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*Department of Medical and Surgical Science, Division of Nephrology, University of Padua, Padua, Italy; Department of Endocrinology, Medical Academy, Bialystoc, Poland; Institute of Preventive and Clinical Medicine, Clinical Pharmacology Department, Bratislava, Slovak Republic; ||First Internal Clinic of Medicine, Faculty Hospital, Bratislava, Slovak Republic; Internal Clinic, Faculty Hospital, Brno, Czech Republic; ¶Second Internal Clinic of Medicine, Diabetology Day-Hospital, Brno, Czech Republic; **Department of Nephrology, The Ludwik Rydygier Medical University in Bydgoszcz, Bydgoszcz, Poland; Department of Medical and Surgical Science, Diabetic Center, Geriatric Hospital, University of Padua, Padua, Italy; oDepartment of Nephrology, Medical Academy, Poznan, Poland; Third Department of Internal Medicine, Faculty Policlinic, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; Chair and Department of Internal Diseases and Diabetology, Medical School, Warsaw, Poland; ¶¶Department and Clinic of Internal Diseases and Diabetology, Silesian School of Medicine, Zabrze, Poland; Department of Medical and Surgical Science, 1st Medical Clinic, University of Padua, Padua, Italy.
Correspondence to Dr. Giovanni Gambaro, Department of Medical and Surgical Sciences, Division of Nephrology, University Hospital, Via Giustiniani 2, 35128 Padova, Italy. Phone: +39-049-8218153; Fax: +39-049-8212151; E-mail: giga{at}unipd.it
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Abstract |
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150 µmol/L and stable BP and metabolic control were recruited. They were randomly allocated to one of four groups: 50 mg/d, 100 mg/d, or 200 mg/d sulodexide daily or placebo for 4 mo (T0 to T4), with 4 mo of follow-up after drug suspension (T4 to T8). Treatment with 200 mg/d sulodexide for 4 mo significantly reduced log albumin excretion rate (logAER) from 5.25 ± 0.18 at T0 to 3.98 ± 0.11 at T4 (P < 0.05), which was maintained till T8 (4.11 ± 0.13; P < 0.05 versus T0). Moreover, the sulodexide-induced percent reductions in AER at T4 were significantly different from the placebo value at T4 and approximately linear to dose increments (30% [confidence limits, 4 to 49%], P = 0.03; 49% [30 to 63%], P = 0.0001; and 74% [64 to 81%], P = 0.0001 in the sulodexide 50, 100, and 200 mg/d groups, respectively. At T8, the sulodexide 200 mg/d group maintained a 62% (45 to 73%) AER significant reduction versus placebo (P = 0.0001). Subanalysis by type of diabetes (DM1 versus DM2, microalbuminuric versus macroalbuminuric, or on concomitant ACE inhibitors versus not on ACE inhibitors) demonstrated similar findings. These effects were obtained without any significant variation in metabolic control and BP or serum creatinine. Very few adverse events were reported; none were serious. In conclusion, a 4-mo course of high doses of sulodexide significantly and dose-dependently improves albuminuria in DM1 and DM2 patients and micro- or macroalbuminuric patients with or without concomitant ACE inhibition. The effect on albuminuria is long-lasting and seemingly additive to the ACE inhibitory effect. |
Introduction |
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The anatomic hallmarks of diabetic nephropathy (DN) include thickening of the glomerular basement membrane (GBM) and mesangial expansion with hyalinosis both in the mesangium and capillary lumen. These lesions lead to glomerular fibrosis, which progressively destroys the renal filtration unit, and eventually cause renal failure. A number of reports indicate the involvement of transforming growth factor-
(TGF-) in the development of DN (5). One of the first clinical markers of DN is microalbuminuria (6), commonly considered either hemodynamic in origin (7), due to endothelial dysfunction (8), or biochemical, due to alteration in GBM glycosaminoglycan composition, leading to an abnormal permselectivity (9).
Data from the Diabetes Control and Complications Trial (10) established that glycemic control plays a central role in the prevention and treatment of DN as shown by the effect on microalbuminuria and proteinuria. A number of studies have demonstrated that angiotensin converting enzyme inhibitors (ACEI) are also effective in reducing albuminuria and slowing the progression from DN to renal failure (11). Interestingly, both strategies can inhibit renal overexpression of TGF-, which may constitute a pharmacologic target for the prevention and treatment of DN (12).
