The Rationale for, and Role of, Heparin in Peritoneal DialysisSharad Goel, Madhukar Misra, Rajiv Saran, Ramesh Khanna
The administration of intraperitoneal (IP) heparin enjoys time-honored use and is felt to be side-effect free. It is administered whenever fibrin is detected in the dialysate effluent. It is believed that there is no absorption of heparin across the peritoneal cavity. The aim of this article was to review the rationale behind the administration of IP heparin, to show that absorption and side effects may occur, and to present recent evidence that questions the routine use of this drug as an additive to dialysate fluid.Key words
Heparin, peritonitis, intraperitoneal, fibrinolytic, coagulationFrom:
Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, USA.Introduction
Peritoneal dialysis (PD) is the renal replacement modality for 16% of the end-stage renal disease (ESRD) population (1,2). During the course of regular PD, peritoneal fibrin is occasionally seen in the dialysate (3). However, this is more common when the course of disease is complicated by peritonitis. The appearance of fibrin in the PD effluent can lead to catheter blockage and, if excessive and unopposed, can in theory result in peritoneal adhesions and loss of peritoneal-membrane function (2). These complications, it is believed, can be prevented by the timely administration of intraperitoneal (IP) heparin. This belief, coupled with the perception that IP use of heparin is risk free, has made heparin the most common additive to PD fluid. The aim of this article is to re-examine the evidence for this practice.Heparin: structure and mode of action
Heparin is an acidic, anionic, sulfated glycosaminoglycan (GAG) of variable molecular weight (mean: 15000 d; range: 1800 - 30000). Only a portion of the molecule in commercial use contains a specific pentasaccharide sequence that is responsible for binding to antithrombin III (AT-III). This process causes conformational changes in AT-III resulting in a multifold increase in its inhibitory potential. This heparin-AT-III complex, besides inhibiting thrombin formation, causes inhibition of activated coagulation factors IX, X, XI, and XII as well.
Heparin also exerts its anticoagulatory actions by mechanisms independent of AT-III, such as HC-II binding to prothrombin, direct binding to coagulant factors, and release of endogenous GAGs with anticoagulant activity (4,5).
The mode of action of IP heparin is not precisely known. Studies (6,7) found that AT-III levels in the dialysate are normally 1.5% of the plasma levels (0.52 ± 0.1 mg/dL vs 33.6 ± 4 mg/dL), and this level is felt by some authors (6) to be too low to explain the anticoagulant action of heparin during stable PD. Others (7) feel that even these levels would suffice. During peritonitis there is a general outpouring of proteins into the peritoneal cavity resulting in a high level of AT-III (7). Whether heparin exerts its anticoagulant effect by AT-III-independent effects in the peritoneum is not known.
In 8 stable patients on continuous ambulatory peritoneal dialysis (CAPD) it was shown that heparin activity in dialysate decreased with time. With a dose of 2.5 U/mL to 5 U/mL the activity decreased by half of the initial level after 1 to 2 hours (7).Indications for IP heparin: standard practice
It is customary at most centers to add heparin whenever fibrin or blood or both is seen in the drainage bag. Fibrin formation is occasionally observed during routine dialysis, but more commonly when the PD catheter is being inserted and at the onset of peritonitis. Once started, heparin is added to each bag until the return-drainage dialysate is clear. Patients are educated on the appearance of fibrin and the method of administering heparin, and asked to call the dialysis center if the anticipated clearing of the dialysate does not occur.What dose of IP heparin to use?
Dosing is based on clinical observations, and varies from center to center with a range for CAPD/IPD (intermittent PD) of 100 to 2500 U/L of dialysate (1,2).
Gries et al. (8) observed the effect of two different heparin concentrations (7500 U/L and 500 U/L) on dialysate fibrinopeptide A (FPA) concentrations in 6 patients. FPA is a specific marker for thrombin action on fibrinogen, and hence of fibrin formation. Heparin given intraperitoneally reduced the fibrin production as measured by FPA; however, there was no difference in reduction of fibrin formation between the two different concentrations of heparin (FPA with 7500 U/L heparin: 20.6 ± 5.6 ng/mL; 500 U/L: 22.8 ± 6 ng/mL; no heparin: 152.2 ± 11.8 ng/mL). They demonstrated that the lower (500 U/L) of the two doses of heparin was sufficient to prevent the formation of fibrin. At the University of Missouri- Columbia our standard practice, therefore, is to use 500 U/L for both CAPD and IPD.Does IP heparin have a systemic effect?
The aim of IP instillation of heparin is to get a local fibrinolytic effect without systemic anticoagulation. The traditional view is that, with the doses used, virtually no heparin gets across the peritoneal membrane. Part of the reason for this could be the anionic charge of heparin and its large molecular weight. This view has been supported by studies that showed that, if administered as recommended, IP heparin had no effect on blood coagulation (7).
Pharmacokinetic studies addressing the question of heparin absorption across the peritoneum in humans are lacking. A study done in an animal model demonstrated significant recovery of heparin from systemic circulation. In this study 99-Tc-labeled heparin was given intraperitoneally along with dialysate in a New Zealand white rabbit model. Three different protocols were used: a single 15-minute cycle with heparin 500 U/L, 6 successive 15-minute cycles with heparin 500 U/L, and a single 3-hr cycle with heparin 2500 U/L. Labeled heparin was found in blood, organs, and urine. The total amount of recovery ranged from 1.5% to 20%, and depended on the amount of heparin used and the duration of its presence in the rabbit peritoneal cavity (9).
Interestingly, a patient on CAPD with deep-vein thrombosis (DVT) was successfully treated with low-molecular-weight heparin with resulting therapeutic antifactor-Xa activity in the plasma of 0.5 to 0.8 units. (Dose used: 6000 to 8000 antifactor Xa U/2-L dialysate bag, given four times a day) (10). Thus the belief that the absence of an effect of IP heparin on systemic coagulation implies an absence of transfer across peritoneal membrane may be inaccurate.Potential problems with adding IP heparin
The anticipated side effects expected from the use of IP heparin are mainly local ones. However, the knowledge that there is absorption of small amounts of heparin across the peritoneal membrane requires one to be alert to the possibility of systemic side effects, such as formation of heparin antibodies, with accompanying problems of thrombocytopenia (4), osteoporosis (11), and increase in transaminases (12).Locally, apart from the potential for increased infection, there is the possibility of mesothelial cell injury. During PD the mesothelial cell undergoes continuous sloughing and regeneration. Addition of heparin to human peritoneal mesothelial cell cultures inhibited their growth (13).
