Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

A randomized, controlled study of sulodexide therapy for the treatment of diabetic nephropathy

Background: 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. Methods: 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 (AFR). Thirty-six patients (18 micro- and 18 macroalbuminuric) were randomized to receive, during 5 days/week for 3 weeks, either a daily dose of 700 lipoproteinlipase releasing units (LRU) of sulodexide by the i.m. route (9 micro- and 9 macroalbuminuric patients), or a matching i.m. placebo (or 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. Results: 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. Conclusions: 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.     

Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients.

BACKGROUND: Predictors of diabetic nephropathy are only partly known. The role of glomerular hyperfiltration is much discussed. We have studied the cumulative incidence of micro and macroalbuminuria and the predictive value of glomerular filtration rate (GFR) and screening value of albumin excretion rate (AER) in type-1 diabetes. METHODS: A cohort of diabetic children was followed up at a mean duration of 29+/-3 years. All 75 children treated in one hospital with diabetes duration > or =8 years were prospectively followed for 8 years examining GFR, AER, blood pressure and HbA1c. After another 8-10 years, 60 of them were traced for endpoint follow-up. RESULTS: Seven patients (12%) developed macroalbuminuria, i.e. persistent overnight AER>200 mg/min, 12 (20%) developed persistent microalbuminuria (AER 15-200 mg/min) and 17 (28%) transient microalbuminuria (>15 mg/min on two consecutive occasions, normalized at endpoint). One baseline screening value of 24-h AER>15 mg/min predicted 93% of patients with persistent micro or macroalbuminuria. The negative predictive value was 78%. Six of seven macroalbuminuric and 10 of 12 microalbuminuric patients had a baseline GFR above the normal limit of the method (> or =125 ml/min/1.73 m(2)). When adjusted for diabetes duration, increased GFR predicted macro or microalbuminuria (odds ratios=5.44, P=0.04). The positive predictive value for having an increased baseline GFR was 53%.The negative predictive value was 77%. Stratification for HbA1c did not change the effect of an increased GFR. CONCLUSIONS: At a mean diabetes duration of 29 years the cumulative incidence of macroalbuminuria was 12%; however, another 20% had persistent microalbuminuria. A screening value of 24-h AER >15 mg/min was a strong predictor, whereas increased GFR was a weaker but significant predictor for micro and macroalbuminuria.     

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients. BACKGROUND: In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 +/- 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients. METHODS: After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (beta-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine). RESULTS: In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the beta-1/Cr (0.65 +/- 4.29 vs. -1.93 +/- 2.35 1/micromol x 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 +/- 24.1 vs. 63.5 +/- 21.3 vs. 41.9 +/- 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0. 001). On multivariate analysis, beta-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (beta = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (beta = 2.426, P = 0.018), high-density lipoprotein cholesterol (beta = -8.797, P = 0.03), baseline UAE (beta = 0.002, P = 0.04), and mean CCr during treatment (beta = -0.211, P = 0.006). CONCLUSION: In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.     

Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.     

Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy

The aim of this study was to investigate the structural characteristics of podocytes and endothelial cells in diabetic nephropathy. We studied 18 patients with type 1 diabetes (seven normoalbuminuric, six microalbuminuric, and five proteinuric), and six normal control subjects. Groups were not different for age. Type 1 diabetic groups were not different for diabetes duration or age at diabetes onset. Podocyte foot process width (FPW), fraction of glomerular basement membrane (GBM) surface with intact nondetached foot processes (IFP), fraction of glomerular capillary luminal surface covered by fenestrated endothelium [S(S)(Fenestrated/cap)] and classic diabetic glomerulopathy lesions were morphometrically measured. Albumin excretion (AER) and glomerular filtration (GFR) rates were also measured. GFR correlated inversely and AER directly with GBM and mesangial measurements in diabetic patients. FPW correlated inversely with GFR (r = -0.71, P = 0.001) and directly with AER (r = 0.66, P = 0.003), GBM, and mesangial parameters. The GBM fraction covered by IFP was decreased in proteinuric versus control subjects (P = 0.001), normoalbuminuric patients (P = 0.0002) and microalbuminuric patients (P = 0.04) and correlated with renal structural and functional parameters, including AER (r = -0.52, P = 0.03). Only 78% of GBM was covered by IFP in proteinuric patients. S(S)(Fenestrated/cap) was reduced in normoalbuminuric (P = 0.03), microalbuminuric (P = 0.03), and proteinuric (P = 0.002) patients versus control subjects. S(S)(Fenestrated/cap) correlated with mesangial fractional volume per glomerulus (r = -0.57, P = 0.01), IFP (r = 0.61, P = 0.007), and FPW (r = -0.58, P = 0.01). These novel studies document that podocyte detachment and diminished endothelial cell fenestration are related to classical diabetic nephropathy lesions and renal function in type 1 diabetic patients and support a need for further studies of podocyte/GBM adherence and podocyte/endothelial cell functional interactions in diabetic nephropathy.     

