DO WE KNOW ALL EFFECTS OF HEPARINS IN HEMODIALYZED PATIENTS?

Heparinizacija izvantjelesnog krvotoka tijekom hemodijalize (HD) rabi se u svrhu protukoagulacije. Bolesnici liječeni HD izloženi su u incima nefrakcioniranih heparina i niskomolekularnih heparina godinama te su uz hemoragijske važni i njihovi drugi učinci (osteoporoza, smanjenje vrijednosti povišenog krvnog tlaka, smanjenje učestalosti hipotenzivnih epizoda tijekom i između postupaka HD, usporavanje procesa koji dovode do vaskularne demencije i Alzheimerove bolesti, učinak na kronične i maligne bolesti). Ti učinci zahtijevaju nova sveobuhvatna istraživanja s pojedina no prilagođenim dozama heparinaAnticoagulation with heparins during hemodialysis (HD) is aimed at preventing the activation of coagulation in the extracorporeal circuit. As HD patients are exposed to unfractionated and low molecular weight heparins (LMWH) for years, non-hemorrhagic effects (osteoporosis, reduction of elevated blood pressure, with lesser intra- and interdialytic hypotensive episodes, effects on brain microvascular circulation and decreasing vascular dementia and Alzheimer’s disease, and chronic and malignant diseases) require new trials with individualized doses of heparin

The efficacy of low nadroparin doses in haemodialysed patients with bleeding risk

Cilj: Bolesnici sa završnim stupnjem kronične bubrežne bolesti koji se liječe hemodijalizom (HD) imaju povećan rizik od krvarenja. Uporaba sistemske protukoagulacije s heparinom za vrijeme HD može prouzročiti ozbiljne komplikacije. Cilj ovog prospektivnog istraživanja bila je procjena učinkovitosti najmanje pojedinačno prilagođene bolus doze niskomolekularnog heparina nadroparina za provođenje sigurne i učinkovite HD u bolesnika s rizikom krvarenja (dijabetičara i nedijabetičara). Ispitanici i metode: Četrdeset ispitanika (18 žena i 22 muškarca) u dobi 64,93±12,34 godine (raspon 36 – 84) liječenih kroničnom HD prosječno 61,63±53,97 mjeseci (raspon 5 – 196) bilo je uključeno u ovo 12-tjedno istraživanje. Ispitanici su bili podijeljeni u 4 skupine sa deset: dijabetičara sa i bez rizika krvarenja i nedijabetičara sa i bez rizika krvarenja. Stvarna početna bolus doza nadroparina (koja je primjenjivana u našem Centru najmanje 2 mjeseca s preporukom proizvođača) tijekom perioda istraživanja smanjena je za 25 % poslije prva 4 tjedna, i dalje smanjena za 25 % od početne doze poslije sljedeća 4 tjedna. Period održavanja doze nadroparina smanjene za 50 % bio je 4 tjedna. Tijekom istraživanja određivani su: čimbenik anti-Xa, aktivirano parcijalno tromboplastinsko vrijeme (aPTV), trombin-antitrombin kompleks (TAT) i D-dimeri, i to na početku, poslije 2 i 4 sata postupka HD (na početku istraživanja, nakon 4, 8 i 12 tjedana). Za procjenu učinkovitosti protukoagulacije bilježeni su učestalost i stupanj zgrušavanja dijalizatora, venske i arterijske kapaljke nakon završetka postupka svake HD (i ocjenjivani ocjenom od 0 = bez zgrušavanja do 4 = zgrušan čitav sistem). Mjereno je i vrijeme zaustavljanja krvarenja na arterijskom i venskom dijelu arterijsko-venske fistule/grafta poslije izvlačenja fistulina nakon završetka postupka HD. Sigurnost protukoagulacije određivana je bilježenjem epizoda "velikih" ili "malih" krvarenja poslije i između postupaka HD. Rezultati: Trideset osam ispitanika završilo je istraživanje, dvoje je transplantirano, nitko nije umro. Sigurno i učinkovito smanjenje početne bolus doze nadroparina (bez komplikacija) zabilježeno je u: dijabetičara s rizikom krvarenja (49,6612,33 naprama 28,789,60 IU/kg/HD; p <0,001); dijabetičara bez rizika krvarenja (50,7015,23 naprama 33,9516,97 IU/kg/HD; p <0,001); i nedijabetičara s rizikom krvarenja (61,2518,68 naprama 32,9610,06 IU/kg/HD; p <0,001). Sveukupno smanjenje početne bolus doze nadroparina bilo je u: dijabetičara s rizikom krvarenja 42,05 %, dijabetičara bez rizika krvarenja 33,04 %, i nedijabetičara s rizikom krvarenja 46,19 %. U nedijabetičara bez rizika krvarenja nije bilo statistički značajne razlike u dozi nadroparina na početku i kraju istraživanja (47,4510,87 naprama 41,7510,91 IJ/kg/HD; p = 0,484). Zabilježeno je 7 epizoda "malih" krvarenja u 4 bolesnika i samo jedna epizoda "velikog" (gastrointestinalnog) krvarenja. Zabilježena je statistički značajna razlika u zgrušavanju dijalizatora samo poslije 8 tjedana istraživanja (HD3): u ispitanika s rizikom krvarenja (dijabetičara i nedijabetičara) stupanj 1 (7 slučajeva), stupanj 2 (4 slučaja); te u ispitanika bez rizika krvarenja (dijabetičara i nedijabetičara): stupanj 1 (11 slučajeva) (χ square test = 4,701; p = 0,048). Druge statistički značajne razlike u zgrušavanju izvantjelesnog krvotoka među skupinama nisu zabilježene. Unatoč činjenici da je čimbenik anti-Xa bio niži od 0,4 IJ/ml nakon završetka postupka HD na završetku istraživanja (u ispitanika dijabetičara i nedijabetičara bez rizika krvarenja), nisu zabilježena značajna zgrušavanja izvantjelesnog krvotoka i krvožilnog pristupa. Zaključak: Rezultati ovog istraživanja pokazuju da je najmanja pojedinačno prilagođena bolus doza niskomolekularnog heparina nadroparina za dijabetičare s rizikom krvarenja 28,789,60 IJ/kg/HD, a za nedijabetičare s rizikom krvarenja 32,9610,06 IJ/kg/HD. Ovo istraživanje pokazalo je da je smanjenje stvarne početne bolus doze nadroparina u dijabetičara s rizikom krvarenja za 42,05 % dovoljno za učinkovitu i sigurnu HD (u nedijabetičara s rizikom krvarenja doza je bila manja za 46,19 %, a u dijabetičara bez rizika krvarenja za 33,04 %). Dalja istraživanja s većim brojem ispitanika pokazat će je li ovaj protukoagulacijski protokol obvezatan za bolesnike s rizikom krvarenja.Introduction: Patients on haemodialysis (HD) have known high risk of bleeding. The use of systemic anticoagulation with heparin during HD can cause serious problems. The aim of this prospective study was to find out what is the lowest single bolus dose of nadroparin for safe and effective HD in patients with bleeding risk (diabetics and non–diabetics). Methods: Forty adult patients (18 females and 22 males) aged 64.93±12.34 years (range 36 – 84), who were on intermittent HD for a mean period of 61.63±53.97 months (range 5 – 196), were enrolled in this 12-weeks long prospective study. Patients were devided into four subgroups with 10 participants (diabetics with and without bleeding risk, non-diabetics with and without bleeding risk). The actual starting bolus dose of nadroparin (which was used in our Center for a minimum of two months according to the manufacturer´s recommendation), was decreased twice by 25%: after the initial 4 weeks (HD2 nadroparin), and again after an additional 4 weeks (HD3 nadroparin). The maintenance period was 4 weeks during which time this dose was adjusted due to clotting of the extracorporeal circuit (HD4 nadroparin). We investigated four dialysis sessions: HD1 (the beggining of the study), HD2 (after 4 weeks), HD3 (after 8 weeks), and HD4 (the end of the study). The levels of factor anti-Xa, activated partial thromboplastin time (aPTT), thrombin-antithrombin complex (TAT) and D-dimers were determined at the beginning, after 2 hours and at the end of investigated HD sessions. The clottings of the extracorporeal circuit and vascular access compression time were noted at the end of the HD sessions. The efficacy was assessed by scoring the dialysers and arterial/venous chambers separately (from 0 = no clot formation to 4 = coagulation of the whole system). The safety was assessed by noting all bleeding episodes: "major" (required hospitalization/transfusion, bleeding into critical organ or space, cause of death) or "minor" (vascular access site, epistaxis, subconjunctival bleeding) Results: Thirty eight patients completed study, two were transplanted, none died. A safe and significant reduction of nadroparin (first vs last HD session) was observed in: diabetics with bleeding risk (49.6612.33 vs 28.789.60 IU/kg/HD; p <0.001), diabetics without bleeding risk (50.7015.23 vs 33.9516.97 IU/kg/HD; p <0.001), and non-diabetics with bleeding risk (61.2518.68 vs 32.9610.06 IU/kg/HD; p <0.001). All together the reduction of nadroparin dose in these groups was: 42.05 %; 33.04 % and 46.19 %, respectively. In non-diabetics without bleeding risk there were no significant differences between nadroparin doses at the beginning and at the end of the study (47.4510.87 vs 41.7510.91 IU/kg/HD; p = 0.484). There were 7 minor and 1 major bleeding episodes (all in patients with bleeding risk). There was significant difference in clot formation of dialyser only in HD3: grade 1 (7 cases), and grade 2 (4 cases) in patients with bleeding risk; and grade 1 (11 cases) in patients without bleeding risk (χ square test = 4.701; p = 0.048). There were no other differences in clott formation in examined groups. Despite anti-Xa at hour 4 at the end of the study was lower than 0.4 IU/ml in our diabetic and non-diabetic patients without risk of bleeding, serious clottings in extracorporeal circuit and vascular access thromboses were not found. Conclusons: From results of this study it seems that the lowest dose of nadroparin for diabetics with bleeding risk is 28.789.60 IU/kg/HD and for non-diabetics with bleeding risk is 32.9610.06 IU/kg/HD. This study demonstrated for the first time that decreased actual starting bolus dose of nadroparin by 42.05 % is sufficant for safe and effective HD in diabetic patients with bleeding risk (in non-diabetics with bleeding risk by 46.19 %, and diabetics without bleeding risk by 33.04 %)

The efficacy of low nadroparin doses in haemodialysed patients with bleeding risk

Cilj: Bolesnici sa završnim stupnjem kronične bubrežne bolesti koji se liječe hemodijalizom (HD) imaju povećan rizik od krvarenja. Uporaba sistemske protukoagulacije s heparinom za vrijeme HD može prouzročiti ozbiljne komplikacije. Cilj ovog prospektivnog istraživanja bila je procjena učinkovitosti najmanje pojedinačno prilagođene bolus doze niskomolekularnog heparina nadroparina za provođenje sigurne i učinkovite HD u bolesnika s rizikom krvarenja (dijabetičara i nedijabetičara). Ispitanici i metode: Četrdeset ispitanika (18 žena i 22 muškarca) u dobi 64,93±12,34 godine (raspon 36 – 84) liječenih kroničnom HD prosječno 61,63±53,97 mjeseci (raspon 5 – 196) bilo je uključeno u ovo 12-tjedno istraživanje. Ispitanici su bili podijeljeni u 4 skupine sa deset: dijabetičara sa i bez rizika krvarenja i nedijabetičara sa i bez rizika krvarenja. Stvarna početna bolus doza nadroparina (koja je primjenjivana u našem Centru najmanje 2 mjeseca s preporukom proizvođača) tijekom perioda istraživanja smanjena je za 25 % poslije prva 4 tjedna, i dalje smanjena za 25 % od početne doze poslije sljedeća 4 tjedna. Period održavanja doze nadroparina smanjene za 50 % bio je 4 tjedna. Tijekom istraživanja određivani su: čimbenik anti-Xa, aktivirano parcijalno tromboplastinsko vrijeme (aPTV), trombin-antitrombin kompleks (TAT) i D-dimeri, i to na početku, poslije 2 i 4 sata postupka HD (na početku istraživanja, nakon 4, 8 i 12 tjedana). Za procjenu učinkovitosti protukoagulacije bilježeni su učestalost i stupanj zgrušavanja dijalizatora, venske i arterijske kapaljke nakon završetka postupka svake HD (i ocjenjivani ocjenom od 0 = bez zgrušavanja do 4 = zgrušan čitav sistem). Mjereno je i vrijeme zaustavljanja krvarenja na arterijskom i venskom dijelu arterijsko-venske fistule/grafta poslije izvlačenja fistulina nakon završetka postupka HD. Sigurnost protukoagulacije određivana je bilježenjem epizoda "velikih" ili "malih" krvarenja