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Predictors of Vascular Access Thrombosis Among Patients on the Cadaveric Renal Transplantation Waiting List
Predictors of Vascular Access Thrombosis Among Patients on the Cadaveric Renal Transplantation Waiting List B. Akman, B. Afsar, F.B. Ataç, A. Ibis, Z. Arat, S. Sezer, F.N. Ozdemir, and M. Haberal ABSTRACT Acute thrombotic complications remain a constant, proportionally increasing complication before and after renal transplantation. We sought to investigate predictors for a prothrombotic state that increased the risk of vascular access thrombosis, among chronic renal failure patients during the waiting period prior to cadaveric renal transplantation. Chronic renal failure patients awaiting cadaveric renal transplantation and followed between January 2002 and January 2005 were included in this study. The 109 subjects including, 61 females and 48 males of mean age: 47.4 ⫾ 12.9 years; There were 36 continuous ambulatory peritoneal dialysis and 73 hemodialysis patients. Serum albumin, prealbumin, CRP, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (immunoglobulins G and M), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total platelet count were measured in each patient. Factor V Leiden, prothrombin 20210, ACE and MTHFR gene mutations were studied in all patients. Vascular Access thrombosis was detected in 62 patients. During follow-up 31 of 109 patients died. Vascular access thrombosis occurred in 78 patients who survived and 31 who died. The patients who died showed a significantly higher rate of thrombosis than those who survived (P ⫽ .003, OR: 4.61, CI: 1.70 to 12.50). Among the above biochemical risk factors, multiple regression analysis and backward logistic analysis revealed that d-dimer was the strongest biochemical predictor of thrombosis (P ⫽ .013, RR: 17.8). Upon evaluation of genetic risk factors, only factor V Leiden mutation was related to vascular access thrombosis (P ⫽ .001). In conclusion, the presence of vascular access thrombosis is a risk factor for mortality during the waiting period for cadaveric renal transplantation. As patients with factor V Leiden mutation or high serum d-dimer levels are at high risk for vascular access thrombosis, we recommend close monitorizing of these patients and use of anticoagulant therapy during the waiting period prior to renal transplantation.
A
CUTE THROMBOTIC COMPLICATIONS before and after renal transplantation are constant problems that increase morbidity and mortality of end-stage renal disease patients. For this purpose early diagnosis is important to detect changes in coagulation or fibrinolysis, which promote an enhanced thrombotic state. Identifying risk factors for thrombosis and focusing on preventive strategies have been the major point of interest among patients in awaiting renal transplantation. Recurrent vascular access thrombosis resulting in failure to continue maintenance hemodialysis (HD) therapy is the most common and important complication of a thrombotic state before renal transplantation.1 The aim of this study was to investigate predictors of a prothrombotic state that increase the risk of © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 413– 415 (2006)
vascular access thrombosis among chronic renal failure patients awaiting cadaveric renal transplantation. MATERIALS AND METHODS This study included 109 patients awaiting cadaveric renal transplantation (61 females, 48 males of mean age 47.4 ⫾ 12.9 years). The treatment for 36 was continuous ambulatory peritoneal dialysis (CAPD), and for 73 HD. They were followed between January From the Departments of Nephrology (B.Ak., B.Af., A.I., Z.A., S.S., F.N.O.), Genetics (F.B.A.), and General Surgery (M.H.), Baskent University Hospital, Ankara, Turkey. Address reprint requests to Beril Akman, Baskent University Hospital, 5. sok No. 48, Bahcelievler, Ankara, 06490, Turkey. E-mail address: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.01.022 413