In a study on Staphylococcus epidermidis biofilm, heparin was shown to antagonize the antibacterial activity of rifampin (14). However no effect was seen on the activity of penicillin, cephalosporins, clindamycin, tobramycin, or vancomycin (15).
Having concluded that IP heparin use is not as risk-free as previously believed, it is time to take a fresh look at the rationale on which this practice is based, and the benefits obtained from it. The two questions that need to be asked are, first, does heparin inhibit fibrin formation? and, second, is there a need for a fibrinolytic agent?Does heparin reduce fibrin formation?
The answer to this question is an unequivocal yes.
Indirect evidence for this was first provided by showing that higher dialysate-inflow and -outflow rates were achieved in 6 patients on CAPD when heparin was added to the dialysate, compared to when it was not (16). This was confirmed by measuring fibrinogen-A in the dialysate from patients on PD (17). Gries et al. were able to show that the addition of heparin (500 U/L) reduced fibrin formation (FP-A) from 153.4 ± 16.8 ng/mL to 11.6 ± 2.6 ng/mL (P < 0.05) in the dialysate (17).
This was also confirmed by Tabata and co-workers (18).Is exogenous fibrinolysis required?
A not very well recognized fact is that the peritoneal mesothelium has synthetic activity. It is involved in the synthesis and secretion of mesothelial surface fluids, which are responsible for the phenomenon of boundary lubrication of slowly moving surfaces. This liquid consists of phospholipids, mainly phosphatidylcholine and serine, with high surfactant and water-repelling properties (19,20).
The mesothelium of rats and guinea pigs has been shown to have fibrinolytic activity. Heparin is not synthesized by the mesothelial cells, but other GAGs, such as hyaluron, are.
In vitro, pure human mesothelial cells deprived of the underlying subserosa were shown to have fibrinolytic activity (21). Tissue-specific and urokinase-like plasminogen-activators (t-PA, u-PA) could be detected in normal and inflamed peritoneum. Plasminogen activator inhibitors (PAI) were detectable only in inflamed peritoneal cells (22). Other workers have shown the presence of PA and PAI in human PD effluent (23).
There is an ongoing presence of natural coagulant and fibrinolytic activity in the peritoneal cavity. There exists a need to ascertain whether, during peritoneal dialysis, the mesothelial fibrinolytic activity suffices to prevent fibrin deposition without the addition of exogenous fibrinolytics like heparin.
Two separate studies have recently addressed this problem.
Sitter and co-workers (24) compared levels of coagulation and fibrinolysis markers in PD effluents from patients without peritonitis in a 6-month interval (Group 1, n = 18) with those from patients with acute peritonitis (Group 2, n = 5).
The markers used were prothrombin fragments F1 and F2, (F1+2), thrombin-antithrombin III complex (TAT), and fibrin monomer (FM) (as parameters of ongoing coagulation), and fibrinogen degradation products (FDP), as a marker of fibrinolysis.
There was high fibrinolytic and coagulant activity not only during peritonitis but also in clinically stable patients. However, the balance between intraperitoneal generation and degradation of fibrin was disturbed in untreated patients in the group with peritonitis (Group 2) as evidenced by a higher FM/FDP ratio (61 vs 27). This indicated that during peritonitis increased fibrin formation resulted. Seven days after treatment with IP antibiotics and heparin all markers of coagulation and fibrinolysis normalized.
They then addressed the question of whether these changes during peritonitis could be explained by altered expression of PAs or PAI in the mesothelial cells. They measured levels of tissue-specific plasminogen activator (t-PA), urokinase-like plasminogen activator (u-PA), plasminogen inhibitors-1 (PAI-1), and tissue factor in mesothelial cells cultured under basal conditions, and exposed to TNFa, IL-1-a, LPS, and tissue factor. These studies showed that on exposure to inflammatory mediators, especially TNFa, cultured mesothelial cells down regulate t-PA production, and enhance expression of PAI-1 and tissue factor, hence tilting the balance in favor of coagulation in PD peritonitis. Thus an imbalance between IP coagulation and fibrinolysis during peritonitis in favor of coagulation does occur. But does it occur in all patients?
This question was addressed in a study by Nadig et al. (23), who collected 194 dialysate samples from 17 patients over a period of 24 months. They measured thrombin-antithrombin III (TAT) complexes as an indicator of thrombin formation, D-dimers as an indicator of fibrinolysis, and plasminogen activator inhibitor-1 (PAI-1). Samples were divided into three groups depending on the leukocyte count: no peritonitis (n = 117), mild peritonitis (n = 31), and severe peritonitis (n = 31). The results of the analysis are shown in Table I.
In the majority of the samples (Figure 1) there was linear correlation between the TAT-c and D-dimer levels. In 15 samples (Figure 2), 11 of which were from 2 patients with peritonitis, there was an imbalance between intraperitoneal coagulation and fibrinolysis; this was secondary to high PAI-1 activity ( >40 ng/mL). They concluded that routine IP heparin was not indicated even in the presence of peritonitis, and that low D-dimer levels in dialysate at initial sampling could identify the minority of cases that had an imbalance favoring coagulation.
Figure 1: Thrombin-antithrombin (TAT) complexes and D-dimers in 179 samples (62 peritonitis) with PAI-I levels £ 40 ng/mL (23).Figure 2: Thrombin-antithrombin (TAT) complex and D-dimers in 15 samples (11 peritonitis) with PAI-I levels ³ 40 ng/mL (23).Conclusion
There normally exists a balance between fibrinolytic and coagulant activity in the peritoneum during the stable state, as well as in the majority of cases with peritonitis. Heparin is effective in reducing fibrin formation, but at the risk of some systemic and local side effects. If the studies of Nadig and co-workers are further confirmed, the use of heparin should be restricted to the minority of patients with defects in fibrinolysis due to high levels of PAI-1. This subset could be identified by demonstrating low levels of D-dimer at the time of dialysate sampling.References
Sharad Goel, md, Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, 65212, USA.
