Elevated urinary prostaglandin excretion and the effect of indomethacin on renal function in incipient diabetic nephropathy

We investigated whether the glomerular synthesis of prostaglandins modulates the glomerular filtration rate and urinary albumin excretion in incipient diabetic nephropathy (defined as urinary albumin excretion between 30 and 300 mg/24 h (microalbuminuria) in two out of three sterile ketone-free 24-h urine collections in patients having insulin-dependent diabetes mellitus (IDDM) without hypertension or other kidney disease). The urinary excretion of prostaglandin E2 was significantly elevated in 8 insulin-dependent diabetic patients with incipient nephropathy as compared with 9 normoalbuminuric IDDM patients and 11 healthy controls: 317 (182-1273); 95 (67-225); 132 (54-263) pg/min, respectively (2p less than 0.01). Glomerular filtration rate (single bolus 51Cr-EDTA technique) and albuminuria (radioimmunoassay) were measured twice within 2 weeks in 8 females having IDDM with incipient nephropathy. The study design was a randomized double-blind trial with the patients receiving either indomethacin (150 mg/day) or placebo for 3 days prior to the kidney function studies. Indomethacin treatment induced a significant reduction in urinary prostaglandin E2 excretion (73%) (2p less than 0.01), urinary albumin excretion rate diminished from 207 (63-253) to 87 (49-147) mg/24 h (2p less than 0.01), fractional clearance of albumin declined (70%) (2p less than 0.01). Glomerular filtration rate remained stable (108 (88-133) versus 110 (95-142) ml/min). Blood glucose and blood pressure were comparable during the placebo and indomethacin treatment (12.6 +/- 3 versus 13.4 +/- 5 mmol/l and 122/79 +/- 3/9 versus 122/82 +/- 4/10 mmHg, respectively). Our results suggest that enhanced glomerular synthesis of vasodilating prostaglandins may accelerate microalbuminuria in incipient diabetic nephropathy.     

Reduced urinary excretion of epidermal growth factor in incipient and overt diabetic nephropathy

To study the relationship between glomerular and tubular function we investigated glomerular filtration rate (GFR), urinary albumin excretion, and urinary excretion of epidermal growth factor (EGF, a mitogenic peptide synthesized in the renal tubular cells) in normal subjects (group I, n = 7) and in Type 1 (insulin-dependent) diabetic patients with normoalbuminuria (group II, n = 11); with incipient nephropathy (microalbuminuria) (group III, n = 9); with nephropathy and normal GFR (group IV, n = 12); and with reduced GFR (group V, n = 8). EGF (nmol 24 h-1) decreased with progressive glomerular involvement, from 7.9 (4.1-10.5) (median and range) in group I, to 6.7 (1.3-9.2) in group II, 5.0 (3.6-7.4) in group III, 4.1 (2.5-9.5) in group IV, and 1.1 (0.1-2.5) in group V. The urinary excretion of EGF was significantly reduced in patients with elevated UAE (group III, IV, and V) compared with normal control subjects (p less than 0.05). A significant correlation between urinary excretion of EGF and GFR (r = 0.71, p less than 0.001) and an inverse correlation between the urinary excretion of EGF and albumin (r = -0.35, p less than 0.05) was demonstrated in the Type 1 diabetic patients with GFR greater than 90 ml min-1. Our study demonstrates that urinary excretion of epidermal growth factor diminishes with increasing nephron impairment, and that renal tubular function as judged by the excretion of EGF is reduced early in the development of diabetic kidney disease.     

Effect of octreotide and insulin on manifest renal and glomerular hypertrophy and urinary albumin excretion in long-term experimental diabetes in rats

Summary Treatment of diabetic rats with octreotide can inhibit early diabetic renal hypertrophy. Octreotide administration for 6 months from the day of diabetes induction inhibits renal hypertrophy and diminishes increase in urinary albumin excretion. To investigate the effect of octreotide on manifest diabetic renal changes, octreotide treatment was given for 3 weeks after an untreated diabetic period of 3 or 6 months. In addition, following 6 months of diabetes, a group of diabetic rats was treated with insulin for 3 weeks. Renal and glomerular hypertrophy, and increased urinary albumin excretion were observed in diabetic rats compared to non-diabetic control rats from 3 months and throughout the study period. Octreotide treatment did not affect body weight, food intake, blood glucose or serum fructosamine levels. We observed no effect of octreotide treatment on renal and glomerular hypertrophy or urinary albumin excretion compared to placebotreated diabetic rats. Insulin treatment for 3 weeks after 6 months of untreated diabetes normalized blood glucose and serum fructosamine levels, and furthermore renal hypertrophy was significantly diminished compared to the placebo-treated diabetic rats. However, insulin treatment had no effect on glomerular hypertrophy or urinary albumin excretion. In conclusion, octreotide treatment for 3 weeks following an untreated diabetic period of 3 or 6 months is unable to reduce the increased renal and glomerular volume or urinary albumin excretion. However, insulin treatment for 3 weeks with induction of euglycaemia diminishes the renal hypertrophy but has no effect on glomerular volume or urinary albumin excretion.Abbreviations UAE Urinary albumin excretion - IGF-I insulin-like growth factor I - IGFBP insulin-like growth factor binding protein - STZ streptozotocin - TGV total glomerular volume - BW body weight - GH growth hormone - RPF renal plasma flow     