Concomitant presence of endothelial nitric oxide 894T and angiotensin II-converting enzyme D alleles are associated with diabetic nephropathy in a Kurdish population from Western Iran

Aim: The present study investigated the influence of insertion (I)/deletion (D) polymorphism of the angiotensin II‐converting enzyme (ACE) gene in combination with endothelial nitric oxide (eNOS) G894T polymorphism on the predisposition to diabetic nephropathy (DN). Methods: Using polymerase chain reaction (PCR) and PCR‐restriction fragment length polymorphism (PCR‐RFLP) method, the ACE and eNOS polymorphisms were genotyped in 72 microalbuminuric, 68 macroalbuminuric and 72 normoalbuinuric type 2 diabetes mellitus (T2DM) patients from Western Iran. Results: The presence of eNOS T or ACE D allele was not associated with increased risk of macroalbuminuria (odds ratio (OR) = 1.36, P = 0.27 and OR = 1.6, P = 0.062, respectively). However, in the presence of both alleles there was a trend towards increased risk of macroalbuminuria (fivefold, P = 0.05). Conclusion: Our study indicates that the concomitant presence of both ACE D and eNOS T alleles tends to be associated with an elevation risk of macroalbuminuria compared with the presence of each polymorphism alone. This risk could be attributed to the increasing activity of ACE and angiotensin II level in the presence of D allele and decreasing NO production in the presence of T allele accelerating diabetic nephropathy.     

Glomerular structure in type-1 (insulin-dependent) diabetic patients with normo- and microalbuminuria.

Kidney biopsies from 15 type-1 (insulin-dependent) diabetic patients with a range of albumin excretion (AER) were analyzed. Nine patients had normal AER, and six had microalbuminuria. Basement membrane thickness, BMT, and mesangial matrix volume fraction, Vv(mat/glom), were obtained from at least three glomeruli per biopsy. Mesangial structures were estimated with electron microscopic analysis at three levels in each glomerulus. Glomerulopathy parameters were significantly increased in micro- versus normoalbuminuric patients with the following means and (CV): BMT 571 nm (0.12) and 442 nm (0.25), P = 0.03; Vv(mes/glom) 0.31 (0.20) and 0.22 (0.14), P = 0.002; Vv(matrix/glom) 0.17 (0.25) and 0.11 (0.28), P = 0.006; matrix star volume 56 microns 3 (0.47) and 22 microns 3 (0.43), P = 0.02. A positive correlation obtained between AER and each of the glomerulopathy parameters, BM thickness, Vv(mes/glom) and Vv(matrix/glom), as well as between AER and a structural index expressing the sum of changes in the peripheral BM and in the mesangium (r = 0.62, P = 0.01). The results indicated a parallel course of mesangial and peripheral BM changes: a positive correlation obtained between BM thickness and mesangial parameters [BMT versus Vv(matrix/glom): r = 0.82, P = 0.0001] and the ratio of the two subsets of glomerular BM material (PBM:matrix) did not show significant difference between normo- and microalbuminuric groups. The data give strong support to the contention that the transition from normo- into the microalbuminuric phase is linked to progressing glomerulopathy.     