414 2002 and January 2005. Patients with acute inflammation/infection, malignancy, acute cardiac problems (severe congestive heart failure, atrial fibrillation, etc), coagulopathies, and surgical interventions within the last month were excluded from the study. None of the patients were using drugs known to produce anticardiolipin antibodies namely, phenytoin, hydralazine, isoniazid, procainamide, penicillin, methyldopa, phenothiazines. All hemodialysis patients had dialysis sessions three times per week with blood flow rates of 300 to 350 mL/min, using hemophane membranes and 5000 U heparin injection. Mean Kt/V was 1.4 ⫾ 0.2. All CAPD patients had peritoneal exchanges with a twin-bag system delivering 1500 to 2500 mL for four to five times a day. Mean Kt/V was 2.1 ⫾ 0.2. Blood samples for biochemical analysis were taken just before the hemodialysis session/peritoneal dialysis exchange before the administration of heparin and anticoagulants. Serum levels for albumin, prealbumin, C-reactive protein, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (immunoglobulin [Ig]G and IgM), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and total platelet count were measured in each patient at the start of our study. Serum albumin levels were measured by a quantitative colorimetric method (Stanbio Laboratory, Inc, San Antonio, Tex, USA). We used the turbidimetric latex agglutination method (Biosystems, SA, Spain) to determine C-reactive protein levels. The quantitative determination of anticardiolipin antibodies of IgG and IgM classes were made using an immunometric enzyme immunoassay (ORGenTec, Diagnostica, Germany). Values ⬎10.0 GPL U/mL for IgG aCL and 7.0 MPL U/mL for IgM aCL were considered positive. Serum levels of total cholesterol, HDL, LDL, and triglyceride were measured by direct quantitative colorimetric method (Human Gesellchaft für Biochemica und Diagnostica mbH, Germany). Other biochemical parameters were measured using standard laboratory methods. Genetic mutations for Factor V Leiden, Pr20210, ACE and MTHFR genes were studied in all patients. Genomic DNA was isolated from ethylenediamine-tetraacetic acid (EDTA)-coagulated blood samples using the standard phenol-chloroform extraction method. The isolated DNA samples were resuspended at a concentration of 100 mg/L in Tris (pH 7.4) containing 0.1 mmol/L EDTA. The samples were kept at ⫺20°C until they were tested. Rapid real-time polymerase chain reaction (PCR) amplification was performed in a Light Cycler (Roche Diagnostics) according to the manufacturer’s instruction using the the light cycler factor V Leiden (Roche, Cat No. 2212161) and prothrombin G20210A (Roche, Cat No. 2236842) detection kits, which were specifically adapted for PCR in glass capillaries. For fluorometric DNA melting curve analysis we differentiated the two alleles (factor V Leiden and prothrombin genes). It was done by determining the melting curves after PCR, according to the instructions of the manufacturer. Hybridization was performed with two different short oligonucleotides for two adjacent internal sequences of the amplified PCR fragment that hybridize during the annealing phase of the PCR cycles. One probe was labelled at the 5= end with a light cycler red fluorophore and phosphorylated at the 3= end. The second probe was labeled with fluorescein. After hybridization, probes in close proximity produce fluorescence energy transfer (FRET) between the two fluorophores. During FRET, fluorescein, the donor fluorophore, is stimulated by the light source of the instrument and part of the energy is transferred to light cycler red, the accepter fluorophore. The emitted fluorescence of the light cycler red fluorophore is quantified by plotting the negative deriv-
AKMAN, AFSAR, ATAÇ ET AL ative of fluorescence with respect to time versus temperature (⫺dF/dt versus T). During the follow-up period, 62 of the 109 patients had vascular access thrombosis and 31 patients died. The Statistical Package for Social Sciences (SPSS Inc, Chicago, Ill, USA) was used for data processing. Student t test, MannWhitney U test, multiple regression analysis, and backward logistic analysis were performed. Categorical data were analyzed by chisquare tests. The results were given as mean values ⫾ standard deviation. Statistical significance was accepted as P ⬍ .05.