poslije i između postupaka HD. Rezultati: Trideset osam ispitanika završilo je istraživanje, dvoje je transplantirano, nitko nije umro. Sigurno i učinkovito smanjenje početne bolus doze nadroparina (bez komplikacija) zabilježeno je u: dijabetičara s rizikom krvarenja (49,6612,33 naprama 28,789,60 IU/kg/HD; p <0,001); dijabetičara bez rizika krvarenja (50,7015,23 naprama 33,9516,97 IU/kg/HD; p <0,001); i nedijabetičara s rizikom krvarenja (61,2518,68 naprama 32,9610,06 IU/kg/HD; p <0,001). Sveukupno smanjenje početne bolus doze nadroparina bilo je u: dijabetičara s rizikom krvarenja 42,05 %, dijabetičara bez rizika krvarenja 33,04 %, i nedijabetičara s rizikom krvarenja 46,19 %. U nedijabetičara bez rizika krvarenja nije bilo statistički značajne razlike u dozi nadroparina na početku i kraju istraživanja (47,4510,87 naprama 41,7510,91 IJ/kg/HD; p = 0,484). Zabilježeno je 7 epizoda "malih" krvarenja u 4 bolesnika i samo jedna epizoda "velikog" (gastrointestinalnog) krvarenja. Zabilježena je statistički značajna razlika u zgrušavanju dijalizatora samo poslije 8 tjedana istraživanja (HD3): u ispitanika s rizikom krvarenja (dijabetičara i nedijabetičara) stupanj 1 (7 slučajeva), stupanj 2 (4 slučaja); te u ispitanika bez rizika krvarenja (dijabetičara i nedijabetičara): stupanj 1 (11 slučajeva) (χ square test = 4,701; p = 0,048). Druge statistički značajne razlike u zgrušavanju izvantjelesnog krvotoka među skupinama nisu zabilježene. Unatoč činjenici da je čimbenik anti-Xa bio niži od 0,4 IJ/ml nakon završetka postupka HD na završetku istraživanja (u ispitanika dijabetičara i nedijabetičara bez rizika krvarenja), nisu zabilježena značajna zgrušavanja izvantjelesnog krvotoka i krvožilnog pristupa. Zaključak: Rezultati ovog istraživanja pokazuju da je najmanja pojedinačno prilagođena bolus doza niskomolekularnog heparina nadroparina za dijabetičare s rizikom krvarenja 28,789,60 IJ/kg/HD, a za nedijabetičare s rizikom krvarenja 32,9610,06 IJ/kg/HD. Ovo istraživanje pokazalo je da je smanjenje stvarne početne bolus doze nadroparina u dijabetičara s rizikom krvarenja za 42,05 % dovoljno za učinkovitu i sigurnu HD (u nedijabetičara s rizikom krvarenja doza je bila manja za 46,19 %, a u dijabetičara bez rizika krvarenja za 33,04 %). Dalja istraživanja s većim brojem ispitanika pokazat će je li ovaj protukoagulacijski protokol obvezatan za bolesnike s rizikom krvarenja.Introduction: Patients on haemodialysis (HD) have known high risk of bleeding. The use of systemic anticoagulation with heparin during HD can cause serious problems. The aim of this prospective study was to find out what is the lowest single bolus dose of nadroparin for safe and effective HD in patients with bleeding risk (diabetics and non–diabetics). Methods: Forty adult patients (18 females and 22 males) aged 64.93±12.34 years (range 36 – 84), who were on intermittent HD for a mean period of 61.63±53.97 months (range 5 – 196), were enrolled in this 12-weeks long prospective study. Patients were devided into four subgroups with 10 participants (diabetics with and without bleeding risk, non-diabetics with and without bleeding risk). The actual starting bolus dose of nadroparin (which was used in our Center for a minimum of two months according to the manufacturer´s recommendation), was decreased twice by 25%: after the initial 4 weeks (HD2 nadroparin), and again after an additional 4 weeks (HD3 nadroparin). The maintenance period was 4 weeks during which time this dose was adjusted due to clotting of the extracorporeal circuit (HD4 nadroparin). We investigated four dialysis sessions: HD1 (the beggining of the study), HD2 (after 4 weeks), HD3 (after 8 weeks), and HD4 (the end of the study). The levels of factor anti-Xa, activated partial thromboplastin time (aPTT), thrombin-antithrombin complex (TAT) and D-dimers were