Heparin, peritonitis, intraperitoneal, fibrinolytic, coagulationFrom:
Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, USA.Introduction
Peritoneal dialysis (PD) is the renal replacement modality for 16% of the end-stage renal disease (ESRD) population (1,2). During the course of regular PD, peritoneal fibrin is occasionally seen in the dialysate (3). However, this is more common when the course of disease is complicated by peritonitis. The appearance of fibrin in the PD effluent can lead to catheter blockage and, if excessive and unopposed, can in theory result in peritoneal adhesions and loss of peritoneal-membrane function (2). These complications, it is believed, can be prevented by the timely administration of intraperitoneal (IP) heparin. This belief, coupled with the perception that IP use of heparin is risk free, has made heparin the most common additive to PD fluid. The aim of this article is to re-examine the evidence for this practice.Heparin: structure and mode of action
Heparin is an acidic, anionic, sulfated glycosaminoglycan (GAG) of variable molecular weight (mean: 15000 d; range: 1800 - 30000). Only a portion of the molecule in commercial use contains a specific pentasaccharide sequence that is responsible for binding to antithrombin III (AT-III). This process causes conformational changes in AT-III resulting in a multifold increase in its inhibitory potential. This heparin-AT-III complex, besides inhibiting thrombin formation, causes inhibition of activated coagulation factors IX, X, XI, and XII as well.
Heparin also exerts its anticoagulatory actions by mechanisms independent of AT-III, such as HC-II binding to prothrombin, direct binding to coagulant factors, and release of endogenous GAGs with anticoagulant activity (4,5).
The mode of action of IP heparin is not precisely known. Studies (6,7) found that AT-III levels in the dialysate are normally 1.5% of the plasma levels (0.52 ± 0.1 mg/dL vs 33.6 ± 4 mg/dL), and this level is felt by some authors (6) to be too low to explain the anticoagulant action of heparin during stable PD. Others (7) feel that even these levels would suffice. During peritonitis there is a general outpouring of proteins into the peritoneal cavity resulting in a high level of AT-III (7). Whether heparin exerts its anticoagulant effect by AT-III-independent effects in the peritoneum is not known.
In 8 stable patients on continuous ambulatory peritoneal dialysis (CAPD) it was shown that heparin activity in dialysate decreased with time. With a dose of 2.5 U/mL to 5 U/mL the activity decreased by half of the initial level after 1 to 2 hours (7).Indications for IP heparin: standard practice
It is customary at most centers to add heparin whenever fibrin or blood or both is seen in the drainage bag. Fibrin formation is occasionally observed during routine dialysis, but more commonly when the PD catheter is being inserted and at the onset of peritonitis. Once started, heparin is added to each bag until the return-drainage dialysate is clear. Patients are educated on the appearance of fibrin and the method of administering heparin, and asked to call the dialysis center if the anticipated clearing of the dialysate does not occur.What dose of IP heparin to use?
Dosing is based on clinical observations, and varies from center to center with a range for CAPD/IPD (intermittent PD) of 100 to 2500 U/L of dialysate (1,2).
Gries et al. (8) observed the effect of two different heparin concentrations (7500 U/L and 500 U/L) on dialysate fibrinopeptide A (FPA) concentrations in 6 patients. FPA is a specific marker for thrombin action on fibrinogen, and hence of fibrin formation. Heparin given intraperitoneally reduced the fibrin production as measured by FPA; however, there was no difference in reduction of fibrin formation between the two different concentrations of heparin (FPA with 7500 U/L heparin: 20.6 ± 5.6 ng/mL; 500 U/L: 22.8 ± 6 ng/mL; no heparin: 152.2 ± 11.8 ng/mL). They demonstrated that the lower (500 U/L) of the two doses of heparin was sufficient to prevent the formation of fibrin. At the University of Missouri- Columbia our standard practice, therefore, is to use 500 U/L for both CAPD and IPD.Does IP heparin have a systemic effect?
The aim of IP instillation of heparin is to get a local fibrinolytic effect without systemic anticoagulation. The traditional view is that, with the doses used, virtually no heparin gets across the peritoneal membrane. Part of the reason for this could be the anionic charge of heparin and its large molecular weight. This view has been supported by studies that showed that, if administered as recommended, IP heparin had no effect on blood coagulation (7).
Pharmacokinetic studies addressing the question of heparin absorption across the peritoneum in humans are lacking. A study done in an animal model demonstrated significant recovery of heparin from systemic circulation. In this study 99-Tc-labeled heparin was given intraperitoneally along with dialysate in a New Zealand white rabbit model. Three different protocols were used: a single 15-minute cycle with heparin 500 U/L, 6 successive 15-minute cycles with heparin 500 U/L, and a single 3-hr cycle with heparin 2500 U/L. Labeled heparin was found in blood, organs, and urine. The total amount of recovery ranged from 1.5% to 20%, and depended on the amount of heparin used and the duration of its presence in the rabbit peritoneal cavity (9).
Interestingly, a patient on CAPD with deep-vein thrombosis (DVT) was successfully treated with low-molecular-weight heparin with resulting therapeutic antifactor-Xa activity in the plasma of 0.5 to 0.8 units. (Dose used: 6000 to 8000 antifactor Xa U/2-L dialysate bag, given four times a day) (10). Thus the belief that the absence of an effect of IP heparin on systemic coagulation implies an absence of transfer across peritoneal membrane may be inaccurate.Potential problems with adding IP heparin
The anticipated side effects expected from the use of IP heparin are mainly local ones. However, the knowledge that there is absorption of small amounts of heparin across the peritoneal membrane requires one to be alert to the possibility of systemic side effects, such as formation of heparin antibodies, with accompanying problems of thrombocytopenia (4), osteoporosis (11), and increase in transaminases (12).Locally, apart from the potential for increased infection, there is the possibility of mesothelial cell injury. During PD the mesothelial cell undergoes continuous sloughing and regeneration. Addition of heparin to human peritoneal mesothelial cell cultures inhibited their growth (13).