RESULTS
During 3-year follow-up, 78 patients survived, of whom 41 did not have vascular access thrombosis (52.6%) and 37 had this problem (47.4%). When the 31 patients who died during the 3-year follow-up period were evaluated, 80.6% (25/31) showed vascular access thrombosis and 19.4% (6/31) did not have this problem. The patients who died had a significantly higher rate of thrombosis than those who survived (P ⫽ .003, OR: 4.61, CI: 1.70 to 12.50). When the biochemical risk factors for thrombosis, namely, albumin, prealbumin, CRP, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (IgG and IgM), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, HDL, LDL, and total platelet count, were analyzed by multiple regression analysis, backward logistic analysis revealed that d-dimer was the strongest predictor of thrombosis (P ⫽ .013, RR: 17.8). D-dimer levels were negatively correlated with serum albumin levels (P ⬍ .001, r: ⫺440). Dialysis duration was not correlated with any of these biochemical parameters (P ⬎ .05). Type of dialysis modality (CAPD and HD patients) affected serum albumin levels significantly (3.6 ⫾ 0.6 g/dL and 4.0 ⫾ 0.5 g/dL, respectively, P ⫽ .001). Although not significant, fibrinogen and d-dimer levels were higher among CAPD than HD patients (Table 1). To evaluate genetic risk factors for thrombosis, only factor V Leiden mutation was significantly correlated with vascular access thrombosis (P ⫽ .001). DISCUSSION
A variety of thrombosis-favoring hematological changes occur in end-stage renal failure patients. Additionally, nontraditional risk factors for thrombosis, such as hyperhomocysteinemia, endothelial dysfunction, inflammation, and malnutrition, exist in the majority of patients.2 Therefore thrombotic events are frequent, contributing substantially to the high morbidity and mortality in this population before and after renal transplantation. Pretransplantation hypercoagulable state on HD therapy has also been shown Table 1. Effects of Dialysis Modality on Fibrinogen, d-Dimer, and Albumin Levels
Albumin Fibrinogen D-dimer
CAPD (n ⫽ 36)
HD (n ⫽ 73)
P
3.6 ⫾ 0.6 478.8 ⫾ 135.4 1.3 ⫾ 2.0
4.0 ⫾ 0.5 433.9 ⫾ 114.6 0.8 ⫾ 0.7
.001 ⬎.05 ⬎.05
PREDICTORS OF VASCULAR ACCESS THROMBOSIS
to be a major risk factor for immediate posttransplantation thrombotic events.3 In this study, we sought to identify a simple screening test for end-stage renal disease patients who show a tendency for thrombosis during the period awaiting renal transplantation. Moreover, we excluded any possible effects of inflammation, infection, or malnutrition. We evaluated genetic and biochemical risk factors for thrombosis. D-dimer levels were elevated in 80% of hemodialysis patients in the absence of acute venous thromboembolism, which indicated a procoagulant state.4 Our results showed that ddimer in the absence of infection/inflammation or acute thrombosis was a strong predictor for vascular access thrombosis. As it is a rapidly available, relatively inexpensive diagnostic test for the evaluation of prothrombotic status, we recommend periodic analysis of d-dimer levels for early detection of an activated coagulation system. In this way, maintenance of vascular access patency may be achieved by early administration of anticoagulant therapy thereby preventing thrombotic complications. In an analysis of different dialysis modalities, CAPD patients were found to be more prone to an hypercoagulable state.5,6 Although it was not significant, our CAPD patients showed higher levels of fibrinogen and d-dimer levels. However, overall analysis of genetic and other biochemical parameters did not reveal a significant difference between CAPD and HD therapies. Therefore, it seems that renal failure itself is the main cause of procoagulant activity in these patients rather than the type of dialysis modality. Among genetic mutations of factor V Leiden, Pr20210, ACE and MTHFR genes, factor V Leiden mutation was the most common hereditary cause of venous thrombosis.7 Pt20210 mutation has been shown to induce arterial thrombosis.7 MTHFR mutation may lead to hyperhomocysteinemia with changes in serum levels of vitamin B12 and folic acid, thereby increasing cardiovascular risk among endstage renal failure patients.8 Among our renal transplant waiting list patients, factor V Leiden mutation was the most significant genetic cause of arteriovenous fistula (AVF) thrombosis an observation that confirms the results of previous studies. The increased tendency toward thrombo-
415
