90 days (31.19±2.263 months; median = 36.0) (p=0.011). Influence of the site of arteriovenous fistula on duration of its functioning: we analyzed 221 cases when site of AVF and duration of its function was known. Using nonparametric Cruscall-Wallis test we found that duration of fistula function statistically reliably differs depending on the site of its formation (p=0.03). 20

21 After we found out that there are differences in the duration of AVF function we determined if this difference is statistically significant. Nonparametric post-hoc criteria showed that duration of function of fistulas formed in the forearm is similar (duration of low radiocephalic fistula (n=152) function was 32.82±2.02 months (median = 23); duration of high radiocephalic fistula (n=40) function was 23.7±3.62 months (median = 16) (p=0.98). No statistically significant difference was found between duration of function of high radiocephalic fistulas and high brachial fistulas (n=29) (duration of function of the brachial fistula (n=152) was 18.93±3.47 months (median = 18)) (p=0.515). There was statistically significant difference between duration of function of low radiocephalic fistulas and high brachial fistulas (p=0.025) (Fig ). Fig Duration of arteriovenous fistula function by site of formed arteriovenous fistula Relationship between underlying kidney disease causing endstage renal failure and duration of function of arteriovenous fistula in the historical group: analysis of AVF function in the historical group by underlying disease causing endstage renal failure showed, that there was no statistically significant differences between groups (Group I: parenchymal kidney diseases, n=141; Group II: blood vessels disease, n=48; Group III: diabetes mellitus, n=44); difference between Group I and Group II, p=0.985; difference between Group I and Group III, p=0.116; and differrence between Group II and Group III, p=

22 Influence of site of central vein catheter before AVF formation on the AVF survival: In order to determine if presence of central vein catheter and its site influence duration of function of AVF, all AVF (use and site of central vein catheter were known before AVF formation in 326 cases) were allocated into three groups: Group I: fistula was formed without use of central vein catheter (n=142); Group II: central venous catheter was inserted and fistula was formed on the same side (n=73); Group III: central vein catheter was inserted and fistula was formed in different sides. Influence of use of central venous catheter and its site on the duration of function of arteriovenous fistula is presented in Fig Fig Influence of site of central venous catheter on the duration of fistula function It was found out that average duration of AVF function in Group I (formed without use of central vein catheter) was 35.09±2.731 months (median = 26.0); in Group II (central vein catheter was inserted and fistula was formed on the same side) 19.44±2.556 months (median = 14.0); and in Group III 30.89±2.915 months (median = 18.0). Nonparametric paired comparison tests showed that duration of function statistically significantly differs between Group I and Group II (p<0.0001) and between Group II and Group III (p=0.011); however, there was no statistically significant differences between Group I and Group III (p=0.192). Therefore it could be stated that formation of the new fistula in 22

23 the place of insertion of central vein catheter statistically significantly shortens duration of fistula function. We analyzed if previous site of central vein catheter is equally important for various AVF sites in the historical group. It was found out that influence of central vein catheter on low radiocephalic fistulas is very negative (compared Group I (n=91) and Group II (n=56), p=0.001; compared Group II and Group III (n=73) p=0.017). In order to avoid possible influence on duration of fistula function only historical group patients comprised these groups. In the first group (n=75) when there was no catheter inserted, average duration of fistula was 29.97±2.7 months (median 24); in the second group (n=39) when central venous catheter and formed fistula were on the same side average duration was 15.49±2.72 months (median = 8); and in the third group (n=53) when central vein catheter and formed fistula were in different sides average duration was 34.06±4.62 months (median = 21). Cruscall-Wollis test showed that duration of AVF function differs between groups (p=0.008) (Fig ). Fig Survival of low radiocephalic fistulas in various sites of central venous catheter in the historical group 23