determined at the beginning, after 2 hours and at the end of investigated HD sessions. The clottings of the extracorporeal circuit and vascular access compression time were noted at the end of the HD sessions. The efficacy was assessed by scoring the dialysers and arterial/venous chambers separately (from 0 = no clot formation to 4 = coagulation of the whole system). The safety was assessed by noting all bleeding episodes: "major" (required hospitalization/transfusion, bleeding into critical organ or space, cause of death) or "minor" (vascular access site, epistaxis, subconjunctival bleeding) Results: Thirty eight patients completed study, two were transplanted, none died. A safe and significant reduction of nadroparin (first vs last HD session) was observed in: diabetics with bleeding risk (49.6612.33 vs 28.789.60 IU/kg/HD; p <0.001), diabetics without bleeding risk (50.7015.23 vs 33.9516.97 IU/kg/HD; p <0.001), and non-diabetics with bleeding risk (61.2518.68 vs 32.9610.06 IU/kg/HD; p <0.001). All together the reduction of nadroparin dose in these groups was: 42.05 %; 33.04 % and 46.19 %, respectively. In non-diabetics without bleeding risk there were no significant differences between nadroparin doses at the beginning and at the end of the study (47.4510.87 vs 41.7510.91 IU/kg/HD; p = 0.484). There were 7 minor and 1 major bleeding episodes (all in patients with bleeding risk). There was significant difference in clot formation of dialyser only in HD3: grade 1 (7 cases), and grade 2 (4 cases) in patients with bleeding risk; and grade 1 (11 cases) in patients without bleeding risk (χ square test = 4.701; p = 0.048). There were no other differences in clott formation in examined groups. Despite anti-Xa at hour 4 at the end of the study was lower than 0.4 IU/ml in our diabetic and non-diabetic patients without risk of bleeding, serious clottings in extracorporeal circuit and vascular access thromboses were not found. Conclusons: From results of this study it seems that the lowest dose of nadroparin for diabetics with bleeding risk is 28.789.60 IU/kg/HD and for non-diabetics with bleeding risk is 32.9610.06 IU/kg/HD. This study demonstrated for the first time that decreased actual starting bolus dose of nadroparin by 42.05 % is sufficant for safe and effective HD in diabetic patients with bleeding risk (in non-diabetics with bleeding risk by 46.19 %, and diabetics without bleeding risk by 33.04 %)

Pegylated interferon for treatment of chronic hepatitis C in hemodialysis patients in Croatia

Hepatitis C virus (HCV) infection is a frequent complication among long-term dialysis patients. The aim of the present study was to evaluate the efficacy and side effects of pegylated interferon-α(2a) (PEG-IFN-α(2a)) treatment in hemodialysis patients. We retrospectively reviewed charts of 16 HCV-RNA-positive hemodialysis patients. There were 11 male and 5 female patients treated with dialysis for 6-28 years. Twelve patients had HCV genotype 1b, 2 patients had 3a, and 1 patient had genotype 2a. Although only 10 out of 16 patients completed 48 weeks of treatment, early virological response and end-of-treatment virological response were achieved in 9 and 13 patients, respectively. Sustained virological response was recorded in 9 patients. The most common side effect was anemia. A flu-like syndrome was documented in 6, myalgia in 4, and arthralgia in 5 patients. Rectorrhagia, endocarditis and severe cough were recorded in 1 patient each. Nine patients received a renal transplant, and all 6 responders remained HCV-RNA-negative. PEG-IFN-α(2a) has limited efficacy in dialysis patients. A significant proportion of patients discontinued treatment because of side effects. Additional studies with long-term follow-up are needed to determine the optimal treatment of HCV infection in the dialysis population