sis among patients with factor V Leiden mutation may increase morbidity and mortality during the renal transplantation waiting period, and can also cause serious thrombotic complications after renal transplantation.9,10 In patients with frequent AVF thrombosis problems, we recommend to screen for factor V Leiden mutation, closely monitor, and take necessary precautions to prevent posttransplant thrombotic events. In conclusion, the presence of vascular access thrombosis is a risk factor for mortality during the waiting period prior to cadaveric renal transplantation. As patients with factor V Leiden mutation or high serum d-dimer levels are at high risk for thrombosis, we recommend close monitorizing of these tests before and after renal transplantation and the use of anticoagulant therapy during the waiting period. REFERENCES 1. Schwab SJ, Harrington JT, Singh A, et al: Vascular access for hemodialysis. Kidney Int 55:2078, 1999 2. Casserly LF, Dember LM: Thrombosis in end-stage renal disease. Semin Dial 16:245, 2003 3. Nampoory MR, Das KC, Johny KV, et al: Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 42:797, 2003 4. Miozzari M, Wahl C: D-dimers in hemodialysis patients. Nephron 88:278, 2001 5. Ambühl PM, Wüthrich RP, Korte W, et al: Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation. Nephrol Dial Transplant 12:2355, 1997 6. Malyszko J, Malyszko JS, Mysliwiec M: Comparison of hemostatic disturbances between patients on CAPD and patients on hemodialysis. Perit Dial Int 21:158, 2001 7. Lane DA, Grant PJ: Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 95:1517, 2000 8. Haviv YS, Shpichinetsky V, Goldschmidt N, et al: The common mutations C677T and A1298C in the human methylenetetrahydrofolate reductase gene are associated with hyperhomocysteinemia and cardiovascular disease in hemodialysis patients. Nephron 92:120, 2002 9. D’Angelo A, Selhub J: Homocysteine and thrombotic disease. Blood 90:1, 1997 10. De Stefano V, Zappacosta B, Persichilli S, et al: Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 106:564, 1999
A
CUTE THROMBOTIC COMPLICATIONS before and after renal transplantation are constant problems that increase morbidity and mortality of end-stage renal disease patients. For this purpose early diagnosis is important to detect changes in coagulation or fibrinolysis, which promote an enhanced thrombotic state. Identifying risk factors for thrombosis and focusing on preventive strategies have been the major point of interest among patients in awaiting renal transplantation. Recurrent vascular access thrombosis resulting in failure to continue maintenance hemodialysis (HD) therapy is the most common and important complication of a thrombotic state before renal transplantation.1 The aim of this study was to investigate predictors of a prothrombotic state that increase the risk of © 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 38, 413– 415 (2006)
vascular access thrombosis among chronic renal failure patients awaiting cadaveric renal transplantation. MATERIALS AND METHODS This study included 109 patients awaiting cadaveric renal transplantation (61 females, 48 males of mean age 47.4 ⫾ 12.9 years). The treatment for 36 was continuous ambulatory peritoneal dialysis (CAPD), and for 73 HD. They were followed between January From the Departments of Nephrology (B.Ak., B.Af., A.I., Z.A., S.S., F.N.O.), Genetics (F.B.A.), and General Surgery (M.H.), Baskent University Hospital, Ankara, Turkey. Address reprint requests to Beril Akman, Baskent University Hospital, 5. sok No. 48, Bahcelievler, Ankara, 06490, Turkey. E-mail address: [email protected] 0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.01.022 413
414 2002 and January 2005. Patients with acute inflammation/infection, malignancy, acute cardiac problems (severe congestive heart failure, atrial fibrillation, etc), coagulopathies, and surgical interventions within the last month were excluded from the study. None of the patients were using drugs known to produce anticardiolipin antibodies namely, phenytoin, hydralazine, isoniazid, procainamide, penicillin, methyldopa, phenothiazines. All hemodialysis patients had dialysis sessions three times per week with blood flow rates of 300 to 350 mL/min, using hemophane membranes and 5000 U heparin injection. Mean Kt/V was 1.4 ⫾ 0.2. All CAPD patients had peritoneal exchanges with a twin-bag system delivering 1500 to 2500 mL for four to five times a day. Mean Kt/V was 2.1 ⫾ 0.2. Blood samples for biochemical analysis were taken just before the hemodialysis session/peritoneal dialysis exchange before the administration of heparin and anticoagulants. Serum levels for albumin, prealbumin, C-reactive protein, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (immunoglobulin [Ig]G and IgM), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and total platelet count were measured in each patient at the start of our study. Serum albumin levels were measured by a quantitative colorimetric method (Stanbio Laboratory, Inc, San Antonio, Tex, USA). We used the turbidimetric latex