24 Nonparametric paired comparison test showed that duration of AVF function differs between Group I and Group II (p=0.003) and between Group II and Group III (p=0.01). Meanwhile, there was no statistically significant difference between Group I and Group III (p=0.867). We analyzed if presence of central vein catheter ant its site influenced survival of high radiocephalic fistulas. Survival of high radiocephalic fistulas was statistically significantly lower when central vein catheter was on the same side where fistula was formed later (Group II vs Group III, p=0.023) (Fig ). Analysis of data on high radiocephalic AVF belonging only to historical group showed that survival also differs depending on use of central vein catheter and its site (Group I vs Group II, p=0.499; between Group I and Group III, p=0.288; and vs Group II and Group III, p=0.041). Fig Duration of function of high radiocephalic fistulas by site of central venous catheter in the historical group 24

25 2.5. Twelve months survival of arteriovenous fistulas Twelve month survival of arteriovenous fistulas in the historical group. In our study we sought to determine average duration of AVF function. However, it was found out that it is impossible to compare AVF of different site and different patient groups, because duration of their function differs dramatically. We studied dependence of 12 month and 36 month survival on various characteristics of AVF patients groups. Twelve month AVF survival by gender. It was established that 12 months survival of the first AVF was 79.7±4.4% among males (n=85) and 73.3±5.6% among females (n=68). There was no statistically significant difference between genders in 12 month survival (p=0.463). There was no statistically significant difference in 12 months survival between all AVF in males (n=123) and females (n=100) (p=0.621). In males one year survival was observed in 72.4±4.1% of patients, and in females in 74.3±4.6% of patients. Twelve months AVF survival by age groups. One year survival of initial and repeated AVF in age groups was analyzed (Group I 40 years old; group II years old; and group III 60 years old). It was found that that there were no statistically significant differences in one year survival of initial and repeated AVF in all age groups. Analysis of all AVF showed that there was no statistically significant difference in one year survival (Group I vs Group II, p=0.948; Group I vs Group III, p=0.297; Group II vs Group III, p=0.295). Data of the first three months were eliminated to exclude the surgical confounding of AVF complications at this period. It was stated that when fistula functioned for the first three months probability of its function during 12 months period is 96.1±2.7 percent in Group I (n=51); 95.8±2.4% in Group II; and 84.9±2.9% in group III (n=160). Statistically significant evidence was obtained showing that in older than 60 years patients incidence of one year AVF function was lower compared to younger patients (Group I vs Group II, p=0.988; Group I vs Group III, p=0.047; and Group II vs Group III, p=0.017) (Fig ). We examined if one year survival of initial AVF (n=153) and repeated AVF (n=70) differs in the historical group. 25

26 Fig Arteriovenous fistulas twelve month survival in three age groups after elimination of data of the first three months It was found out that 77±3.5% of initial AVF one year survival, and in repeated AVF one year survival was observed in 63.9±5.9%. There was statistically significant difference in one year survival between initial and repeated AVF (p=0.043) (Fig ). Significance of central venous catheter for 12 month survival of AVF: historical group (n=220) data were analyzed taking into account use and site of central vein catheter: Group I: no central vein catheter was inserted; Group II: central vein catheter and formed fistula were in the same side; Group III: central vein catheter was inserted and fistula formed in the opposite side. Statistically significant difference between site of central vein catheter and fistula 12 months survival in the historical group was found. 26

27 Fig One year survival of initial AVF and repeated AVF in the historical group AVF one year survival was much better (76.4±4.5%) in historical Group I (no catheter was inserted) (n=91) compared to group II (central vein catheter and formed fistula were in the same side) (n=56); in this group one year function was observed in 57.1±6.8% of cases (p=0.011). There was statistically significant difference in AVF one year survival between Group II and Group III (n=73) when central vein catheter was inserted and fistula formed in the opposite side. Fistula functioned for one year in 81.1±4.8% of Group III patients (p=0.003). Meanwhile, there were no statistically significant difference in fistula one year survival in Group I and Group III (p=0.485) (Fig ). 27