Effect of 3 years of antihypertensive therapy on renal structure in type 1 diabetic patients with albuminuria: the European Study for the Prevention of Renal Disease in Type 1 Diabetes (ESPRIT)

In the treatment of diabetic nephropathy, ACE inhibitor therapy reduces albumin excretion and slows the rate of decline in glomerular filtration rate (GFR). Our study was designed to investigate whether these effects lay in amelioration of the underlying glomerular structural abnormalities. A total of 54 type 1 diabetic patients with albuminuria and blood pressure (BP) <150/90 mmHg were randomized to receive 10 mg enalapril once daily, 10 mg nifedipine retard twice daily, or placebo in a multicenter double-blind study of 3 years' duration. Renal biopsy was performed at baseline and follow-up, and tissue was analyzed by standard morphometric methods. BP, GFR, albumin excretion rate (AER), and HbA1c were measured every 6 months. Enalapril lowered AER after 6 months by 26% (P < 0.05); however, this reduction was not sustained at 3 years. There was no significant effect of nifedipine or placebo on AER. GFR decreased by a similar average rate of 4.1 ml x min(-1) x year(-1) (95% CI 2.6-5.6) in all three groups. BP and HbA1c were unchanged throughout the study in all groups. At baseline, nearly all biopsies showed classic appearances of diabetic glomerulopathy. There was no detectable effect of enalapril compared with either nifedipine or placebo on renal structure over 3 years. However, we found that patients with increased AER have established glomerulopathy and a progressive average decline in GFR of 4.1 ml x min(-1) x year(-1) in the absence of overt hypertension, and baseline AER appeared predictive of subsequent mesangial volume fraction (r = 0.20, P = 0.0018). In this small cohort of nonhypertensive patients studied for 3 years, disease evolution appears unaffected by treatment with either enalapril or nifedipine.     

Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes

Type 2 diabetes is frequently associated with an inflammatory status; the relationships between low-grade inflammation and diabetic nephropathy are still unclear. The aim of this study was to evaluate the relationships between acute-phase markers of inflammation, glomerular structure, and albumin excretion rate (AER) in type 2 diabetes. In 74 patients with type 2 diabetes (23 normoalbuminuric, 30 microalbuminuric, and 21 proteinuric) fibrinogen, serum amyloid A protein (SAA), C-reactive protein (CRP), and IL-6 were determined. AER was measured on three 24-h urine collections; GFR was measured by 51Cr EDTA plasma clearance. A kidney biopsy was performed, and mesangial fractional volume [Vv(mes/glom)] and glomerular basement membrane (GBM) width were estimated by electron microscopic morphometric analysis. CRP, fibrinogen, SAA, and IL-6 differed among groups, with proteinuric patients having the highest levels. SAA and fibrinogen correlated with AER (P < 0.03 and P < 0.001, respectively). GBM width and Vv(mes/glom) increased from normoalbuminuric to proteinuric patients [P < 0.005 normoalbuminuric and microalbuminuric versus proteinuric for GBM, P < 0.01 normoalbuminuric versus proteinuric for Vv(mes/glom)]. In patients with increased GBM width (> 396 nm), CRP, SAA, and IL-6 were higher than in patients with normal GBM width (P < 0.003, P < 0.004, and P < 0.0004, respectively). GBM width was directly correlated with fibrinogen (r = 0.33, P < 0.002) and IL-6 (r = 0.25 P < 0.05). In conclusion, this study demonstrates that acute-phase markers of inflammation are associated with nephropathy status and GBM thickening, suggesting a role for inflammation in the pathogenesis of diabetic glomerulopathy.     

Exaggerated sensitivity to NE-induced vasoconstriction in IDDM patients with microalbuminuria. Possible etiology and diagnostic implications.

Increased urinary albumin excretion rate (AER) in the microalbuminuric phase of diabetic nephropathy has been attributed to intraglomerular hypertension. This could be caused by constriction of efferent glomerular arterioles, which carry alpha-adrenoceptors. We tested the hypothesis that insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria are hypersensitive to vasoconstriction induced by norepinephrine (NE). We studied 15 IDDM patients with microalbuminuria (AER 32-295 mg/24 h), 13 IDDM patients with normal AER (5-24 mg/24 h), and 9 nondiabetic subjects (AER 8-22 mg/24 h). All were normotensive. NE-induced vasoconstriction was measured in dorsal hand veins, which carry alpha-receptors similar to those of glomerular efferent arterioles. Vein diameter was measured with a linear displacement probe during a stepped NE infusion (1-32 ng/min) into the vein, and venoconstriction was expressed as a percentage of the maximum passively distended venous diameter. Microalbuminuric IDDM patients exhibited significantly greater vasoconstriction (P less than 0.005) at all NE infusion rates than both other groups. The NE infusion rate producing 50% of maximal venoconstriction (ED50) in the microalbuminuric IDDM group (median 1.1 ng/min, range 0.2-25.2 ng/min) was significantly less than in both the normoalbuminuric IDDM group (median 12.5 ng/min, range 4.9-40.5 ng/min, P = 0.00007) and the nondiabetic group (median 17.7 ng/min, range 5.9-42.2 ng/min, P = 0.0003). Dose-response curves and ED50 did not differ significantly between normalbuminuric IDDM and nondiabetic groups. IDDM patients with microalbuminuria are hypersensitive to NE-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlates of ACE activity in macroalbuminuric type 2 diabetic patients treated with chronic ACE inhibition.

