glucuronyl-glucosamine-glycan-sulfate and Albuminuria

It has been suggested that sulodexide is able to lower blood pressure (BP). This may be attributed to its ability to restore the endothelial surface layer (ESL). As ESL perturbation is known to be related to the degree of kidney damage, we investigated whether albuminuria, reflecting ESL status, modified the BP-lowering potential of sulodexide.. A post hoc analysis of the double-blind, randomized, placebo-controlled sulodexide microalbuminuria (Sun-MICRO) and macroalbuminuria (Sun-MACRO) studies, including 1056 microalbuminuric and 843 macroalbuminuric subjects with type 2 diabetes receiving maximal tolerated renin-angiotensin-aldosterone system inhibitor therapy, was carried out. We compared the effect of placebo and sulodexide on systolic BP (SBP) among albuminuria groups.. Analysis of covariance, including data from both trials, showed that baseline urine albumin-to-creatinine ratio (UACR) was the only modifier of the SBP response (interaction with treatment P = 0.001). In subjects with an UACR >1000 mg g. The BP-reducing potency of sulodexide is modified by the degree of albuminuria in subjects with type 2 diabetes. As ESL status deteriorates with increasing albuminuria and nephropathy severity, this suggests that ESL restoration may represent a new target for BP treatment in subjects with diabetic nephropathy.

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycosaminoglycans; Humans; Male; Middle Aged; Severity of Illness Index

Glycosaminoglycans or sulodexide has shown benefits in early experimental diabetic nephropathy (DN) models, but its efficacy in patients with early stage of DN is unknown. Methods. Twenty patients were randomly assigned to the placebo group and another 20 patients were randomly assigned to receive sulodexide 100 mg/day for 14 weeks. Primary outcome was a change of urinary TGF-beta1, albuminuria, and glomerular filtration rate (GFR). All patients had stable metabolic profiles for at least 90 days before randomization. Results. Urinary TGF-beta1 increased significantly in the placebo group but did not change significantly in the sulodexide group. Additionally, the mean change of urine TGF-beta1 in the placebo group was significantly higher than that in the sulodexide group (8.44 ± 9.21 versus 2.17 ± 6.96 pg/mg Cr, P = 0.02). Mean changes of urinary albumin were 15.05 ± 30.09 μg/mg Cr (P = 0.038) in the placebo group and 13.89 ± 32.25 μg/mg Cr (P = 0.069) in the sulodexide group. No consistent patterns of side effects were observed. Conclusion. In this 14-week trial, benefits of sulodexide in preventing the increase of urinary TGF-beta1 were observed in patients with normoalbuminuric type 2 diabetes. The study suggests that sulodexide treatment may provide additional renoprotection in early stage DN. This trial is registered with TCTR20140806001.

Topics: Aged; Albumins; Albuminuria; Biomarkers; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Glycosaminoglycans; Humans; Hypoglycemic Agents; Kidney; Kidney Diseases; Male; Middle Aged; Transforming Growth Factor beta1; Treatment Outcome

Sulodexide, a mixture of naturally occurring glycosaminoglycan polysaccharide components, has been reported to reduce albuminuria in patients with diabetes, but it is unknown whether it is renoprotective. This study reports the results from the randomized, double-blind, placebo-controlled, sulodexide macroalbuminuria (Sun-MACRO) trial, which evaluated the renoprotective effects of sulodexide in patients with type 2 diabetes, renal impairment, and significant proteinuria (>900 mg/d) already receiving maximal therapy with angiotensin II receptor blockers. The primary end point was a composite of a doubling of baseline serum creatinine, development of ESRD, or serum creatinine ≥6.0 mg/dl. We planned to enroll 2240 patients over approximately 24 months but terminated the study after enrolling 1248 patients. After 1029 person-years of follow-up, we did not detect any significant differences between sulodexide and placebo; the primary composite end point occurred in 26 and 30 patients in the sulodexide and placebo groups, respectively. Side effect profiles were similar for both groups. In conclusion, these data do not suggest a renoprotective benefit of sulodexide in patients with type 2 diabetes, renal impairment, and macroalbuminuria.