In a study on Staphylococcus epidermidis biofilm, heparin was shown to antagonize the antibacterial activity of rifampin (14). However no effect was seen on the activity of penicillin, cephalosporins, clindamycin, tobramycin, or vancomycin (15).
Having concluded that IP heparin use is not as risk-free as previously believed, it is time to take a fresh look at the rationale on which this practice is based, and the benefits obtained from it. The two questions that need to be asked are, first, does heparin inhibit fibrin formation? and, second, is there a need for a fibrinolytic agent?Does heparin reduce fibrin formation?
The answer to this question is an unequivocal yes.
Indirect evidence for this was first provided by showing that higher dialysate-inflow and -outflow rates were achieved in 6 patients on CAPD when heparin was added to the dialysate, compared to when it was not (16). This was confirmed by measuring fibrinogen-A in the dialysate from patients on PD (17). Gries et al. were able to show that the addition of heparin (500 U/L) reduced fibrin formation (FP-A) from 153.4 ± 16.8 ng/mL to 11.6 ± 2.6 ng/mL (P < 0.05) in the dialysate (17).
This was also confirmed by Tabata and co-workers (18).Is exogenous fibrinolysis required?
A not very well recognized fact is that the peritoneal mesothelium has synthetic activity. It is involved in the synthesis and secretion of mesothelial surface fluids, which are responsible for the phenomenon of boundary lubrication of slowly moving surfaces. This liquid consists of phospholipids, mainly phosphatidylcholine and serine, with high surfactant and water-repelling properties (19,20).
The mesothelium of rats and guinea pigs has been shown to have fibrinolytic activity. Heparin is not synthesized by the mesothelial cells, but other GAGs, such as hyaluron, are.
In vitro, pure human mesothelial cells deprived of the underlying subserosa were shown to have fibrinolytic activity (21). Tissue-specific and urokinase-like plasminogen-activators (t-PA, u-PA) could be detected in normal and inflamed peritoneum. Plasminogen activator inhibitors (PAI) were detectable only in inflamed peritoneal cells (22). Other workers have shown the presence of PA and PAI in human PD effluent (23).
There is an ongoing presence of natural coagulant and fibrinolytic activity in the peritoneal cavity. There exists a need to ascertain whether, during peritoneal dialysis, the mesothelial fibrinolytic activity suffices to prevent fibrin deposition without the addition of exogenous fibrinolytics like heparin.
Two separate studies have recently addressed this problem.
Sitter and co-workers (24) compared levels of coagulation and fibrinolysis markers in PD effluents from patients without peritonitis in a 6-month interval (Group 1, n = 18) with those from patients with acute peritonitis (Group 2, n = 5).
The markers used were prothrombin fragments F1 and F2, (F1+2), thrombin-antithrombin III complex (TAT), and fibrin monomer (FM) (as parameters of ongoing coagulation), and fibrinogen degradation products (FDP), as a marker of fibrinolysis.
There was high fibrinolytic and coagulant activity not only during peritonitis but also in clinically stable patients. However, the balance between intraperitoneal generation and degradation of fibrin was disturbed in untreated patients in the group with peritonitis (Group 2) as evidenced by a higher FM/FDP ratio (61 vs 27). This indicated that during peritonitis increased fibrin formation resulted. Seven days after treatment with IP antibiotics and heparin all markers of coagulation and fibrinolysis normalized.
They then addressed the question of whether these changes during peritonitis could be explained by altered expression of PAs or PAI in the mesothelial cells. They measured levels of tissue-specific plasminogen activator (t-PA), urokinase-like plasminogen activator (u-PA), plasminogen inhibitors-1 (PAI-1), and tissue factor in mesothelial cells cultured under basal conditions, and exposed to TNFa, IL-1-a, LPS, and tissue factor. These studies showed that on exposure to inflammatory mediators, especially TNFa, cultured mesothelial cells down regulate t-PA production, and enhance expression of PAI-1 and tissue factor, hence tilting the balance in favor of coagulation in PD peritonitis. Thus an imbalance between IP coagulation and fibrinolysis during peritonitis in favor of coagulation does occur. But does it occur in all patients?
This question was addressed in a study by Nadig et al. (23), who collected 194 dialysate samples from 17 patients over a period of 24 months. They measured thrombin-antithrombin III (TAT) complexes as an indicator of thrombin formation, D-dimers as an indicator of fibrinolysis, and plasminogen activator inhibitor-1 (PAI-1). Samples were divided into three groups depending on the leukocyte count: no peritonitis (n = 117), mild peritonitis (n = 31), and severe peritonitis (n = 31). The results of the analysis are shown in Table I.
In the majority of the samples (Figure 1) there was linear correlation between the TAT-c and D-dimer levels. In 15 samples (Figure 2), 11 of which were from 2 patients with peritonitis, there was an imbalance between intraperitoneal coagulation and fibrinolysis; this was secondary to high PAI-1 activity ( >40 ng/mL). They concluded that routine IP heparin was not indicated even in the presence of peritonitis, and that low D-dimer levels in dialysate at initial sampling could identify the minority of cases that had an imbalance favoring coagulation.
Figure 1: Thrombin-antithrombin (TAT) complexes and D-dimers in 179 samples (62 peritonitis) with PAI-I levels £ 40 ng/mL (23).Figure 2: Thrombin-antithrombin (TAT) complex and D-dimers in 15 samples (11 peritonitis) with PAI-I levels ³ 40 ng/mL (23).Conclusion
There normally exists a balance between fibrinolytic and coagulant activity in the peritoneum during the stable state, as well as in the majority of cases with peritonitis. Heparin is effective in reducing fibrin formation, but at the risk of some systemic and local side effects. If the studies of Nadig and co-workers are further confirmed, the use of heparin should be restricted to the minority of patients with defects in fibrinolysis due to high levels of PAI-1. This subset could be identified by demonstrating low levels of D-dimer at the time of dialysate sampling.References
- Nolph KD, Gokal R, eds. The textbook of peritoneal dialysis. 1st ed. Dordrecht, Boston, London: Kluwer Academic, 1994.
- Oreopoulos DG, Robson M, Faller B, Oglivie R, Rapoport A, deVeber GA. Continuous ambulatory peritoneal dialysis: a new era in the treatment of chronic renal failure. Clin Nephrol 1979; 11:1258.