The activity of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the development and progression of diabetic nephropathy. However, the effect of angiotensin-converting enzyme (ACE) inhibition on the RAAS appears to be modulated by a number of factors including the I/D polymorphism of the ACE genotype. In this study, we attempted to find independent correlates of ACE activity in 121 macroalbuminuric type 2 diabetic Iranian patients under chronic ACE inhibition. Both univariate and multivariate analyses were used. The presence of the D allele was independently associated with significantly higher levels of ACE activity (with the II genotype as reference, P < 0.001, B = 27.3, 95% CI = 17.6-37.1), and this association was not eliminated by potentially confounding variables. In conclusion, the D allele is a significant independent correlate of ACE activity in macroalbuminuric type 2 diabetic Iranian patients under long-term ACE inhibition.     

Dextromethorphan-associated epidural patient-controlled analgesia provides better pain- and analgesics-sparing effects than dextromethorphan-associated intravenous patient-controlled analgesia after bone-malignancy resection: a randomized, placebo-controlled, double-blinded study

Pain after bone malignancy surgery is intense and requires large amounts of analgesics. The augmented antinociceptive effects of dextromethorphan (DM), a N-methyl-D-aspartate receptor antagonist, were demonstrated previously. We assessed the use of postoperative patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) in patients undergoing surgery for bone malignancy under standardized combined general and epidural anesthesia with or without DM. Patients (n = 120) were randomly allocated to receive PCEA (ropivacaine 3.2 mg plus fentanyl 8 microg/dose) or IV-PCA (morphine 2 mg/dose) postoperatively, starting at subjective visual analog scale pain intensity >or=4 of 10 for up to 96 h. Placebo or DM 90 mg orally (30 patients/group/set) was given in a double-blinded manner before surgery and for 2 days afterwards. Diclofenac 75 mg IM was available as a rescue drug. DM patients used PCA and rated their pain >50% less than their placebo counterparts in each set, especially during the first 2 postoperative days (P < 0.01). Hourly and overall maximal pain intensity among PCEA patients was approximately 50% less than in the IV-PCA set (P < 0.01). Diclofenac was used 42% less (P < 0.01) by the PCA-DM patients compared with their placebo counterparts. Seven PCEA-DM and 11 IV-PCA-DM individuals reported having side effects compared with 44 in the PCEA-placebo and the IV-PCA-placebo groups (P < 0.01). Time to first ambulation was similar with both analgesia techniques but shorter among the DM-treated patients compared with the placebo recipients (1.5 +/- 0.8 versus 2.1 +/- 1.1 days, P = 0.02). Thus, DM afforded better pain control and reduced the demand for analgesics, augmented the PCEA effect versus IV-PCA, and was associated with minimal untoward effects in each analgesia set. DM patients ambulated earlier than placebo recipients. IMPLICATIONS: Patients undergoing bone-malignancy surgery under combined general and epidural anesthesia received randomly patient-controlled epidural analgesia (PCEA) or IV patient-controlled analgesia (PCA) postoperatively and dextromethorphan (DM) 90 mg or placebo double-blindly for 3 days (n = 30/group/set). The DM effect was recorded with minimal untoward effects: it afforded better pain control and reduced the demand for analgesics compared with the placebo, especially when associated with PCEA. DM patients ambulated earlier than placebo recipients.     

Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes.