The search for innovative and ancillary approaches to the prevention and treatment of DN is warranted because strict metabolic control can be difficult and sometimes dangerous; even DM patients responding to ACEI therapy and metabolic control show progressive renal damage and eventually ESRD (10,11). A number of drugs are currently being investigated, glycosaminoglycans (GAGs; see Appendix) are particularly interesting because they theoretically can target the generalized endothelial dysfunction and the metabolic defect in matrix and basement membrane synthesis, which, according to the Steno hypothesis, are responsible for DN and possibly also for the high rate of cardiovascular mortality observed in DN patients (9,13).
Experiments in rats with streptozotocin-induced DM demonstrated that low molecular weight (LMW) heparin and other GAGs prevented diabetes-induced albuminuria, loss of anionic sites and thickening of the GBM, and glomerulosclerosis (14–16). Interestingly, we have demonstrated that these favorable effects accompany inhibition of renal TGF- (17). Furthermore, GAGs have been shown to restore anionic charges lost from the endothelial surface (18) and a number of other endothelial dysfunctions relevant to diabetic micro- and macroangiopathy (13). Recent explorative studies have also described favorable results on albuminuria in DN patients treated with a LMW heparin (19,20), danaparoid, a mixture of sulfated GAGs consisting mainly of heparan sulfate (21), and sulodexide (22–29).
Sulodexide is composed of the two GAGs that are active in preventing diabetic nephropathy in the experimental model (14). It has also been shown to inhibit TGF- overexpression and matrix synthesis induced by high concentrations of glucose in mesangial cells (Gambaro G and Schleicher E, manuscript in preparation) to the same extent as the single components and to rectify endothelial dysfunctions observed in DM (13).
The small number of patients investigated in the above pilot studies means a number of clinical issues have been left unsolved, particularly the optimal dosage of oral sulodexide. The Diabetic Nephropathy and Albuminuria Sulodexide (Di.N.A.S.) study was designed to answer this question.
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Materials and Methods |
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Participants and Definition
Study participants were DM1 and DM2 patients of either gender aged between 18 and 65 yr with micro- (20 to 200 µg/min) or macro- (>200 µg/min) albuminuria. They were required to have stable metabolic control: 10% variation from baseline in monthly HbA1C levels for over 3 mo with either insulin, oral antidiabetic agents, or diet and BP <160/90 mmHg for at least 6 mo with or without antihypertensive therapy. Exclusion criteria were as follows: neoplasms; severe liver, cardiac, or systemic disease; known hypersensitivity to any GAGs; chronic treatment with corticosteroids, corticothropine, immunosuppressants or alkylating agents; serum creatinine >150 µmol/L; urinary protein excretion rate >3 g/24 h; symptomatic urinary tract infections; hematuria; pregnancy or lactation.
Sample Size
Bearing in mind the primary dose-range finding aim of the study, the sample size was estimated according to two independent hypotheses: (1) rejection of the hypothesis that P1 = P2 (where P is the number of patients with a 50% reduction in albuminuria after 4 mo of therapy); (2) rejection of the null hypothesis that µ1 = µ2 = µ3 after 4 mo of therapy, only if each independent variable accounts for at least 20% of the variation (behavior of albuminuria), 
= 0.05 and 1- is 90% (analyzed by one-way ANOVA with groups 1 to 3 containing the same number of subjects but treated with 3 different doses of sulodexide). A 20% withdraw and drop-out rate was also added to the calculation. Altogether, 88 patients were necessary (22 per treatment group). Therefore, the number of patients enrolled (55 per group, making a total of over 220 patients) was considered adequate. The analyses performed on the subgroups should be considered observational and not inferential.
Study Design
Randomization and Blinding.
After screening and baseline evaluation, a computer-generated block randomization list (8 per block) prepared by the Sponsor’s Medical Department was used to assign all eligible patients to treatment with 25 mg, 50 mg, or 100 mg oral sulodexide twice daily or placebo. There was no stratification for clinical characteristics. Each center was expected to receive the same number of blocks. Clinical trial drug supply was managed by Unival, Bolton, UK. The study medication and placebo were packaged indistinguishably and labeled with a patient number.
Treatment.
Each patient received four gelcaps twice daily: in the placebo group, 4 placebo gelcaps; in the 50 mg/d group, 1 sulodexide gelcap and 3 placebo gelcaps; in the 100 mg/d group, 2 sulodexide gelcaps and 2 placebo gelcaps; in the 200 mg/d group, 4 sulodexide gelcaps.