- Gries E, Paar D, Graben N, Bock KD. Intraperitoneal heparin in peritoneal dialysate and its effect on fibrinopeptide A in the plasma and the dialysate. Hemostasis 1989; 1:215.
- Stiekema JCJ. Heparin and its biocompability. Clin Nephrol 1986; 26(Suppl 1):S38.
- Freedman MD. Pharmacodynamics, clinical indications and adverse effects of heparin. J Clin Pharmacol 1992; 32:58496.
- Furman KI, Comperts ED, Hockley J. Activity of intraperitoneal heparin during peritoneal dialysis Clin Nephrol 1978; 9:1518.
- Takahashi S, Shimada A, Okada K, Kuno T, Nagura Y, Hatano M. Effect of intraperitoneal administration of heparin to patients on continuous ambulatory peritoneal dialysis (CAPD). Perit Dial Int 1991; 11:813.
- Gries E, Paar D, Graben N, Bock KD. How much heparin intraperitoneally is necessary in CAPD? Nephron 1988; 9:256.
- Canavese C, Salomone M, Mangiarotti G, et al. Heparin transfer across the rabbit peritoneal membrane. Clin Nephrol 1986; 26:11620.
- Schrader J, Tonnis HJ, Scheler F. Long-term intraperitoneal application of low molecular weight heparin in a continuous ambulatory peritoneal dialysis patient with deep vein thrombosis. Nephron 1986; 42:834.
- Sackler JP, Liu L. Heparin induced osteoporosis. Br J Radiol 1973; 46:54850.
- Saffle JR, Russo J, Dukes GE, Warden OD. The effect of low dose heparin on serum platelets and transaminase levels. Surg Res 1980; 28:297305.
- Tsai T-J , Yen C-J, Fang C-C, Yang C-C, Lee P-H, Yen T-S. Effect of intraperitoneally administered agents on human peritoneal mesothelial cell growth. Nephron 1995; 71(1):238.
- Gagnon RF , Harris AD, Prentis J, Richards GK. The effects of heparin on rifampin activity against Staphylococcus epidermidis biofilms. In: Khanna R, Nolph KD, Prowant BF, Twardowski ZJ, Oreopoulos DG, eds. Advances in peritoneal dialysis. Toronto: Peritoneal Dialysis Bulletin, 1989; 5:13842.
- Sewell DL, Golper TA, Brown SD, Nelson E, Knower M, Kimbrough RC. Stability of single and combined antimicrobial agents in various peritoneal dialysates in the presence of insulin and heparin. Am J Kidney Dis 1983; 3(3):20912.
- Thayssen P , Pindborg T. Peritoneal dialysis and heparin. Scand J Urol Nephrol 1978; 12:734.
- Gries E, Paar D, Graben N, Bock KD. Intraperi-toneal fibrin-formation and its inhibition in CAPD. Clinical Nephrol 1986; 26:20912.
- Tabata T, Shimada H, Emoto M, Morita A, Furumitsu Y, Fujita J, et al. Inhibitory effect of heparin and/or antithrombin III on intraperitoneal fibrin formation in continuous ambulatory perito-neal dialysis. Nephron 1990; 56:3915.
- Hills BA, Butler BD, Barrow RE. Boundary lubri-cation imparted by pleural surfaces and their identification. J Appl Physiol 1982; 53:463-9.
- DiPaolo N. The peritoneal mesothelium: an excretory organ. Perit Dial Bull 1989; 9:1513.
- Whitaker D, Papadimitriou M, Walters M. The mesothelium: its fibrinolytic properties. J Pathol 1982; 136:2919.
- Vipond MN, Whawell SA, Thompson JN, Dudley HAF. Peritoneal fibrinolytic activity and intra-abdominal adhesions. Lancet 1990; 335:11202.
- Nadig C, Binswanger U, von Felten A. Is heparin therapy necessary in CAPD peritonitis? Perit Dial Int 1997; 17:4936.
- Sitter T, Spannagal M, Schiffl H, Held E, van Hinsberg VW, Kooistra T. Imbalance between intraperitoneal coagulation and fibrinolysis during peritonitis of CAPD patients: the role of mesothelial cells. Nephrol Dial Transplant 1995; 10:67783.
Sharad Goel, md, Division of Nephrology, University Hospital and Clinics, Columbia, Missouri, 65212, USA.
HEPARIN AND THE PERITONEAL MEMBRANE
+Author Affiliations
- Division of Nephrology, St. Joseph's Hospital Department of Medicine, McMaster University Hamilton, Ontario, Canada
- e-mail: [email protected]
Next Section
An original article in this issue of Peritoneal Dialysis Internationaldescribes a rodent model of peritoneal dialysate exposure in which the effect of chronic heparin administration is evaluated (1). Schilte and colleagues use a daily infusion of 3.86% glucose conventional peritoneal dialysis (PD) fluid through a tunneled catheter over 5 weeks. They identify a number of changes that developed in the peritoneal tissue in response to chronic exposure to peritoneal dialysate. Peritoneal fluid was supplemented with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) and a control group was treated with dialysis fluid only. Of note, the addition of heparin did not appear to ameliorate the damage induced by peritoneal fluid exposure.
Heparin is a variable mixture of sulfated disaccharide polymers and is a member of the glycosaminoglycan family, which includes keratan sulfate, dermatan sulfate, chondroitin sulfate, heparan sulfate, and hyaluronic acid. Heparin binds to antithrombin and induces a conformational change that allows for the binding and inactivation of enzymes involved in the coagulation pathway, such as thrombin and factor Xa (2). Heparin was first discovered in 1916 and was purified for clinical use by the Connaught Laboratories, Toronto, which is famous for production of insulin (3).
LMWH is manufactured through the depolymerization of UFH. The longer polysaccharide chains in UFH are important for providing a scaffold to support the interaction between thrombin and antithrombin. This scaffold is not required for the interaction between factor Xa and antithrombin (3). Aside from greater bioavailability, LMWH has greater anti-factor Xa activity than antithrombin effect.