agglutination method (Biosystems, SA, Spain) to determine C-reactive protein levels. The quantitative determination of anticardiolipin antibodies of IgG and IgM classes were made using an immunometric enzyme immunoassay (ORGenTec, Diagnostica, Germany). Values ⬎10.0 GPL U/mL for IgG aCL and 7.0 MPL U/mL for IgM aCL were considered positive. Serum levels of total cholesterol, HDL, LDL, and triglyceride were measured by direct quantitative colorimetric method (Human Gesellchaft für Biochemica und Diagnostica mbH, Germany). Other biochemical parameters were measured using standard laboratory methods. Genetic mutations for Factor V Leiden, Pr20210, ACE and MTHFR genes were studied in all patients. Genomic DNA was isolated from ethylenediamine-tetraacetic acid (EDTA)-coagulated blood samples using the standard phenol-chloroform extraction method. The isolated DNA samples were resuspended at a concentration of 100 mg/L in Tris (pH 7.4) containing 0.1 mmol/L EDTA. The samples were kept at ⫺20°C until they were tested. Rapid real-time polymerase chain reaction (PCR) amplification was performed in a Light Cycler (Roche Diagnostics) according to the manufacturer’s instruction using the the light cycler factor V Leiden (Roche, Cat No. 2212161) and prothrombin G20210A (Roche, Cat No. 2236842) detection kits, which were specifically adapted for PCR in glass capillaries. For fluorometric DNA melting curve analysis we differentiated the two alleles (factor V Leiden and prothrombin genes). It was done by determining the melting curves after PCR, according to the instructions of the manufacturer. Hybridization was performed with two different short oligonucleotides for two adjacent internal sequences of the amplified PCR fragment that hybridize during the annealing phase of the PCR cycles. One probe was labelled at the 5= end with a light cycler red fluorophore and phosphorylated at the 3= end. The second probe was labeled with fluorescein. After hybridization, probes in close proximity produce fluorescence energy transfer (FRET) between the two fluorophores. During FRET, fluorescein, the donor fluorophore, is stimulated by the light source of the instrument and part of the energy is transferred to light cycler red, the accepter fluorophore. The emitted fluorescence of the light cycler red fluorophore is quantified by plotting the negative deriv-
AKMAN, AFSAR, ATAÇ ET AL ative of fluorescence with respect to time versus temperature (⫺dF/dt versus T). During the follow-up period, 62 of the 109 patients had vascular access thrombosis and 31 patients died. The Statistical Package for Social Sciences (SPSS Inc, Chicago, Ill, USA) was used for data processing. Student t test, MannWhitney U test, multiple regression analysis, and backward logistic analysis were performed. Categorical data were analyzed by chisquare tests. The results were given as mean values ⫾ standard deviation. Statistical significance was accepted as P ⬍ .05.
RESULTS
During 3-year follow-up, 78 patients survived, of whom 41 did not have vascular access thrombosis (52.6%) and 37 had this problem (47.4%). When the 31 patients who died during the 3-year follow-up period were evaluated, 80.6% (25/31) showed vascular access thrombosis and 19.4% (6/31) did not have this problem. The patients who died had a significantly higher rate of thrombosis than those who survived (P ⫽ .003, OR: 4.61, CI: 1.70 to 12.50). When the biochemical risk factors for thrombosis, namely, albumin, prealbumin, CRP, d-dimer, fibrinogen, antithrombin III, anticardiolipin antibodies (IgG and IgM), homocystein, vitamin B12, folic acid, total cholesterol, triglyceride, HDL, LDL, and total platelet count, were analyzed by multiple regression analysis, backward logistic analysis revealed that d-dimer was the strongest predictor of thrombosis (P ⫽ .013, RR: 17.8). D-dimer levels were negatively correlated with serum albumin levels (P ⬍ .001, r: ⫺440). Dialysis duration was not correlated with any of these biochemical parameters (P ⬎ .05). Type of dialysis modality (CAPD and HD patients) affected serum albumin levels significantly (3.6 ⫾ 0.6 g/dL and 4.0 ⫾ 0.5 g/dL, respectively, P ⫽ .001). Although not significant, fibrinogen and d-dimer levels were higher among CAPD than HD patients (Table 1). To evaluate genetic risk factors for thrombosis, only factor V Leiden mutation was significantly correlated with vascular access thrombosis (P ⫽ .001). DISCUSSION
A variety of thrombosis-favoring hematological changes occur in end-stage renal failure patients. Additionally, nontraditional risk factors for thrombosis, such as hyperhomocysteinemia, endothelial dysfunction, inflammation, and malnutrition, exist in the majority of patients.2 Therefore thrombotic events are frequent, contributing substantially to the high morbidity and mortality in this population before and after renal transplantation. Pretransplantation hypercoagulable state on HD therapy has also been shown Table 1. Effects of Dialysis Modality on Fibrinogen, d-Dimer, and Albumin Levels