Treatment lasted for 4 mo (T0 to T4) with a subsequent 4-mo follow-up period (T4 to T8), as shown in Figure 1. Each patient was examined by a physician at randomization, every month during treatment, and every 2 mo during follow-up. At each examination, body weight (BWt) and BP were measured and complete urinalysis was performed, including albumin excretion rate (AER) on one (at T1, T2, T3, T6) and three (at T0, T4, T8) timed overnight collections. Compliance was evaluated by pill count at each monthly visit. Complete blood count, aPTT, fibrinogen, HbA1C, blood chemistry (glucose, lipids, urea, creatinine, total protein, albumin, and liver functions), and a funduscopic examination were carried out on entry and at 4 and 8 mo.
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Outcome Measures
The primary outcome measure was AER at T0, T4, and T8 determined by a turbidimetric method using antibodies against human albumin. Patients were asked to collect three overnight, 8-h urine samples for each time point, indicating the beginning and end of the collection period. The adequacy of urine collection was evaluated by both interviewing the patient and determining urine creatinine excretion. If incomplete, urine collection was immediately repeated. Although sample size limits the subgroup analyses, the secondary outcome measures included AER in specific patient subgroups (all DM1 patients, all DM2 patients, all initially microalbuminuric patients, and all initially macroalbuminuric patients) at T0, T4, and T8. Additional secondary end points included the assessment of AER at T0, T4, and T8 in all patients receiving concomitant ACEI therapy.
Statistical Analyses
Analyses were performed according to the intent-to-treat model on all randomized patients in their assigned groups, regardless of adherence to treatment regimen. Analysis was also performed on data from the evaluable patients. Baseline values between groups were compared using the Kruskal-Wallis test for continuous variables and the 
2 test for categorical variables. The primary endpoint was changes in AER. Three different analyses were performed:
50% reduction of basal AER at T4. Values at this time point are better defined, being the average of three determinations. Empirical values were used, rather than log-transformed data. Time of improvement was the first time in which a 50% reduction of the T0 AER value was observed, if confirmed by the T4 value. For this analysis, the log-rank test was used with correction for multiple comparisons. Patients who failed to maintain the sulodexide effect (>50% reduction of basal AER at T4) during the follow-up period (T4 to T8) were defined as relapsers. For the statistical approaches in 1 and 2, the percent reduction in AER achieved by each sulodexide group relative to T0 or placebo, for each timepoint was calculated as:
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| (1) |
where 
is the difference in adjusted mean logAER at T4 and T8 versus the placebo group (analysis in 1) or the respective T0 value (analysis in 2).
For analysis purposes, the logAER (or AER in the statistical approach in 3) at a given time point was defined as the average of the logAERs (or AERs) of the three measurements. Logistic regression analysis was also performed; AER at T4 or T8 compared with T0 placebo was considered a dependent variable, and baseline AER values were considered independent variables. It was not considered appropriate to introduce center as a factor in the statistical analysis because each center entered a relatively small number of patients (mean = 17) split across four treatment groups.
The intent-to-treat data are presented; however, efficacy and dose-range finding analyses for the evaluable patients (195 subjects) at completion of treatment (T4) and completion of follow-up (T8) produced similar results (data not shown).
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Results |
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2 out of 3 collections at enrollment, a common finding as observed by Caramori et al. (30).
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Effect of Sulodexide on AER in DM1 and DM2 Patients.
Sulodexide was shown to be effective in both DM1 and DM2 patients (Table 4). In DM1 patients, a 17% reduction in baseline AER was observed in the 100 mg/d sulodexide group, and 44% in the 200 mg/d group (both P < 0.05). Interestingly, AER was still 23% lower than baseline in the 200 mg/d group at the end of follow-up (P < 0.05).
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Effect of Sulodexide on AER in Micro- and Macroalbuminuric Diabetic Patients.
Both micro- and macroalbuminuric patients were sensitive to sulodexide (Table 5). Administration of 100 and 200 mg/d sulodexide reduced baseline AER in microalbuminuric patients by 23% and 40%, respectively (both P < 0.05). In the 200 mg/d group, reduction in AER was still statistically significant (31%) at the end of follow-up. In macroalbuminuric patients, a 45% statistically significant reduction in AER was observed in the 200 mg/d sulodexide group (P < 0.05), and AER was still significantly lower (29%) than baseline at T8 (P < 0.05).