There are numerous reports of heparins having effects beyond anticoagulation. Anticoagulation has been widely used in patients with cancer, with some unexpected improvements in overall mortality rates reported in some studies (4). Heparin, through inhibition of thrombin and fibrin deposition, may inhibit the necessary environment for tumor cells and their associated blood vessels to develop (4). Heparin may have direct antiangiogenic properties through binding of endostatin (2). Heparin also blocks endothelial P-selectin and may thus impair metastatic seeding (5). There is some evidence that heparin, especially LMWH, may interfere with growth factors binding to their receptors, thus inhibiting cellular proliferation (4). Specifically, LMWH can inhibit fibroblast growth factor and vascular endothelial growth factor activity (5).
Heparin has been shown to have anti-inflammatory properties. Several mechanisms have been demonstrated, including inhibition of production of tumor necrosis factor-alpha (6), binding to P-selectin to inhibit leukocyte migration, and systemic release of tissue factor pathway inhibitor (7). Heparin inhibits the production of reactive oxygen species (8) and has a vasodilatory effect through increased production of nitric oxide (9).
All this provides ample rationale for the study of heparin in PD. Specifically, the peritoneum is subjected to inflammation, angiogenesis, and fibrosis during the course of PD therapy (10). These changes are associated with increased solute transport, which in turn is associated with ultrafiltration dysfunction (11) and increased mortality risk (12). Therefore, the anti-inflammatory and antiangiogenic properties of heparin are of possible value in preventing the complications of long-term peritoneal membrane injury. Furthermore, heparin is already used intermittently in PD patients during episodes of peritonitis and when fibrin is observed in the PD effluent.
The fibrin inhibitory effect of heparin may have benefits for long-term PD patients beyond the usual use in maintenance of catheter patency. It is known that the first steps in wound healing involve platelet aggregation and subsequent blood clotting. This fibrin-rich clot provides a matrix to support angiogenesis and migration of fibroblasts (13). Honda and Oda have demonstrated that fibrin deposition occurs at the surface of the fibrous adhesions seen in encapsulating peritoneal sclerosis (EPS) (14). From these observations it was concluded that fibrin deposition is a “key event in the pathogenesis of EPS” (14). Ongoing exudation of fibrinogen from these vessels and subsequent fibrin deposition without dilution and washing with PD fluid may explain the increased incidence of EPS after cessation of PD therapy.
There are few in vitro studies of heparin in PD. One worrisome observation was made by Manalaysay and colleagues: they found that heparin had inhibitory effects on mesothelial cell growth and protein production (15). This was confirmed by a second study (16).
As outlined by Schilte and colleagues (1), other animal studies have been carried out using chronic exposure to glucose-based dialysis fluids supplemented with heparin. Pawlaczyk and colleagues treated rats daily with dialysis fluid (17). They found that heparin increased ultrafiltration at an early time point in the experiment (day 10) but had minimal effect by day 30. Solute transport, measured by glucose absorption, was not different between groups.
Bazargani and colleagues carried out an interesting study with a single intraperitoneal (IP) infusion of dialysis fluid supplemented with LMWH (18). They used both direct IP injection and injection via an indwelling catheter. LMWH reduced inflammation and increased ultrafiltration in this experiment. The presence of the catheter induced complement activation, which was not inhibited by heparin.
De Vriese and colleagues compared the effects of IP heparin administration with a heparin-coated catheter and found that the heparin-coated catheter optimally preserved catheter function (19). This observation was supported by another study by Zareie and colleagues (20). Opposed to these observations, Kim and colleagues studied the effects of heparinized PD catheters in a rat model of daily dialysis exposure (21). This study was essentially negative for an effect on biofilm formation, exit-site changes, and peritonitis rates.
Human studies are similarly few and with mixed results. The LMWH tinzaparin was administered IP and membrane transport was assessed in a double-blind crossover study of 21 PD patients (22). In that 3-month study, solute transport was significantly reduced with LMWH [16% reduction in dialysate-to-plasma ratio (D/P) of creatinine], with a significant increase in ultrafiltration. Only 11 patients completed the study. The authors did not observe any bleeding complications. Peritonitis rates were very high in this study, related possibly to the need to add heparin to the dialysate fluids. In a second publication from this same patient sample, Sjoland and colleagues observed a decrease in systemic and IP inflammatory markers in patients treated with LMWH (23).
Mizuiri and colleagues treated 11 stable chronic PD patients with 5000 U heparin in the long dwell over 60 days (24). They were interested mainly in the effect of heparin on the formation of advanced glycation end products (AGEs). Interestingly, they found an increase in AGEs in the peritoneal effluent with IP heparin treatment. This was associated with increased D/P urea and creatinine. This was not a randomized trial and the changes in peritoneal AGEs and solute transport may not have been related to administration of heparin. Ponce and colleagues also observed an increase in solute transport in a single-dwell study using UFH (25).
The rationale therefore for routine IP heparin use in PD patients is strong. In vitro, animal, and human studies all demonstrate mixed results. Some variability in the observed results may be related to dose and systemic bioavailability. Schilte and colleagues observed limited effects of IP heparin on parameters of systemic coagulation (1). This has also been observed in patients on continuous ambulatory PD being treated with IP heparin (26). De Vriese and colleagues observed local accumulation of heparin in the peritoneal tissues (19). The purported anti-inflammatory effects of heparin, such as binding to P-selectin, may require systemic distribution to be effective. The one positive clinical trial used tinzaparin, a LMWH that may have better systemic bioavailability when delivered IP (22).