Topics: Aged; Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged; Treatment Failure

Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes.. We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy.. Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required.. The study drug was sulodexide, 200 mg/d.. The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >25%) or 50% decrease in baseline ACR.. In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 ± 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups.. We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract.. Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Kidney Diseases; Male; Middle Aged

Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial.. A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR < 20 mg/g with a decrease of at least 25%) or (2) a decrease in ACR of at least 50% from the baseline value. All patients used a maximum tolerated recommended FDA approved dose of an ACEI or ARB for at least 60 days and had stable blood pressure prior to randomization.. The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed.. Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longer-term trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.

Topics: Aged; Albuminuria; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Confidence Intervals; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged; Pilot Projects; Probability; Reference Values; Severity of Illness Index; Treatment Outcome; Urinalysis

Patients with Type 2 diabetes and albuminuria are at high risk to progress to end-stage renal disease (ESRD). Although angiotensin receptor blockers confer renoprotection, many diabetic patients still develop overt nephropathy and reach ESRD. Glycosaminoglycans belong to the same family as heparin and heparinoids. Pilot studies with sulodexide, a glycosaminoglycan, have shown that sulodexide can reduce urinary albumin excretion rates in diabetic patients. No hard renal end-point data are available.. Two multicentre, double-masked, randomized placebo controlled trials were designed to study the renoprotective potential of sulodexide. The Sulodexide Microalbuminuria Trial examined the efficacy of sulodexide given over 26 weeks in 1000 patients with Type 2 diabetes, hypertension and microalbuminuria. The Sulodexide Overt Nephropathy Trial examined the efficacy of sulodexide in 2240 patients with Type 2 diabetes, hypertension and proteinuria > or = 900 mg/24 h.. The primary outcome of The Sulodexide Microalbuminuria Trial was (i) conversion to normoalbuminuria and at least a 25% decrease in the urinary albumin creatinine ratio (UACR), or (ii) at least a 50% reduction in UACR. The primary outcome of The Sulodexide Overt Nephropathy Trial was time to a composite end point of doubling of serum creatinine or ESRD.. The sulodexide nephropathy programme will document whether therapy with sulodexide confers renal protection in Type 2 diabetes and nephropathy.

Topics: Albuminuria; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypertension; Hypoglycemic Agents; Kidney Failure, Chronic; Male; Treatment Outcome

Albuminuria is the best and most readily available marker for glomerular damage and progressive renal function loss in patients with diabetic nephropathy. Recently, administration of the oral glycosaminoglycan sulodexide (a mixture of 80% fast-moving heparin and 20% dermatan sulphate) was shown to effectively decrease albumin excretion rate in diabetics with nephropathy.. To evaluate whether the hypoalbuminuric effect of sulodexide is associated with improvement of the renal vascular or tubule function.. Forty-five type 1 diabetic patients, affected by diabetic nephropathy with albuminuria for at least 5 years, were randomly allocated to sulodexide or untreated. Those allocated to sulodexide were given 100 mg of sulodexide daily for 120 days. Renal vascular function (DIR) and N-acetyl-beta-D-glucosaminidase (NAG) excretion were estimated before and at the end of the study, the former in thesulodexide group only. DIR was measured as two Cr(cl) lasting 120 min (before and during 2 mug/kg b.w. i.v. dopamine).. The analysis of trends during the study demonstrated a marked reduction of albuminuria in the sulodexide group (from 126.1 +/- 15.41 to 93.6 +/- 13.7 mg/day). DIR rose from 13.2 +/- 2.1% to 15.44 +/- 1.9% (relative increase: +16.9%), and NAG excretion showed a decreasing trend decreased in the sulodexide group only (from 5.1 +/- 0.62 to 4.7 +/- 0.40 U/g(creat)).. The findings presented in this study indicate for the first time that orally available sulodexide may favorably affect the renal vascular function in type 1 diabetic patients with nephropathy and microalbuminuria. The effect of sulodexide on NAG is strongly influenced by the baseline NAG values, with a significant NAG reduction in the patients with the highest baseline NAG values.

