|Year : 2016 | Volume
| Issue : 6 | Page : 1194-1199
|Effect of intraperitoneal injection of sulodexide on peritoneal function and albumin leakage in continuous ambulatory peritoneal dialysis patients
Yosra Guedri1, K Najla Damma1, Melek Toumi2, Wissal Sahtout1, Awatef Azzabi1, Sinda Mrabet1, Safa Nouira1, Dalila Saidane2, Samira Amor1, Anis Belarbia1, Dorsaf Zellama1, Abdellatif Achour1
1 Department of Nephrology, Dialysis and Transplantation, Sahloul Hospital, Sousse, Tunisia
2 Faculty of Pharmacy, Monastir, Tunisia
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|Date of Web Publication||28-Nov-2016|
| Abstract|| |
Peritoneal protein loss is one of the inevitable consequences during continuous ambulatory peritoneal dialysis (CAPD). Our objective was to study the effect of sulodexide on the protein loss and efficiency of dialysis. This study included six patients receiving CAPD treated with sulodexide at the dose of 600 IU/day given by intraperitoneal injection for 10 days. Clinical and biologic parameters were assessed before starting the treatment (D0 and after 10 days of treatment (D10. We also evaluated the benefit of therapy persisting 20 days after the end of treatment (D30. The sulodexide administration produced a significant improvement of the peritoneal function as determined by a significant increase in the following ratios measured at the 4 th h of dwell time on D0 and D30: dialysate-to plasma (D/P) creatinine from 0.63 ± 1.45 to 0.85 ± 0.073 (P = 0.028) and D/P urea from 0.63 ± 0.15 to 79 ± 0.2 (P = 0.048). A significant decrease of albumin leakage was observed, which was 0.90 ± 0.40 g/L at baseline, 0.67 ± 0.36 g/L on the 10 th day, and 0.43 ± 0.22g/L 20 days after the end of treatment. Within 10-day treatment period, use of sulodexide resulted in a reduction in the peritoneal loss of albumin, in addition to improvement of the quality of dialysis and the residual renal function among these patients.
|How to cite this article:|
Guedri Y, Damma K N, Toumi M, Sahtout W, Azzabi A, Mrabet S, Nouira S, Saidane D, Amor S, Belarbia A, Zellama D, Achour A. Effect of intraperitoneal injection of sulodexide on peritoneal function and albumin leakage in continuous ambulatory peritoneal dialysis patients. Saudi J Kidney Dis Transpl 2016;27:1194-9
|How to cite this URL:|
Guedri Y, Damma K N, Toumi M, Sahtout W, Azzabi A, Mrabet S, Nouira S, Saidane D, Amor S, Belarbia A, Zellama D, Achour A. Effect of intraperitoneal injection of sulodexide on peritoneal function and albumin leakage in continuous ambulatory peritoneal dialysis patients. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Jan 26];27:1194-9. Available from: http://www.sjkdt.org/text.asp?2016/27/6/1194/194611
| Introduction|| |
Peritoneal dialysis (PD) is an effective form of renal replacement therapy that is currently being used by approximately 11% of the global dialysis population. A morphologically and functionally intact peritoneum is required for a prolonged and effective use of the PD. 
The cumulative dose of glucose used, repeated episodes of infection, the bio-incompatibility of dialysis solutions, uremia, and chronic inflammation, all these play a major role in the changes of the peritoneal function.  The consequence of these changes results in inadequate dialysis with loss of ultrafiltration capacity and PD efficiency due to the increase of the exchange surface of the peritoneal capillaries and development of peritoneal fibrosis.  Although the mechanisms of morphological alterations of the peritoneum are not completely understood, the growth factors and cytokines secreted by mesothelial cells, macrophages, and fibroblasts were found to be related to peritoneal fibrosis.
The protein leak, which is an undesirable, but inevitable, effect of the PD, is observed from the beginning of the treatment with an average excretion of 5-15 g/day, but its importance is directly related to the alteration of the peritoneal membrane. ,
It has been shown that peritoneal protein loss is an independent predictor of survival in patients starting treatment with PD and a marker of endothelial dysfunction.  This has necessitated pharmacological interventions that can prevent or delay the alterations of the peritoneal membrane and thus reduce the leakage of albumin.
The administration of glycosaminoglycans (GAGs) such as sulodexide has demonstrated a preventive effect in diabetic nephropathy by maintaining the thickness of the glomerular basement membrane with consequent prevention of the onset of albuminuria or at least its reduction. In a similar manner, it has been reported that GAGs have a protective effect on the structure and the function of peritoneum with consequent reduction of the protein leakage in PD patients. ,,,
Given the importance of maintaining the integrity of the peritoneal membrane, we conducted this study to test the effect of a GAG (sulodexide) on the protein loss and the dialysis efficiency.
| Patients and Methods|| |
Six patients (three women and three men) with a mean age of 28.5 ± 11.2 years, treated in the Nephrology Department of Sahloul University Hospital, Tunisia, were randomly selected from patients on long-term continuous ambulatory PD (CAPD) for at least more than three months. For patients followed up for less than six months (between 3 and 6 months) only those with no episodes of peritonitis were accepted for inclusion and among those who were on CAPD for more than 6 months, only one episode of peritonitis was acceptable and none in the last six months before the study.