What does the Schilte study add to our understanding of chronic IP heparin use in PD patients? Despite certain limitations, that careful study clearly demonstrates that UFH or LMWH administration does not ameliorate the peritoneal membrane damage induced by exposure to high-glucose bioincompatible PD solution. We study animal models for two main reasons: to answer basic biological questions and as a prelude to human clinical studies. The study by Schilte and colleagues was carefully carried out and the results analyzed appropriately. Does this study provide insight into the activity and mechanism of heparin in the peritoneum? Clearly, UFH and LMWH did not have a beneficial effect on the peritoneal membrane. With evidence for antithrombin, anti-inflammatory, and antiangiogenic activity of heparin, the remaining question is, Why was heparin not effective in this model? Is the nature of the inflammatory response in the rodent model with an indwelling catheter different to what would be observed in the peritoneum of PD patients (18)? Was the dose of heparin used too low? Is a greater systemic exposure required for an anti-inflammatory action? Would different results be found if the model were optimized [perhaps with heparinized catheters and antibiotics (19)] to limit catheter malfunction? Antithrombin levels in the rodent peritoneum were not assessed in this experiment. In the noninflamed human peritoneum, antithrombin levels are very low (27), which may limit the effect of heparin as an anti-fibrin agent. Finally, heparin was not used during the terminal dwell, so an acute effect of heparin on peritoneal solute transport was not assessed. Future carefully conducted animal studies may help answer some of these questions and provide further mechanistic insights into the role of IP heparin in PD patients.
The second issue is whether this animal study will influence future clinical investigation. Animal models of chronic PD fluid exposure have been refined over time and have yielded important insights into peritoneal membrane injury. Can these concepts be directly translated to PD patients? The one positive clinical study by Sjoland and colleagues was very small (11 patients completed the study) and of limited duration (3 months of exposure) (22). However, the findings were strikingly positive, with a decrease in D/P creatinine of about 0.1, which, according to a recent meta-analysis (12), could potentially translate into a 15% reduced mortality risk. Clearly, there are risks with heparin therapy. LMWH has been associated with increased bleeding risk in patients with end-stage kidney disease (28). Heparin binds platelet-activating factor 4. This complex is antigenic in some people and may cause heparin-induced thrombocytopenia, a rare and serious side effect of heparin administration. More recently, heparin contaminated with over-sulfated chondroitin sulfate made its way into clinical use, leading to several well publicized deaths (29). Finally, the Sjoland study demonstrated a very high risk of peritonitis, perhaps from repeatedly adding heparin into the dialysis fluid (22). With potential risks and benefits weighed, it would still be reasonable to repeat the Sjoland study to confirm or refute these benefits.
Despite the additional insight provided by the Schilte study, the potential long-term benefits of heparin, especially LMWH, as a dialysate additive in PD patients remains to be elucidated.
- © 2009 International Society for Peritoneal Dialysis
Diabetics with end-stage renal disease.
ORIGINAL ARTICLE
Continuous Ambulatory Peritoneal Dialysis in Diabetics with End-Stage Renal DiseasePablo Amair, M.D., Ramesh Khanna, M.D., Bernard Leibel, M.D., Andreas Pierratos, M.D., Stephen Vas, M.D., Ph.D., F.R.C.P.(C), Erik Meema, M.D., F.R.C.P.(C), Gordon Blair, B.Sc., M.D., F.R.C.P.(C), Lionel Chisolm, M.D., F.R.C.S.(C), Magdalene Vas, M.D., Walter Zingg, M.D., George Digenis, M.D., and Dimitrios Oreopoulos, M.D., F.A.C.P.
N Engl J Med 1982; 306:625-630March 18, 1982DOI: 10.1056/NEJM198203183061101
AbstractTwenty diabetics with end-stage renal disease who had never previously received dialysis treatment were treated with continuous ambulatory peritoneal dialysis for periods of two to 36 months (average, 14.5). Intraperitoneal administration of insulin achieved good control of blood sugar. Even though creatinine clearance decreased significantly (P = 0.001), control of blood urea nitrogen and serum creatinine was adequate. Hemoglobin and serum albumin levels increased significantly (P = 0.005 and 0.04, respectively). Similarly, there was a significant increase in serum triglycerides and alkaline phosphatase (P = 0.02 and 0.05). Blood pressure became normal without medications in all but one of the patients. Retinopathy, neuropathy, and osteodystrophy remained unchanged. Peritonitis developed once in every 20.6 patient-months — a rate similar to that observed in nondiabetics. The calculated survival rate was 93 per cent at one year; the calculated rate of continuation on ambulatory peritoneal dialysis was 87 per cent.
We conclude that continuous ambulatory dialysis with intraperitoneal administration of insulin is a good alternative treatment for diabetics with end-stage renal disease. (N Engl J Med. 1982; 306:625–30.)
Continuous Ambulatory Peritoneal Dialysis in Diabetics with End-Stage Renal DiseasePablo Amair, M.D., Ramesh Khanna, M.D., Bernard Leibel, M.D., Andreas Pierratos, M.D., Stephen Vas, M.D., Ph.D., F.R.C.P.(C), Erik Meema, M.D., F.R.C.P.(C), Gordon Blair, B.Sc., M.D., F.R.C.P.(C), Lionel Chisolm, M.D., F.R.C.S.(C), Magdalene Vas, M.D., Walter Zingg, M.D., George Digenis, M.D., and Dimitrios Oreopoulos, M.D., F.A.C.P.
N Engl J Med 1982; 306:625-630March 18, 1982DOI: 10.1056/NEJM198203183061101
AbstractTwenty diabetics with end-stage renal disease who had never previously received dialysis treatment were treated with continuous ambulatory peritoneal dialysis for periods of two to 36 months (average, 14.5). Intraperitoneal administration of insulin achieved good control of blood sugar. Even though creatinine clearance decreased significantly (P = 0.001), control of blood urea nitrogen and serum creatinine was adequate. Hemoglobin and serum albumin levels increased significantly (P = 0.005 and 0.04, respectively). Similarly, there was a significant increase in serum triglycerides and alkaline phosphatase (P = 0.02 and 0.05). Blood pressure became normal without medications in all but one of the patients. Retinopathy, neuropathy, and osteodystrophy remained unchanged. Peritonitis developed once in every 20.6 patient-months — a rate similar to that observed in nondiabetics. The calculated survival rate was 93 per cent at one year; the calculated rate of continuation on ambulatory peritoneal dialysis was 87 per cent.
We conclude that continuous ambulatory dialysis with intraperitoneal administration of insulin is a good alternative treatment for diabetics with end-stage renal disease. (N Engl J Med. 1982; 306:625–30.)
Glucose absorption during continuous ambulatory peritoneal dialysis.