Topics: Acetylglucosaminidase; Adult; Albuminuria; Anticoagulants; Diabetic Nephropathies; Endothelium, Vascular; Female; Glomerular Filtration Rate; Glycosaminoglycans; Humans; Kidney Glomerulus; Male

Diabetic nephropathy may be effectively prevented and treated by controlling glycemia and administering angiotensin-converting enzyme (ACE) inhibitors. However, strict metabolic control can be difficult, and ACE inhibitors may be poorly tolerated and only partially effective, particularly in diabetes mellitus type 2 (DM2), warranting the search for ancillary treatment. Sulodexide is a glycosaminoglycan, a new class of drug that has demonstrated nephroprotective activity in experimental investigations. The Di.N.A.S. study was a randomized, double-blind, placebo-controlled, multicenter, dose-range finding trial to evaluate the extent and duration of the hypoalbuminuric effect of oral sulodexide in diabetic patients. A total of 223 microalbuminuric and macroalbuminuric DM1 and DM2 patients with serum creatinine < or =150 micromol/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.

Topics: Administration, Oral; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Double-Blind Method; Glycosaminoglycans; Humans

Experimental and clinical studies showed a decrease in albuminuria, a marker of diabetic nephropathy after administration of heparin or other glycosaminoglycans (GAG).. To study the effect of sulodexide on albumin excretion rate (AER) in patients with type 1 or type 2 diabetes mellitus (DM).. Twenty patients (12 of type 1 DM) aged 33-63 yrs (median 45) with microalbuminuria (AER 20-200 micrograms/min) or macroalbuminuria (AER > 200 micrograms/min) were enrolled in open study and received sulodexide 60 mg/day i.m. for 3 weeks with further 6-week follow-up without treatment. In the 2nd phase, sulodexide 100 mg/day was given p.o. for 8 weeks with further 8-weeks follow-up. Albuminuria in overnight urine samples was analyzed by the RIA method and results (medians with lower and upper quartiles) were compared by the Wilcoxon test.. In the 1st phase, AER (microgram/min) decreased from 167 (54-378) at baseline to 118 (78-220) at week 1 (p < 0.05), 105 (68-341) at week 2 (p < 0.05), and to 114 (56-354) at week 3 (NS). After stopping the treatment, AER gradually raised to baseline values. During the oral phase, AER decreased from 253 (37-961) to 137 (35-323) after 1 month (p < 0.05) and to 144 (47-588) after 2 months (NS). This effect was prolonged for further 2 months after treatment withdrawal (AER 110 (65-363) micrograms/min, p < 0.05). In both phases, the decrease in AER was shown only in patients with macroalbuminuria, but not in those with microalbuminuria. Blood pressure, glomerular filtration rate and metabolic compensation of DM were not changed.. A short-term treatment with sulodexide i.m. or p.o. significantly decreased albuminuria in DM patients. This effect was prolonged for further 2 months after oral administration. Therefore, sulodexide could be useful in the treatment of diabetic nephropathy. (Tab. 3, Ref. 20.)

Topics: Adult; Albuminuria; Diabetes Mellitus; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged

To determine the effect of oral administration of glycosaminoglycans on metabolic control and albumin excretion rate (AER) in NIDDM patients with increased urinary albumin excretion.. Twelve NIDDM hypertensive patients (age 52 +/- 3 years, HbA1c 7.7 +/- 0.2%) on antihypertensive treatment were enrolled in a double-blind placebo-controlled study, assuming either placebo or sulodexide (100 mg/day) for 4 months; at the end of this period, a crossover was performed. We have evaluated routine biochemical parameters plus AER and coagulative function every 2 months.. Both plasma fibrinogen (from 4.15 +/- 0.32 to 2.77 +/- 0.47 mmol/l) and AER (from 128.3 +/- 40.6 to 39.6 +/- 11.9 micrograms/min) decreased significantly after treatment with glycosaminoglycans in respect to placebo; moreover, blood pressure control ameliorated, also in the absence of any variation of therapy.. Glycosaminoglycan therapy, likely in association with a satisfactory control of blood pressure values, seems to prevent the progression of diabetic nephropathy in NIDDM.