28 Fig Arteriovenous fistula 12 months duration in the historical group by use and site of central vein catheter 2.6. Arteriovenous fistula 36 months survival in the historical group Patient gender and age, disease causing endstage renal failure had no influence on AVF 36-months survival. One hundred fifty three initial and 70 repeated AVF were explored in the historical group. It was found out that 65.4±42% of initial AVF was functioning for 36 month, and among repeated AVF 36 months function was observed in 36.9±7.5% of cases. Difference in AVF 36 months function between initial and repeated AVF was statistically significant (p=0.002) (Fig ). 28

29 Fig Initial and repeated fistula 36 months function in the historical group There was statistically significant difference in 36 months survival between Group I (central venous catheter was not inserted) (n=91) and Group II (n=56) (central venous catheter and formed fistula were on the same side). It was found that 61.4±5.6% of AVF in Group I functioned for 36 months, and in Group II 41.8±7.3 AVF functioned for 36 months (p=0.005). Difference was found also between Group II and Group III (n=73) (central venous catheter and formed fistula were on different sides, AVF 36 months functioned in 64.1±6.6% of cases) (p=0.002). Meanwhile, there was no statistically significant difference in 36 month survival between Group I and Group III (p=0.636) (Fig ). 29

30 Fig Thirty six months function of all arteriovenous fistulas taking into account use and site of central venous catheter in the historical group 2.7. Preoperative vascular ultrasound examination before arteriovenous fistula creation Preoperative vascular examination introduced a few years ago and quickly became routine in our clinic. In the historical group preoperative vascular examination was done only in 4.8% of all cases AVF creation. In the partial monitoring group preoperative vascular examination was done before 20.8% AVF creation operations and in monitoring group 96.6%. Because preoperative ultrasound examination is started only few years ago, is a statistically significant correlation between the observation group and the preoperative ultrasound frequency (p<0.001) Analysis of primary AVF dysfunction has found, that preoperative vascular examination did not reduce the frequency of repeated AVF formation during the same hospitalization. Used χ 2 test (contingency coefficient 0.057, p=0.302). 30

31 We examined the influence of preoperative vascular ultrasound examination on AVF one year survival in the historical group. It was found information about 206 AVF creation cases when data about the performance of ultrasound vascular study or omission prior to surgery was known. It was found, that preoperative vascular examination before the first AVF creation operation has no influence on one year survival: without the ultrasound examination the first year survival was 79.7±3.6% (n=131), after ultrasound examination 70.0±18.2% (n=8) (p=0.482). 31

32 CONCLUSIONS 1. Monitoring of AVF function statistically significantly improved one year survival of fistulas. Thrombosis risk was times lower in monitoring group fistulas compared to historical group; thrombosis risk in partially monitored group was times lower compared with historical group. 2. Duration of hospital stay for patients who underwent urgent HD treatment through central venous catheter was statistically significantly longer (average duration of hospital stay was 33.15±1.55 days) compared to patients who underwent HD through matured AVF (average duration of hospital stay was 15.12±1.15 days) (p<0.001). Duration of hospital stay was statistically significantly prolonged by complications of central venous catheter. In cases of central venous catheter thrombosis average duration of hospital stay was 44.87±6.93 days (p=0.021); in cases of catheter sepsis 42.31±3.023 days (p=0.032); in cases with no complications of central venous catheter average duration of hospital stay was 28.67±1.56 days. 3. AVF function associations with following factors were established: Demographic factors (gender, age, underlying disease causing endstage renal failure) did not influence AVF function; 12 and 36 months survival of initial AVF was statistically significantly higher than survival of repeated AVF (one-year functioning duration was observed in 77±3.5 percent of initial AVF and 63.9±5.9% of repeated AVF, p=0.043; three-years functioning was observed in 65.4±4.2% of initial AVF and 36.9±7.5% of repeated AVF, p=0.002). 4. Placement and localisation of the central vein catheter before AVF formation was very important to the functioning of the AVF: Duration of AVF functioning and survival of AVF functioning were statistically significantly lower when central vein catheter and formed AVF were in the same side. It was found out that in Group I patients (central vein catheter was not inserted) average duration of AVF function was 35.09±2.731 months, in Group II patients (central vein catheter and formed AVF were in the same side) 19.44±2.55 months, and in Group III patients (central vein catheter and formed AVF were on different sides) 30.89±