This study was designed to elucidate the cellular basis of risk of or protection from nephropathy in patients with type 1 diabetes. Entry criteria included diabetes duration of > or =8 years (mean duration, 22.5 years) and glomerular filtration rate (GFR) >30 ml x min(-1) x 1.73 m(-2). Patients were classified, on the basis of the estimated rate of mesangial expansion, as "fast-track" (upper quintile) or "slow-track" (lower quintile). A total of 88 patients were normoalbuminuric, 17 were microalbuminuric, and 19 were proteinuric. All three groups had increased glomerular basement membrane (GBM) width and mesangial fractional volume [Vv(Mes/glom)], with increasing severity from normoalbuminuria to microalbuminuria to proteinuria but with considerable overlap among groups. Vv(Mes/glom) (r = 0.75, P < 0.001) and GBM width (r = 0.63, P < 0.001) correlated with albumin excretion rate (AER), whereas surface density of peripheral GBM per glomerulus [Sv(PGBM/glom)] (r = 0.50, P < 0.001) and Vv(Mes/glom) (r = -0.48, P < 0.001) correlated with GFR. Vv(Mes/glom) and GBM width together explained 59% of AER variability. GFR was predicted by Sv(PGBM/glom), AER, and sex. Fast-track patients had worse glycemic control, higher AER, lower GFR, more hypertension and retinopathy, and, as expected, worse glomerular lesions than slow-track patients. Thus, there are strong relationships between glomerular structure and renal function across the spectrum of AER, but there is considerable structural overlap among AER categories. Given that normoalbuminuric patients may have advanced glomerulopathy, the selection of slow-track patients based on glomerular structure may better identify protected patients than AER alone.     

Increased circulating nitric oxide in young patients with type 1 diabetes and persistent microalbuminuria: relation to glomerular hyperfiltration

Hyperglycemia has been causally linked to vascular and glomerular dysfunction by a variety of biochemical mechanisms, including a glucose-dependent abnormality in nitric oxide (NO) production and action. NO is a candidate for mediating hyperfiltration and the increased vascular permeability induced by diabetes. Serum nitrite and nitrate (NO2-+ NO3-) concentrations were assessed as an index of NO production in 30 adolescents and young adults with type 1 diabetes, 15 with and 15 without microalbuminuria (albumin excretion rate [AER] between 20 and 200 microg/min), compared with a well-balanced group of healthy control subjects. In all subjects, glomerular filtration rate (GFR) was determined by radionuclide imaging. Our study showed that NO2- + NO3- serum content and GFR values were significantly higher in microalbuminuric diabetic patients than in the other 2 groups. GFR was significantly and positively related to AER levels (r2 = 0.75, P < 0.0001), whereas NO2- + NO3- serum content was independently associated with both AER and GFR values (beta = 2.086, P = 0.05, beta = 1.273, P = 0.0085, respectively), suggesting a strong link between circulating NO, glomerular hyperfiltration, and microalbuminuria in young type 1 diabetic patients with early nephropathy. Interestingly, mean HbA1c, serum concentration was significantly higher in microalbuminuric than in normoalbuminuric diabetic subjects (P < 0.05) and was independently associated with AER values, suggesting a role for chronic hyperglycemia in the genesis of diabetic nephropathy. Moreover, HbA1c serum concentration was significantly and positively related to NO2 + NO3 serum content (r2 = 0.45, P = 0.0063) and GFR values (r2 = 0.57, P = 0.0011), suggesting that chronic hyperglycemia may act through a mechanism that involves increased NO generation and/or action. In conclusion, we suggest that in young type 1 diabetic patients with early nephropathy, chronic hyperglycemia is associated with an increased NO biosynthesis and action that contributes to generating glomerular hyperfiltration and persistent microalbuminuria.     

Captopril acutely lowers albuminuria in normotensive patients with diabetic nephropathy.

Angiotensin-converting enzyme (ACE) inhibitors decrease albuminuria in patients with diabetic nephropathy. To study the change in albuminuria in relation to changes in systemic and renal hemodynamics, nine normotensive patients with type 1 (insulin-dependent) diabetes mellitus and persistent proteinuria were given a single oral dose of 25 mg of the ACE inhibitor captopril. Blood pressure, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and albumin excretion rate (AER) were measured in two periods of 40 minutes before and in four periods of 40 minutes after administration of captopril. A constant water diuresis was maintained. Blood pressure did not decrease significantly (130/79 +/- 4/3 v 124/74 +/- 4/3 mm Hg; mean +/- SEM), median AER decreased from 403 (interquartile range [IQR], 812) micrograms/min to 333 (707) micrograms/min (P < 0.01). GFR did not change (123 +/- 13 v 117 +/- 14 mL/min), but ERPF increased significantly from 609 +/- 56 to 714 +/- 55 mL/min (P < 0.01). Consequently, the filtration fraction (FF; quotient of GFR and ERPF) decreased from 0.20 +/- 0.014 to 0.17 +/- 0.014 (P < 0.01). A strong correlation was found between the decrease of AER and the decrease of FF (rs = 0.75; P < 0.02). No correlation was found between the decrease in AER and changes in GFR or blood pressure. In the normotensive patient with diabetic nephropathy, captopril causes an acute reduction of AER, which is probably mediated by a lowering of the intraglomerular pressure.     