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Discussion |
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The hypoalbuminuric effect of 200 mg/d oral sulodexide was particularly evident in microalbuminuric patients, and 60% of them can be considered responders.
Microalbuminuria in diabetic patients has been considered to be of hemodynamic origin (7), due to endothelial dysfunction (8) or abnormal charge permselectivity (9). Our data do not support an effect of sulodexide on renal hemodynamics. Indeed, the hypoalbuminuric effect was achieved in our study without any detectable variation in renal hemodynamics, reflected by serum creatinine and creatinine clearance. Moreover, we did not observe any change in BP control during treatment or follow-up, suggesting that the hypoalbuminuric effect of GAGs is probably not mediated through mechanisms related to renal hemodynamics (14). This concept is also supported by the unprecedented findings that the hypoalbuminuric effect of sulodexide was noted in the subgroup of patients already benefiting from ongoing ACEI therapy (roughly to the same extent as that observed in patients not on ACEI), in which the hemodynamic-dependent component of albuminuria was conceivably already offset by ACE inhibition.
The concept of abnormal charge permeability as a cause of albuminuria has been recently challenged, at least in severe proteinuric conditions (31). Furthermore, the significance of alterations in differential clearance of neutral and anionic-dextrans as a marker of glomerular charge permselectivity has also been disputed (32). Finally, mechanisms underlying albuminuria in diabetic patients have been also linked to the tubular degradation of albumin during renal passage (33). All three observations question the concept that abnormal charge permselectivity is the initial GBM disorder responsible for microalbuminuria. Therefore, the most plausible explanation of the improvement in microalbuminuria is sulodexide’s well-known favorable effect on the endothelium (13).
However, macroalbuminuric patients also responded to 200 mg/d sulodexide. Thus, even at the more advanced stage of overt DN, a high dose of sulodexide significantly reduces AER. Macroalbuminuria is associated with clear, pronounced glomerular abnormalities, which alter glomerular permeability due to the development of large pores (34), implying sulodexide probably effects the glomerular and GBM structure and not only endothelial permeability dysfunction, as in microalbuminuria.
It has already been proposed that GAGs may reduce albuminuria in DN by favorably interfering with mechanisms responsible for the altered GBM and composition and function (permselectivity) of the mesangial extracellular matrix (13,35). Several observations suggest that sulodexide activity in the kidney is complex, possibly modulating the renal expression of genes involved in renal remodeling: first, the persistence of the hypoalbuminuric effect up to 4 mo after cessation of therapy with the higher doses of sulodexide; second, the number of responders increases over the 4 mo of treatment, suggesting the hypoalbuminuric effect of sulodexide increases over time; and third, the similar extent of the hypoalbuminuric effect in patients with/without concomitant ACEI-therapy and the sharp difference between the persistent, posttreatment urinary albumin lowering effect of sulodexide and the rapid rise in AER seen shortly after discontinuation of ACEI therapy (36).
Treatment with GAGs prevents and rectifies the abnormal metabolism of glycosaminoglycans seen in the GBM and mesangium of diabetic animals (15). In addition, heparin has been shown to induce heparan-sulfate proteoglycan synthesis and enhance its sulfation in endothelial cells (37). Furthermore, in diabetic animals, GAGs very similar in structure to sulodexide suppress the TGF-1–mediated enhanced expression of mesangial matrix and collagens (15–17). Finally, sulodexide suppresses high-glucose–induced overexpression of TGF-1 and fibronectin in cultured mesangial cells (Gambaro G and Schleicher E, manuscript in preparation).
Previous studies in DM1 patients advanced the possibility that the hypoalbuminuric effect of sulodexide is long-lasting (24,26). The present investigation confirms this, and shows that it also occurs in DM2, a much more heterogeneous condition.
Despite the limitation in the subgroup analysis due to the small sample size, the additive antiproteinuric effect of sulodexide in patients with well-controlled BP and already receiving ACEI therapy is noteworthy because it promises a favorable effect on the dismal evolution of DN. The actions of ACEI and sulodexide overlap in some ways, but there are differences that may explain sulodexide’s additive effects to those of ACE inhibition alone. For example, although sulodexide diminishes the hyperglycemia-induced overexpression of TGF-1, the mechanism of TGF-1 modulation by ACEI is most likely different (35,38).