Topics: Administration, Oral; Adult; Aged; Albuminuria; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cholesterol; Cholesterol, HDL; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Time Factors; Triglycerides

Fifteen out-patients with type I diabetes mellitus and microalbuminuria (mean +/- SEM: 95.4 +/- 13.9 micrograms/min), were administered the glycosaminoglycan sulodexide, with the aim of investigating its influence on the rate of albumin excretion. Sulodexide was given intramuscularly in a dose of 600 lipoproteinlipase releasing units/day for three weeks. Albumin excretion was measured before dosing, at weekly intervals during dosing and also during the subsequent follow-up period of six weeks. Sulodexide yielded a clear-cut and statistically significant lowering of albumin excretion after the first week of treatment (from 95.4 +/- 13.9 micrograms/min to 53.6 +/- 11.1 micrograms/min; p = 0.0055); albumin excretion was further decreased after three weeks of treatment (26.5 +/- 6.05 micrograms/min; p = 0.0007) and was maintained during the follow-up period, at the end of which the mean value was still significantly lower than at baseline (39.6 +/- 10.3 micrograms/min; p = 0.01). Sulodexide short-term administration did not influence the routine haematological, haematochemical and coagulative tests performed contemporaneously. Patients' compliance with treatment was very good and no adverse events were reported.

Topics: Adolescent; Adult; Aged; Albuminuria; Diabetes Mellitus, Type 1; Female; Glycosaminoglycans; Humans; Injections, Intramuscular; Male; Middle Aged; Patient Compliance; Pilot Projects

A novel pathogenetic approach to treatment of diabetic nephropathy (DN) as a severe complication of diabetes mellitus is aimed at inhibiting DN progression or its involution by means of reestablishment of heparan sulfate synthesis by glycosaminoglycane drug. In the study of 9 patients with microalbuminuria and 9 with proteinuria this drug was low-molecular heparin-sulodexide (Alfa-Wasserman, Italy). The treatment course of 3 weeks resulted in albuminuria fall in 89% of patients. In patients with microalbuminuria protein excretion returned to normal values in a week of treatment. This effect was persistent after the drug discontinuation. This was not so for protein excretion in proteinuria patients which became low after 3 weeks of treatment, but the effect was not long-lasting. The authors believe that glycosaminoglycanes hold great promise in DN, especially at early stages of renal diabetic affection.

Topics: Adolescent; Adult; Albuminuria; Chronic Disease; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glycosaminoglycans; Heparin, Low-Molecular-Weight; Humans; Hypoglycemic Agents; Middle Aged; Time Factors

Albuminuria is a dominant biochemical feature of developing diabetic nephropathy. A disturbed metabolism of heparan sulphate characterized by an increased loss of anionic charges in the basement membrane has been considered as one of the main factors causing an increased albumin output into urine. All therapeutic approaches inducing a reduction of the albumin excretion rate (AER) have a protective effect on renal function. The effect of glycosaminoglycan sulodexide on albuminuria was studied in a group of 53 diabetic patients (26 Type 1 and 27 Type 2) with micro and macroalbuminuria. Sulodexide (Vessel Due F) was administered intramuscularly in one daily dose (600 lipasemic units) for 3 weeks followed by a 6 week wash-out period. A significant decrease of AER was found in a total cohort of patients following just 1 week of sulodexide treatment (mean 162 micrograms/min, range 10-2708 micrograms/min vs mean 248 micrograms/min, range 20-3160 micrograms/min, P < 0.001). This effect lasted 3-6 weeks after drug withdrawal. Similar results were obtained if Type 1 and Type 2 diabetic patients were evaluated separately but a delay of the AER reduction was observed in the latter group. In all patients the mean AER was reduced to 60-65% of the initial values. A greater effect of sulodexide on albuminuria was observed in patients with AER above 200 micrograms/min than in those with microalbuminuria (a reduction to 47 vs 65% of the initial output). Sulodexide did not significantly reduce albuminuria in 28% of diabetic patients ('non-responders'). In conclusion, glycosaminoglycan sulodexide may reduce AER in patients with micro or macroalbuminuria and it could slow down development of diabetic nephropathy.