End-stage renal failure was due to chronic glomerulonephritis in one case and to chronic interstitial nephropathy in the remaining cases. No patients had diabetes mellitus, liver insufficiency, thrombocytopenia, or known sensitivity to GAGs and/or heparin. All patients gave written informed consent to participate in the study.
The dialysis program consisted of three 2000 mL isotonic bags containing: glucose 75.5 mmol/L, sodium 132 mEq/L, magnesium 1.5 mEq/L, bicarbonate 35 mEq/L, chlorine 102 mEq/L, and calcium 3.5 mEq/L with an intraperitoneal dwell time of 4 h for the day exchanges and one 2000 mL mediotonic bag containing glucose 126 mmol/L for the long night dwell.
Sulodexide was the GAG used in our study at the dose of 600 IU/day during 10 days given by intraperitoneal injection.
Urea, creatinine, and glucose were measured using the urease enzymatic method, creatinase, and glucose oxidase methods, respectively.
Albumin loss was determined by its level in the drained fluid after 4 h stasis (T4h) by using turbidimetry with the help of a specific antialbumin antibody, before starting (D0) the treatment and after 10 days of the treatment (D10). In addition, we evaluated the persistence of benefit of therapy, 20 days after the end of treatment (D30).
The dialysate-to plasma (D/P) ratios for urea, creatinine, albumin, and the clearance of creatinine were measured at T4h. PD was considered adequate if it had a value of Kt/V >1.7 and a peritoneal clearance value greater than weekly creatinine at 45 L/week/1.73 m 2.  Statistical analysis was performed with Statistical Package for the Social Sciences software (Version 19.0. Armonk, NY). Wilcoxon test was used for the comparison of paired samples of the biochemical values of the samples collected at 4 h at the initiation (D0), the 10 th day of treatment (D10), and the 30 th day (D30).
| Results|| |
The comparison of clinical and laboratory parameters in patients treated with sulodexide is shown in [Table 1].
Effect of sulodexide on residual renal function and quality of peritoneal dialysis
Our results show that treatment with sulodexide produced improvement in dialysis adequacy evaluated by the Kt/V, but this was not statistically significant. However, a significant improvement was seen between the peritoneal creatinine clearance values at the initiation of therapy and the 30 th day [Table 2]. In addition, the treatment with sulodexide resulted in a statistically significant increase in the improvement of the residual renal function (RRF) [Table 3].
|Table 2: Effect of Sulodexide on proteinuria and peritoneal albumin leakage.|
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|Table 3: Effects of Sulodexide on peritoneal function quality of PD and on RRF.|
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In addition to the improvement of quality of dialysis in our patients, sulodexide also produced a significant improvement of the peritoneal function determined by a significant increase in the following ratios: D/P creatinine and D/P urea [Table 3].
Effects of sulodexide on proteinuria and on peritoneal albumin leakage
A significant decrease in proteinuria was observed in patients treated with sulodexide after 10 days of treatment and this effect persisted even at D30 . Intraperitoneal administration of sulodexide was associated with a significant decrease in the loss of albumin in the drained fluid after 4 h dialysis dwell time [Table 2].
| Discussion|| |
Patients treated by PD can lose about 5-15 g of total protein and about 6-8 g/day of albumin across the peritoneal membrane. , This has necessitated pharmacological interventions that can prevent or delay the alterations of the peritoneal membrane and thus reduce the leakage of albumin. It has been reported that GAGs have a protective effect on the structure and function of the peritoneum with consequent reduction of the protein leakage in PD patients. GAGs are long chain compounds composed of repeating disaccharide units. One of the two sugar residues is always an amino carbohydrate (N-acetyl glucosamine or Nacetylgalactosamine) and the second is usually an uronic acid (glucuronic or iduronic acid). GAGs are divided into four main types: hyaluronic acid, chondroitin sulfate, heparan sulfate, and keratan sulfate. 