The effect of sulodexide on albuminuria probably reflects a favorable effect on glomerular remodeling. In the experimental model, the reduction of AER obtained with similar GAGs accompanies the prevention of glomerulosclerosis (15–17). It is interesting to observe that like strict glycemic control and ACEI therapy, the two well-known strategies capable of improving DN, sulodexide also improves both AER and TGF- overexpression, suggesting that it too may have a favorable effect on DN evolution. The reduction of AER by sulodexide per se could have a positive effect on the kidney by reducing the albuminuria-induced nephrotoxicity. Albumin (in the macroalbuminuric range) (39), glycated albumin (40), and lipid-rich albumin (41) (possibly also in the microalbuminuric range) in the glomerular filtrate are toxic to tubular epithelial cells and cause cytokine and endothelin-mediated tubulointerstitial inflammation and scarring.
The efficacy of oral GAGs on overt (macroalbuminuric) DN in DM2 patients represents an interesting new finding. In fact, the effect of oral sulodexide in DM2 has only been investigated in two smaller, randomized studies, which included only microalbuminuric patients (27,28). Both demonstrated that sulodexide was effective as a hypoalbuminuric agent. The effect of GAGs on macroalbuminuria in DM2 patients has been explored in two studies; however, tinzaparin (42) and danaparoid (21) were administered parenterally, making direct comparison difficult. The negative results obtained from both studies have raised the doubt that DM2 patients are less sensitive to GAGs than DM1 patients. Different GAG preparations and different routes of administration were used in the above cited studies; therefore, we cannot make any direct comparison.
During the Di.N.A.S. study, no severe adverse effect was observed. This is consistent with findings from numerous human trials with sulodexide for a variety of vascular indications, including one large study in which 2016 postmyocardial infarction patients, 25% of which were diabetic, received sulodexide for 1 yr (43). Interestingly, there were no clinically significant alterations in coagulation parameters, platelet count, or ophthalmologic findings, confirming the conclusions from previous studies that modest, clinically significant changes in blood coagulation tests are observed only at very high doses of oral heparins and GAGs. Although the use of anticoagulant doses of heparins may increase the risk of vitreal and retinal hemorrhage in diabetic retinopathy, reports have shown that the long-term use of a parenteral GAG, such as danaparoid, does not worsen diabetic retinopathy in DM2 patients (44). In DM1 patients, the long-term use of a parenteral GAG (45) can even reduce retinal hard exudates, lesions pathophysiologically resembling albuminuria.
In conclusion, this study has demonstrated that a 4-mo course of oral sulodexide can significantly improve albuminuria in both DM1 and DM2 patients with either micro- or macroalbuminuria, with approximately linear dose-response. Most importantly, the effect of 200 mg/d sulodexide on albuminuria is a sustained one (rather than simple stabilization). This strongly suggests that a chemical/anatomical change was induced in renal tissues by sulodexide. The albuminuria-lowering effect was additive to and independent of the effects achieved with ACEI therapy. Major adverse effects were not seen. Although this was a short-term study and longer trials with different end points (either clinical or GFR) must be performed to confirm safety and efficacy on the evolution of DN, the results suggest some important possible uses for sulodexide: (1) as a valid complementary treatment for patients who respond incompletely to ACEI therapy; (2) to treat patients unable to tolerate ACEI due to concomitant renal vascular disease, advanced renal insufficiency, hyperkalemia, or cough; and (3) to provide cardiovascular protection as well as nephroprotection. Sulodexide possesses antithrombotic activity (13) and has been shown to significantly reduce cardiovascular mortality in nondiabetic patients (43), a potentially very useful effect in a population at high risk of cardiovascular morbidity and mortality as albuminuric diabetic patients certainly are (9).
Appendix
The term GAGs is generally used in the text indicating a broad category of molecules including heparin(s), LMW heparin(s), heparan sulfate, dermatan-sulfate, and mixed formulation of glycosaminoglycans, such as sulodexide and danaparoid. This use has its rationale in the fact that they share common biologic and namely nephroprotective activities. Specific GAG molecules have been defined whenever necessary.
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Acknowledgments |
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References |
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by anti-TGF- antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45: 522–530, 1996[Abstract]
1(IV) collagen expression and deposition in long-term diabetic rats is prevented by chronic glycosaminoglycan treatment. Lab Invest 74: 484–495, 1996[Medline]
1 overexpression and pathologic changes in renal tissue of long-term diabetic rats. J Am Soc Nephrol 11: 2324–2336, 2000
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