33 months (Group I vs Group II, p<0.0001; Group II vs Group III, p=0.011; no statistically significant differences between Group II vs Group III, p=0.192). AVF one year function was observed in 76.4±4.5% of Group I patients, 57.1±6.8% of Group II patients and 81.1±4.8% of Group III patients (Group I vs Group II, p=0,011; Group II vs Group III, p=0.003; and no statistically significant differences were observed between Group II and Group III, p=0.482). AVF three years function was observed in 61.4±5.6% of Group I patients, 41.8±7.3% of Group II patients and 64.1±6.6% of Group III patients (Group I vs Group II, p=0.005; Group II vs Group III, p=0.002; and no statistically significant differences were observed between Group II and Group III, p=0.636). 5. Influence of AVF maturation time on the survival of AVF was established: There was no statistically significant difference in AVF survival between AVF matured <14 days and 14 days. Duration of AVF function was statistically significantly longer when AVF were matured 90 days (44.14±5.94 months) compared to those matured <90 days (31.19±2.23 months) (p=0.011). 6. Preoperative ultrasound examination of the blood vessels did not lowered incidence of primary fistula dysfunction and did not prolong duration of AVF function. 33

34 PRACTICAL RECOMENDATIONS Based on results of our study and foreign authors researches data we propose, that in order to ensure timely and proper formation of AVF and maximum duration of its function, cooperation between family physician, nephrologist, radiologist, HD center nurses and surgeons should be ensured. Only teamwork allows starting scheduled HD through matured AVF and ensures long-term fistula function. We recommend apply the following measures during AVF formation, monitoring and treatment of AVF complications: 1. Close cooperation of family physicians and nephrologists in order to ensure timely AVF formation (AVF matured 90 days functions longer) and scheduled start of HD procedures through matured AVF in order to avoid use of central venous catheter which prolongs duration of patients' hospital stay and increase risk of catheter sepsis. 2. In case of necessity insert central venous catheter at the beginning of HD or in case of AVF thrombosis, insertion in the same side as anticipated or already formed AVF should be avoided because the same side of central venous catheter and new AVF shortens duration of fistula function. 3. To train nurses of HD centers to perform clinical examination of fistula function; 4. To implement in all Lithuanian HD centers uniform methodology of AVF monitoring, uniform indications for ultrasound examination and PTA. 5. Close cooperation between nephrologists and radiologists is necessary to ensure preoperative ultrasound examination of blood vessels in order to select proper blood vessels for AVF formation, timely diagnostics of fistula complications and treatment of fistula complications using percutaneous transluminal angioplasty. 6. It is important to form AVF teams (including nephrologist, radiologist, invasive radiologist, surgeon, nurse working in HD center) in all hospitals where HD is performed; these teams will ensure timely and quality AVF formation and monitoring of its function. 7. Further analysis are warranted to specify other surgical variables precluding the beneficial preoperative ultrasound examination for succenful primary functional and long term survival. 34

35 PUBLICATION 1. Sondra Kybartienė, Inga Skarupskienė, Edita Žiginskienė, Vytautas Kuzminskis.Vascular access for hemodialysis: creation, functioning, and complications (Data of the Hospital of Kaunas University of Medicine). Medicina 2010;46(8): Algidas Basevičius, Sondra Kybartienė, Algirda Venclauskienė, Vytautas Kuzminskis. Diagnosis and treatment of complications of vascular access in haemodialysis patients. Lietuvos bendrosios praktikos gydytojas 2009;13(2): Sondra Kybartienė, Vaidas Žvinys, Rytis Rimdeika, Ksenija Gecevičiūtė, Vytautas Kuzminskis. Creation of arteriovenous fistulas for chronic hemodialysis in Kaunas University of Medicine Hospital during Medicina 2007;43(1): Sondra Kybartienė, Vaidas Žvinys, Rytis Rimdeika, Vytautas Kuzminskis Early thrombosis of radiocephalic fistula in patients on chronic hemodialysis (results of Kaunas University of Medicine Hospital ). Medicina 2005;41: Sondra Kybartienė, Vytautas Kuzminskis. Problems of arterio-venous access at the start of hemodialysis (results of Kaunas University of Medicine Hospital ). Medicina 2003;39(1): Kuzminskis Vytautas, Kybartienė Sondra, Antuševa Jelena, Gustaitytė Jūratė. Analysis of vascular access formation in Kaunas university of medicine clinics during period of Lietuvos endokrinologija 2004;12(2):