One year course of oral sulodexide in the management of diabetic nephropathy

BACKGROUND: Diabetic nephropathy is a multifactorial diabetic complication whose long-term consequences involve chronic renal insufficiency and increased rate of cardiovascular death. Besides oxidative stress, and hemodynamic changes, glycosaminoglycans (GAGs) are an additional component implicated in the onset of glomerular abnormalities. GAG replacement therapy was envisaged in the nineties for the treatment of diabetic nephropathy and sulodexide is the most extensively investigated GAG to reduce albuminuria in diabetic patients. METHODS: In this study we have evaluated the effect of a long-term course of oral sulodexide at a moderate dosage in the treatment of patients affected by diabetic nephropathy. Thirty patients with type 1 and 2 diabetes mellitus (DM) have been treated with 50 mg/ daily oral sulodexide for 12 months while thirty matched diabetic patients constituted the control group. All the patients attended monthly visits and controls of biochemical and metabolic parameters. RESULTS: At 12 months albuminuria was greatly reduced in patients treated with sulodexide and increased in the control group (260% and +29% vs baseline, respectively; p = 0.0001). The drug appeared active in both type 1 and type 2 diabetes and in both micro- and macroalbuminuric patients. No change in metabolic control and no systemic side effects were reported. CONCLUSIONS: In our diabetic patients sulodexide therapy has been proven to greatly reduce albuminuria, and to have the potential to delay progression from incipient to overt nephropathy.     

Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy.

OBJECTIVE: Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether alpha-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles. RESEARCH DESIGN AND METHODS: Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER <20 microg/min or <30 mg/24 h), microalbuminuria (20 200 microg/min or >300 mg/24 h). Alpha-defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes alpha-defensin isoforms 1-3. RESULTS: Total serum alpha-defensin (-1, -2 and -3) concentrations were higher (P < 0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis alpha-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers. CONCLUSIONS; Serum alpha-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.     

Plasma prekallikrein: a risk marker for hypertension and nephropathy in type 1 diabetes

The relevance and significance of the plasma kallikrein/kinin system as a risk factor for the development of vascular complications in diabetic patients was explored in a cross-sectional study. We measured the circulating levels of plasma prekallikrein (PK) activity, factor XII, and high-molecular weight kininogen in the plasma of 636 type 1 diabetic patients from the Diabetes Control and Complications Trial/Epidemiology and Diabetes Intervention and Complications Study cohort. The findings demonstrated that type 1 diabetic patients with blood pressure > or =140/90 mmHg have increased PK levels compared with type 1 diabetic patients with blood pressure <140/90 (1.53 +/- 0.07 vs. 1.27 +/- 0.02 units/ml; P < 0.0001). Regression analysis also determined that plasma PK levels positively and significantly correlated with diastolic (DBP) and systolic blood pressures (SBP) as continuous variables (r = 0.17 and 0.18, respectively; P < 0.0001). In multivariate regression analysis, the semipartial r(2) value for PK was 2.93% for SBP and 2.92% for DBP (P < 0.0001). A positive correlation between plasma PK levels and the urinary albumin excretion rate (AER) was also observed (r = 0.16, P < 0.0001). In categorical analysis, patients with macroalbuminuria had a significantly higher level of plasma PK than normoalbuminuric patients (1.45 +/- 0.08 vs. 1.27 +/- 0.02 units/ml; P < 0.01), whereas microalbuminuric patients had an intermediate PK value (1.38 +/- 0.05 units/ml; P = NS). Among patients in the microalbuminuric subgroup, we observed a positive and independent correlation between PK and AER in univariate and multivariate regression analysis (r = 0.27, P < 0.03; n = 63). We concluded that in type 1 diabetes, 1) PK levels are elevated in association with increased blood pressure; 2) PK levels are independently correlated with AER and are categorically elevated in patients with macroalbuminuria; and 3) although the positive correlation between PK and AER within the subgroups of patients with microalbuminuria suggest that PK could be a marker for progressive nephropathy, longitudinal studies will be necessary to address this issue.