The GAG used in this study is sulodexide which is a highly purified mixture of glycosaminoglycans composed of low-molecular weight heparin (80%) and dermatan sulfate (20%). The pharmacological effect of sulodexide is significantly different from the unfractionated heparin and is mainly characterized by a prolonged half-life and a reduced effect on coagulation parameters. Moreover, sulodexide has anticoagulant, anti-inflammatory, and antioxidant properties. ,
One of the main factors limiting the prolonged use of the PD is the anatomical and functional alteration of the peritoneal membrane caused primarily by the nature of dialysis solutions used. It has been demonstrated that the administration of GAGs during short dwell prevents the morphological and functional alterations of the peritoneum and improves the dialysis efficiency as well as the selective permeability of the peritoneal membrane by increasing the transport of two neutral molecules (urea and creatinine) and reducing the loss of large negative molecules (total protein and mainly albumin). 
In addition to its anticoagulant activity, several experimental studies in animals have shown that intraperitoneal injection of lowmolecular weight heparin may improve ultrafiltration, inhibit the formation of thrombin, and prevent peritoneal fibrosis, all of which improves the structural and functional properties of the peritoneal membrane.  Pletinck et al have shown that oral administration of sulodexide has caused a significant decrease in transforming growth factor beta (TGF beta) and vascular endothelial growth factor which are known to be involved in the peritoneal fibrosis. 
The administration of sulodexide has a potentially beneficial effect in patients treated with PD through the preservation of the integrity of the peritoneal membrane. Oral administration of sulodexide resulted in an increase in peritoneal transport rate of creatinine and glucose, which suggests better conservation of the peritoneal membrane function and improved dialysis efficiency.  The dose of 125 mg/day of sulodexide was associated to a significant increase in D/P ratios for urea and creatinine. Further, sulodexide induces a significant decrease in the peritoneal loss of albumin from a dose of 75 mg/day. This effect is mainly observed by the significant reduction in the D/P albumin and albuminuria. , Similar results were found with intraperitoneal injection of sulodexide. Moreover, sulodexide is also known for its anti-inflammatory, immunomodulatory, and antiangiogenic effects, in addition to its anticoagulant properties. 
The addition of heparin to the dialysis solution is usually used to prevent the obstruction of the catheter in case of peritonitis or drainage of the solution containing fibrous substances or protein.  However, several studies have shown the effect of heparin in preventing the alteration of the peritoneal membrane. Indeed, it has an inhibitory effect on the growth of mesothelial cells, modulates the synthesis and the composition of the extracellular matrix, and also preserves the thickness of the peritoneal membrane and the anionic charge of the latter. , Intraperitoneal administration of heparin resulted in a clear increase in ultrafiltration and a decrease in D/P albumin, systemic inflammatory markers, and the permeability of the peritoneal membrane. 
Our results confirm the beneficial effect of sulodexide on the peritoneal membrane function determined by a significant increase in the values of D/P creatinine and D/P urea. This beneficial effect has been maintained even after 20 days of discontinuing treatment as shown by a sustained increase of these values.
Our study also showed that a dose of 600 IU/day of sulodexide for 10 days was sufficient to decrease the peritoneal albumin loss after 10 days. This effect persisted even 20 days after stopping treatment. Intraperitoneal administration of sulodexide in our patients has also led to a significant improvement in the RRF.
The beneficial effect of GAGs on proteinuria was clearly established by many studies; Achour et al have shown that administration of a dose of 50 mg of sulodexide a day during a whole year has reduced significant albuminuria in patients with diabetes (type 1 and 2).  Sulodexide allows maintenance of the selective permeability of the glomerular wall by three mechanisms: the return of the negative charge of the BGM, inhibiting the expansion of the extracellular matrix, and preventing the thickening of the basement membrane. Thus, sulodexide reduces proteinuria due to its restorative and antiproliferative actions. ,
In 2002, Gambaro et al in a study that included 223 diabetic patients showed that higher doses of sulodexide (200 mg/day) were required to obtain a significant reduction of albuminuria, which persists four months after the end of treatment.  Masola et al found similar results in patients with various non-diabetic glomerular nephropathies. The oral administration of sulodexide 250 mg twice daily for 13.5 months with proteinuria monitoring for every three months reduced proteinuria significantly, and the value of the latter even reached physiological values in four patients. 
Similarly in CAPD patients also, sulodexide possibly reduces protein loss due to its restorative and antiproliferative actions.  In our PD patients, treatment with sulodexide given orally as well as by intraperitoneal injection for 10 days resulted in a significant reduction in proteinuria. This effect was sustained even after 20 days of stopping the treatment.
| Conclusion|| |
Within 10-day treatment period, sulodexide induced a reduction in the loss of albumin by peritoneum in patients on long-term CAPD. Added to that, the quality of dialysis and the RRF also improved. Thus, sulodexide can be useful for maintaining the integrity of the peritoneal membrane, but these results need to be confirmed by larger controlled long-term trials.
Conflict of interest: None declared.
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Department of Nephrology, Dialysis and Transplantation, Sahloul Hospital, Sousse
[Table 1], [Table 2], [Table 3]
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