Topics: Adult; Aged; Albuminuria; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Fasting; Female; Glycated Hemoglobin; Glycosaminoglycans; Humans; Hypolipidemic Agents; Male; Middle Aged; Pilot Projects; Serum Albumin; Time Factors

Glycosaminoglycans (GAGs) play an important role in the physiopathology of diabetic nephropathy; they are essential for the maintenance of glomerular charge selectivity and their administration can reduce albuminuria in diabetic patients.. Following a randomized block design, controlled versus placebo, we investigated, in insulin-dependent diabetic patients with micro- or macroalbuminuria, whether GAG therapy can influence an altered albumin excretion rate (AER). Thirty-six patients (18 micro- and 18 macroalbuminuric) were randomized to receive, during 5 days/week for 3 weeks, either a daily dose of 600 lipoproteinlipase releasing units (LRU) of sulodexide by the i.m. route (9 micro- and 9 macroalbuminuric patients), or a matching i.m. placebo (9 micro- and 9 macroalbuminuric patients). All patients were followed-up for further 6 weeks. AER was evaluated before treatment, weekly during it and every 3 weeks during follow-up.. Seventeen of the 18 sulodexide-treated patients showed a trend towards decrease in AER, more evident and statistically significant in microalbuminurics (P < 0.01 after the first week). At the end of follow-up, AER was still significantly reduced in microalbuminurics, while macroalbuminurics showed again increased values. Placebo-treated patients evidenced no AER variations during all the study period. No statistically significant differences vs baseline, concerning blood pressure, haematological, haematochemical, and coagulative tests, and urinalysis, were ever observed, apart from a clear-cut decrease in blood cholesterol and triglycerides at the end of treatment, in a subgroup of hyperlipidaemic, sulodexide-treated subjects. No adverse events were registered.. Our results suggest that the GAG sulodexide exerts a positive activity in type I diabetic patients with micro- and macroalbuminuria, by reducing the abnormally high AER levels.

Topics: Adult; Albuminuria; Diabetic Nephropathies; Female; Glycosaminoglycans; Humans; Male

The aim of this study was to investigate whether sulodexide treatment is capable of influencing urinary albumin excretion rate (UAER) in insulin-dependent diabetes mellitus patients (type I) with micro- or macroalbuminuria. A total of 14-inpatients (seven with micro and seven with macroalbuminuria) were enrolled and were treated first intramuscularly with a 60 mg vial of sulodexide/day for 10 days, and then orally with 25 mg capsules twice a day for 21 days. UAER was estimated before starting treatment (T0), after the i.m. treatment phase (T1) and at the end of the oral treatment (T2). No statistically significant differences in hematochemical and coagulative parameters were registered after treatment, with respect to basal values. On the contrary, a marked decrease in UAER mean values was registered at the end of both the parenteral and the oral treatment periods (T0: 349.9 mg/24 h, range 80-820; T1: 237 mg/24 h, range 7-620; T2: 91.4 mg/24 h, range: 2-306). All the differences were statistically significant (P < 0.001) versus baseline. At T2, a normalisation of UAER was observed in three microalbuminuric and in two macroalbuminuric patients, and a remarkable decrease was found in additional four and five patients, respectively. UAER was found to be still significantly lower than at baseline after 6 weeks of follow-up. This preliminary study suggests that sulodexide is effective in reducing UAER in type I patients with diabetic nephropathy.

Topics: Adolescent; Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Reference Values; Time Factors; Treatment Outcome