36 SUMMARY IN LITHUANIAN Darbo tikslas: nustatyti veiksnius, susijusius su arterioveninių jungčių (AVJ) dializuojamiems pacientams funkcionavimo trukme bei įvertinti jungčių funkcijos monitoravimo naudą jų funkcionavimo trukmei prailginti. Darbo uždaviniai: 1. Įvertinti AVJ funkcijos monitoravimo naudą jos funkcionavimo trukmei prailginti. 2. Nustatyti pirmosios hemodializės procedūros atlikimo būdo ryšį su paciento stacionarizavimo trukme. 3. Nustatyti veiksnius, susijusius su AVJ funkcionavimo trukme. 4. Nustatyti centrinės venos kateterio buvimo ir lokalizacijos reikšmę AVJ funkcionavimo trukmei. 5. Įvertinti AVJ brandinimo trukmės ryšį su AVJ funkcionavimo trukme. 6. Įvertinti priešoperacinio kraujagyslių ultragarsinio ištyrimo reikšmę pirminių jungties disfunkcijų išsivystymui bei AVJ funkcionavimo trukmei. DARBO METODIKA Tyrimas atliktas Lietuvos sveikatos mokslų universiteto Nefrologijos klinikoje, gavus Kauno regioninio tyrimų etikos komiteto leidimą Nr. BE Dalis duomenų buvo renkama retrospektyviai, naudojant medicinos dokumentaciją, kita dalis informacijos apie pacientų laboratorinių tyrimų duomenis bei HD procedūros parametrus buvo renkama viso tyrimo eigoje. Visos AVJ pagal buvo suskirstytos į tris grupes: 1. Istorinė grupė monitoravimas taikytas nebuvo (187 pacientai, 260 AVJ); 2. Monitoruota grupė AVJ buvo monitoruojamos nuo pirmosios per ją atliktos HD (29 pacientai, 31 AVJ); 3. Dalinai monitoruota grupė AVJ naudojamos HD iki 2008 m. gruodžio 31 d., o vėliau buvo įtrauktos į tyrimą (60 pacientų, 78 AVJ). 36

37 Pagal nustatytus kriterijus pacientai buvo nukreipiami arterioveninės jungties ultragarsiniam ištyrimui, ir jungties perkutaninei transliuminalinei angiografija ir angioplastika. IŠVADOS 1. AVJ funkcijos monitoravimas statistiškai patikimai pagerino vienerių metų jungčių funkcionavimą. Monitoruotos grupės AVJ turėjo 0,245 karto mažesnę riziką trombuotis nei istorinės grupės AVJ; dalinai monitoruotos grupės AVJ turėjo 0,132 karto mažesnę riziką trombuotis nei istorinės grupės jungtys. 2. Pacientai, kuriems HD buvo pradėtos skubiai, stacionare buvo gydyti statistiškai patikimai ilgiau (vidutinė trukmė 33,15±1,55 d.) nei pradedant HD per subrendusią AVJ (vidutinė trukmė 18,12±1,15 d.) (p<0,001). Stacionarizavimo trukmę prailgindavo centrinės venos kateterių komplikacijos: įvykus trombozei vidutinė stacionarizavimo trukmė 44,87±6,93 d. (p=0,021), išsivysčius kateteriniam sepsiui 42,31±3,023d (p=0,032), kai kateterio komplikacijų nebuvo, vidutinė stacionarizavimo trukmė 28,67±1,56 dienos. 3. Nustatytos AVJ funkcionavimo trukmės sąsajos su šiais veiksniais: Demografiniai veiksniai (lytis, amžius, pagrindinis susirgimas, lėmęs galutinį inkstų funkcijos nepakankamumą) AVJ funkcionavimo trukmei reikšmės neturėjo; Statistiškai patikimai dažniau pirminės AVJ funkcionavimo vienus ir trejus metus dažniau nei pakartotinai suformuotos AVJ (pirmosios AVJ vienerius metus funkcionavo 77±3,5 proc. atvejų, o pakartotinai suformuotos 63,9±5,9 proc. atvejų p=0,043; trejus metus pirmosios AVJ funkcionavo 65,4±4,2 proc. atvejų, o pakartotinai suformuotos 36,9±7,5 proc. atvejų p=0,002); 4. Centrinės venos kateterio buvimas toje pačioje pusėje kaip ir suformuota AVJ statistiškai patikimai sutrumpina jungties funkcionavimo laiką bei pablogina vienerių ir trijų metų jungties funkcionavimo dažnį. I grupėje, kur centrinės venos kateteris nenaudotas AVJ vidutiniškai funkcionavo 35,09±2,731 mėn., II grupėje (centrinės venos kateteris ir suformuota AVJ yra toje pačioje pusėje) 19,44±2,55 mėn., o III grupėje (centrinės venos kateteris ir suformuota AVJ skirtingose pusėse 30,89±2,915 mėn. (tarp I ir II 37