Albumin Fibrinogen D-dimer
CAPD (n ⫽ 36)
HD (n ⫽ 73)
P
3.6 ⫾ 0.6 478.8 ⫾ 135.4 1.3 ⫾ 2.0
4.0 ⫾ 0.5 433.9 ⫾ 114.6 0.8 ⫾ 0.7
.001 ⬎.05 ⬎.05
PREDICTORS OF VASCULAR ACCESS THROMBOSIS
to be a major risk factor for immediate posttransplantation thrombotic events.3 In this study, we sought to identify a simple screening test for end-stage renal disease patients who show a tendency for thrombosis during the period awaiting renal transplantation. Moreover, we excluded any possible effects of inflammation, infection, or malnutrition. We evaluated genetic and biochemical risk factors for thrombosis. D-dimer levels were elevated in 80% of hemodialysis patients in the absence of acute venous thromboembolism, which indicated a procoagulant state.4 Our results showed that ddimer in the absence of infection/inflammation or acute thrombosis was a strong predictor for vascular access thrombosis. As it is a rapidly available, relatively inexpensive diagnostic test for the evaluation of prothrombotic status, we recommend periodic analysis of d-dimer levels for early detection of an activated coagulation system. In this way, maintenance of vascular access patency may be achieved by early administration of anticoagulant therapy thereby preventing thrombotic complications. In an analysis of different dialysis modalities, CAPD patients were found to be more prone to an hypercoagulable state.5,6 Although it was not significant, our CAPD patients showed higher levels of fibrinogen and d-dimer levels. However, overall analysis of genetic and other biochemical parameters did not reveal a significant difference between CAPD and HD therapies. Therefore, it seems that renal failure itself is the main cause of procoagulant activity in these patients rather than the type of dialysis modality. Among genetic mutations of factor V Leiden, Pr20210, ACE and MTHFR genes, factor V Leiden mutation was the most common hereditary cause of venous thrombosis.7 Pt20210 mutation has been shown to induce arterial thrombosis.7 MTHFR mutation may lead to hyperhomocysteinemia with changes in serum levels of vitamin B12 and folic acid, thereby increasing cardiovascular risk among endstage renal failure patients.8 Among our renal transplant waiting list patients, factor V Leiden mutation was the most significant genetic cause of arteriovenous fistula (AVF) thrombosis an observation that confirms the results of previous studies. The increased tendency toward thrombo-
415
sis among patients with factor V Leiden mutation may increase morbidity and mortality during the renal transplantation waiting period, and can also cause serious thrombotic complications after renal transplantation.9,10 In patients with frequent AVF thrombosis problems, we recommend to screen for factor V Leiden mutation, closely monitor, and take necessary precautions to prevent posttransplant thrombotic events. In conclusion, the presence of vascular access thrombosis is a risk factor for mortality during the waiting period prior to cadaveric renal transplantation. As patients with factor V Leiden mutation or high serum d-dimer levels are at high risk for thrombosis, we recommend close monitorizing of these tests before and after renal transplantation and the use of anticoagulant therapy during the waiting period. REFERENCES 1. Schwab SJ, Harrington JT, Singh A, et al: Vascular access for hemodialysis. Kidney Int 55:2078, 1999 2. Casserly LF, Dember LM: Thrombosis in end-stage renal disease. Semin Dial 16:245, 2003 3. Nampoory MR, Das KC, Johny KV, et al: Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 42:797, 2003 4. Miozzari M, Wahl C: D-dimers in hemodialysis patients. Nephron 88:278, 2001 5. Ambühl PM, Wüthrich RP, Korte W, et al: Plasma hypercoagulability in haemodialysis patients: impact of dialysis and anticoagulation. Nephrol Dial Transplant 12:2355, 1997 6. Malyszko J, Malyszko JS, Mysliwiec M: Comparison of hemostatic disturbances between patients on CAPD and patients on hemodialysis. Perit Dial Int 21:158, 2001 7. Lane DA, Grant PJ: Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 95:1517, 2000 8. Haviv YS, Shpichinetsky V, Goldschmidt N, et al: The common mutations C677T and A1298C in the human methylenetetrahydrofolate reductase gene are associated with hyperhomocysteinemia and cardiovascular disease in hemodialysis patients. Nephron 92:120, 2002 9. D’Angelo A, Selhub J: Homocysteine and thrombotic disease. Blood 90:1, 1997 10. De Stefano V, Zappacosta B, Persichilli S, et al: Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 106:564, 1999