Sulodexide is a mixture of glycosaminoglycans that may reduce proteinuria in diabetic nephropathy (DN), but its mechanism of action and effect on renal histology is not known. We investigated the effect of sulodexide on disease manifestations in a murine model of type I DN.. Male C57BL/6 mice were rendered diabetic with streptozotocin. After the onset of proteinuria, mice were randomized to receive sulodexide (1 mg/kg/day) or saline for up to 12 weeks and renal function, histology and fibrosis were examined. The effect of sulodexide on fibrogenesis in murine mesangial cells (MMC) was also investigated.. Mice with DN showed progressive albuminuria and renal deterioration over time, accompanied by mesangial expansion, PKC and ERK activation, increased renal expression of TGF-β1, fibronectin and collagen type I, III and IV, but decreased glomerular perlecan expression. Sulodexide treatment significantly reduced albuminuria, improved renal function, increased glomerular perlecan expression and reduced collagen type I and IV expression and ERK activation. Intra-glomerular PKC-α activation was not affected by sulodexide treatment whereas glomerular expression of fibronectin and collagen type III was increased. MMC stimulated with 30 mM D-glucose showed increased PKC and ERK mediated fibronectin and collagen type III synthesis. Sulodexide alone significantly increased fibronectin and collagen type III synthesis in a dose-dependent manner in MMC and this increase was further enhanced in the presence of 30 mM D-glucose. Sulodexide showed a dose-dependent inhibition of 30 mM D-glucose-induced PKC-βII and ERK phosphorylation, but had no effect on PKC-α or PKC-βI phosphorylation.. Our data demonstrated that while sulodexide treatment reduced proteinuria and improved renal function, it had differential effects on signaling pathways and matrix protein synthesis in the kidney of C57BL/6 mice with DN.

Topics: Albuminuria; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Gene Expression Regulation; Glucose; Glycosaminoglycans; Humans; Male; Mesangial Cells; Mice; Mice, Inbred C57BL; Phosphorylation; Signal Transduction

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Glycosaminoglycans; Humans; Kidney Diseases; Male

Glycosaminoglycan sulodexide may influence morphology and functional properties of the basement membranes in microvessels. The aim of this study was to evaluate the effect of sulodexide administration on albuminuria and on different biochemical variables indicating endothelial dysfunction, oxidative stress and fibrinolysis in diabetic patients. Twenty diabetic patients of both types with micro- or macroalbuminuria were selected for sulodexide treatment. Daily dose of 600 U (60 mg) was injected intramuscularly five days a week. Fifteen doses were applied during 3 weeks. The patients were examined before and after treatment as well as 6 months later. No changes of diabetes control were observed during the study and after 6 months of wash-out period. Significant decrease of albuminuria (p < 0.001) was observed during the sulodexide administration with the following increase to pretreated values during the wash-out period. A decrease of serum N-acetyl-beta-glucosaminidase (NAG) activity (p < 0.03) at the end of treatment as compared to pretreated values was found in the whole group of diabetic patients. Slight reduction of oxidative stress expressed by malondialdehyde and superoxide dismutase was apparent after treatment but no simultaneous change in fibrinolysis was observed. Sulodexide may have some protective effects influencing functional properties of the basement membrane as manifested by lowered albuminuria. In addition, it may slightly decrease oxidative stress in diabetic patients and it could stabilize endothelial cells.

Topics: Acetylglucosaminidase; Adult; Aged; Albuminuria; Diabetes Mellitus; Diabetic Angiopathies; Female; Fibrinolysis; Glycosaminoglycans; Humans; Hypoglycemic Agents; Injections, Intramuscular; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Superoxide Dismutase

The authors administered to type 1 diabetics (n = 15) or type 2 diabetics (n = 20) with microalbuminuria or macroalbuminuria for a period of 15 days i.m. doses of sulodexide (Vessel Due F), 600 i.u. (i.e. 60 mg). The evaluation of the whole group revealed a statistically significant reduction of the original mean value of albuminuria (509 +/- 127 ug/min) already during the first week of sulodexide administration (382 +/- 105). A further decrease was recorded after the second and third week of treatment (326 +/- 89, 319 +/- 85 ug/min). While in diabetics with microalbuminuria < 100 micrograms/min the mean levels of excreted albumin were not affected, in diabetics with macroalbuminuria 200 ug/min a significant reduction of albuminuria persisted (p < 0.001) achieved during sulodexide treatment persisted for three weeks after completed treatment. No differences were found between the results of type 1 and type 2 diabetics.. Seventy-seven per cent type 1 and type 2 diabetics responded to parenteral sulodexide administration for 15 days by a statistically significant reduction of albumin.

Topics: Adult; Aged; Albuminuria; Diabetes Mellitus; Female; Glycosaminoglycans; Humans; Hypoglycemic Agents; Male; Middle Aged