38 grupių p<0,0001; tarp II ir III grupių p=0,011, o tarp II ir III grupių p=0,192). I grupės pacientams vienerius metus AVJ funkcionavo 76,4±4,5 proc. atvejų, II grupės 57,1±6,8 proc. atvejų, III grupės 81,1±4,8 proc. pacientų (tarp I ir II grupių p=0,011; tarp II ir III grupių p=0,003, o tarp II ir III grupių p=0,482). I grupės pacientams tris metus AVJ funkcionavo 61,4±5,6 proc. atvejų, II grupės 41,8±7,3 proc. atvejų, III grupės 64,1±6,6 proc. pacientų (tarp I ir II grupių p=0,005; tarp II ir III grupių p=0,002, o tarp II ir III grupių statistiškai patikimo skirtumo negauta, p=0,636) 5. Nustatyta AVJ brandinimo trukmės įtaka jos funkcionavimo trukmei: Lyginant AVJ, kurios buvo brandintos < 14 d. ar 14 d., jų funkcionavimo trukmė statistiškai patikimai nesiskyrė (p=0,099); AVJ, kurios buvo brandintos 90 d. funkcionavo statistiškai patikimai ilgiau (44,14±5,94 mėn.) nei tos, kurios buvo brandintos < 90 d. (31,19±2,23 mėn.) (p=0,011). 6. Priešoperacinis kraujagyslių ultragarsinis tyrimas nesumažino pirminio AVJ disfunkcijos dažnio ir neprailgino AVJ funkcionavimo trukmės. PRAKTINĖS REKOMENDACIJOS Remiantis mūsų tyrimo duomenimis ir užsienio autorių tyrimais siūlome rekomendacijas, kurios padėtų užtikrinti, kad AVJ būtų laiku sėkmingai suformuota ir funkcionuotų maksimaliai ilgą laiką: 1. Siekti kuo glaudesnio šeimos gydytojų ir nefrologų bendradarbiavimo, kad užtikrintume savalaikį AVJ suformavimą ir planinių HD procedūrų pradžią per subrendusias AVJ. 2. Esant būtinybei įvesti centrinės venos kateterį HD pradžiai ar įvykus AVJ trombozei, vengti jo įvedimo toje pačioje pusėje, kur yra numatoma ar jau suformuota AVJ. 3. Apmokyti slaugytojas, dirbančias HD centruose kliniškai ištirti jungties funkcionavimą. 4. Visuose Lietuvos HD centruose tikslinga įdiegti vienodą AVJ monitoravimo metodiką, vienodas indikacijas AVJ ultragarsiniam tyrimui ir PTA atlikimui. 38