Glucose absorption during continuous ambulatory peritoneal dialysis. Patients undergoing continuous ambulatory peritoneal dialysis (CAPD) are exposed to a continuous infusion of glucose via their peritoneal cavity. We performed studies to quantitate the amount of energy derived from dialysate glucose. Net glucose absorption averaged 182 (sd) 61 g/day in 19 studies with a dialysate dextrose concentration of 1.5 or 4.25 g/dl. The amount of glucose absorbed per liter of dialysate (y) varied with the concentration of glucose in dialysate (x), (y = 11.3x - 10.9, r = 0.96), The amount of glucose absorbed per day during a given dialysis regimen was constant. Energy intake from dialysate glucose was 8.4 2.8 kcal/kg of body wt per day, or 12 to 34% of total energy intake. This additional energy may contribute to the anabolic effect reported during CAPD. The ability to vary glucose absorption by altering the dialysate glucose concentration may prove a useful tool to modify energy intake.
Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis.
Metabolic balance studies and dietary protein requirements in patients undergoing continuous ambulatory peritoneal dialysis. Balance studies for nitrogen, potassium, magnesium, phosphorus, and calcium were carried out in eight men undergoing continuous ambulatory peritoneal dialysis (CAPD) to determine dietary protein requirements and mineral balances. Patients were fed high energy diets for 14 to 33 days which provided either 0.98 (seven studies) or 1.44 g (six studies) of primarily high biological value protein/kg body wt/day. Mean nitrogen balance was neutral with the lower protein diet (+0.35 0.83 sem g/day) and strongly positive with the higher protein diet (+2.94 0.54 g/day). With the higher protein diet the balances for potassium, magnesium, and phosphorus were strikingly positive, there was an increase in body weight in all patients, and a rise in mid-arm muscle circumference in five of the six patients. The relation between protein intake and nitrogen balance suggests that the daily protein requirement for clinically stable CAPD patients should be at least 1.1 g/kg/day; to account for variability among subjects 1.2 to 1.3 g protein/kg/day is probably preferable. Potassium balance correlated directly with nitrogen balance (r = 0.81). High fecal potassium losses (19 1.2 mEq/day) in all patients probably helped maintain normal serum potassium concentrations. Mean serum magnesium was increased (3.1 0.1 mg/dl), and magnesium balances were positive suggesting that the dialysate magnesium of 1.85 mg/dl is excessive. The net gain of calcium from dialysate was 84 18 mg/day; this correlated inversely with serum calcium levels (r = -0.90).
Bilans métaboliques et besoins protéiques alimentaires de malades en dialyse péritonéale continue ambulatoire. Des études de bilan de l'azote, du potassium, du magnésium, du phosphore et du calcium, étaient fait en sept hommes en dialyse péritonéale continue ambulatoire (CAPD), pour déterminer leurs besoins protéiques alimentaires et leur bilan minéral. Les malades ont reçu pendant 14 à 33 jours des régimes hautement énergétiques, apportant soit 0,98 (sept études), soit 1,44 g (six études) de protéines de haute valeur biologique par kg de poids et par jour. Le bilan azoté moyen etait nul avec le régime comportant la plus faibie teneur protéique (+ 0,35 0,88 g/j sem) et était fortement positive avec le régime à plus forte teneur protéique (+2,94 0,54 g/j). Avec le régime à haute teneur en protéine, les bilans potassique, magnésien et phosphoré étaient fortement positifs; le poids corporel s'est élevé chez tous les malades; la circonférence musculaire mesurée du milieu du bras a augmenté chez cinq sur six malades. La relation existant entre l'apport protéique et le bilan azoté suggère que les besoins journaliers en protéines pour des malades cliniquement stables en CAPD devraient être au moins de 1,1 g/kg/j; 1,2 à 1,3 g de protéines/kg/j sont sans doute préférables pour tenir compte de la variabilité entre les sujets. Le bilan potassique était directement corrélé avec la balance azotée (r = 0,81). De fortes pertes potassiques fécales (19 1,2 mEq/j) chez tous les malades ont probablement contribué à maintenir normales les concentrations sériques du potassium. La magnésémie moyenne était élevée (3,1 0,1 mg/dl), et les bilans magnésiens aient positifs suggérant que le magnésium du dialysat (1,85 18 mg/dl) était trop élevé. Le gain net en calcium à partir du dialysat était de 84 18 mg/j; ce gain était inversement corrélé avec la calcémie (r = 0,90).
Bilans métaboliques et besoins protéiques alimentaires de malades en dialyse péritonéale continue ambulatoire. Des études de bilan de l'azote, du potassium, du magnésium, du phosphore et du calcium, étaient fait en sept hommes en dialyse péritonéale continue ambulatoire (CAPD), pour déterminer leurs besoins protéiques alimentaires et leur bilan minéral. Les malades ont reçu pendant 14 à 33 jours des régimes hautement énergétiques, apportant soit 0,98 (sept études), soit 1,44 g (six études) de protéines de haute valeur biologique par kg de poids et par jour. Le bilan azoté moyen etait nul avec le régime comportant la plus faibie teneur protéique (+ 0,35 0,88 g/j sem) et était fortement positive avec le régime à plus forte teneur protéique (+2,94 0,54 g/j). Avec le régime à haute teneur en protéine, les bilans potassique, magnésien et phosphoré étaient fortement positifs; le poids corporel s'est élevé chez tous les malades; la circonférence musculaire mesurée du milieu du bras a augmenté chez cinq sur six malades. La relation existant entre l'apport protéique et le bilan azoté suggère que les besoins journaliers en protéines pour des malades cliniquement stables en CAPD devraient être au moins de 1,1 g/kg/j; 1,2 à 1,3 g de protéines/kg/j sont sans doute préférables pour tenir compte de la variabilité entre les sujets. Le bilan potassique était directement corrélé avec la balance azotée (r = 0,81). De fortes pertes potassiques fécales (19 1,2 mEq/j) chez tous les malades ont probablement contribué à maintenir normales les concentrations sériques du potassium. La magnésémie moyenne était élevée (3,1 0,1 mg/dl), et les bilans magnésiens aient positifs suggérant que le magnésium du dialysat (1,85 18 mg/dl) était trop élevé. Le gain net en calcium à partir du dialysat était de 84 18 mg/j; ce gain était inversement corrélé avec la calcémie (r = 0,90).