Association between plasma osteoprotegerin concentrations and urinary albumin excretion in Type 2 diabetes

Aims Osteoprotegerin (OPG) is a recently identified inhibitor of bone resorption. Recent studies indicate that OPG is also associated with endothelial dysfunction in Type 2 diabetes. The aim was to investigate the relationship between plasma OPG levels and urinary albumin excretion (UAE) in Type 2 diabetic patients. Methods This study included 154 newly diagnosed Type 2 diabetic patients and 46 healthy subjects. Plasma OPG and 24‐h UAE were measured. High‐resolution ultrasound was used to measure flow‐mediated (endothelium‐dependent arterial) dilation (FMD). Results Compared with the normoalbuminuric subgroup, OPG levels in the microalbuminuric subgroup were significantly higher, and OPG levels in macroalbuminuria subgroup were significantly higher than those in the normoalbuminuria and albuminuria subgroups. Multiple regression analysis showed that only FMD (r = ?0.26), C‐reactive protein (r = 0.23), fasting blood glucose (r = 0.25), 2‐h blood glucose (r = 0.21), HbA_1c (r = 0.28), UAE (r = 0.27) and retinopathy (r = 0.27) were significant factors associated with OPG. Pearson’s correlation analyses showed a positive correlation between OPG and logUAE (r = 0.440) and negative correlations between OPG and FMD (r = ?0.284), and between FMD and logUAE (r = ?0.602). Conclusions Plasma OPG levels are significantly associated with UAE in Type 2 diabetic patients.     

Coronary heart disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients

Summary Associations between overnight urinary albumin excretion rate and prevalent coronary heart disease and its major risk factors were examined in a cross-sectional study of 141 Type 2 (non-insulin-dependent) diabetic patients. Mean albumin excretion rate was higher in men (geometric mean 13.5 g/min; 95% confidence interval 10.3–17.6) than women (7.5 g/min; 5.7–9.8, p<0.01). In diabetic men and women mean albumin excretion rate was higher in those with electrocardiographic and/or symptomatic evidence of coronary heart disease than in those without (men, 23.1 g/ min; 95% confidence interval 13.7–39.0 versus 10.6 g/min; 7.9–14.2, p<0.01, women, 13.7 g/min; 8.0–23.5 versus 5.4 g/min; 4.2–6.8, p<0.01). Multiple logistic regression analysis was used to allow for confounding between variables. In the diabetic group as a whole, raised albumin excretion rate (p<0.001), gender (p<0.05) and systolic blood pressure (p=0.06) entered the best model for coronary heart disease prediction. In women, albumin excretion rate alone (p<0.01) and in men albumin excretion rate (p<0.01) and age (p=0.05) entered the best models. We conclude that albumin excretion rate is significantly associated with coronary heart disease morbidity after taking into account the confounding effects of raised blood pressure and other cardiovascular risk factors.     

Protein intake and urinary albumin excretion rates in the EURODIAB IDDM Complications Study

Summary For people with insulin-dependent diabetes mellitus (IDDM) renal disease represents a life-threatening and costly complication. The EURODIAB IDDM Complications Study, a cross-sectional, clinic-based study, was designed to determine the prevalence of renal complications and putative risk factors in stratified samples of European individuals with IDDM. The present study examined the relationship between dietary protein intake and urinary albumin excretion rate (AER). Food intake was assessed centrally by a standardized 3-day dietary record. Urinary AER was determined in a central laboratory from a timed 24-h urine collection. Complete data were available from 2696 persons with IDDM from 30 centres in 16 European countries. In individuals who reported protein consumption less than 20 % of total food energy intake, mean AER was below 20 μg/min. In those in whom protein intake constituted more than 20 %, mean AER increased, a trend particularly pronounced in individuals with hypertension and/or poor metabolic control. Trends reached statistical significance for intakes of total protein (% of energy, p = 0.01) and animal protein (% of energy, p = 0.02), while no association was seen for vegetable protein (p = 0.83). These findings support the current recommendation for people with diabetes not to exceed a protein intake of 20 % of total energy. Monitoring and adjustment of dietary protein appears particularly desirable for individuals with AER exceeding 20 μg/min (approximately 30 mg/24 h), especially when arterial pressure is raised and/or diabetic control is poor. [Diabetologia (1997) 40: 1219–1226] Received: 11 April 1997 and in revised form: 10 June 1997     

Intravenous insulin decreases urinary albumin excretion in long-term diabetics with nephropathy

Summary The effect of intravenous injection of insulin on heart rate, plasma noradrenaline and urinary excretion rates of albumin and beta-2-microglobulin was examined in 10 long-term diabetics, 5 of whom had albuminuria. — In patients without albuminuria intravenous injection of insulin resulted in changes similar to but less pronounced than those previously observed in short-term diabetics: albumin excretion, plasma noradrenaline and heart rate increased, creatinine excretion decreased significantly. —Intravenous injection of insulin increased heart rate but not plasma noradrenaline in long-term diabetics with albuminuria. Arterial blood pressure did not change after insulin. Contrary to expectation insulin decreased urinary albumin excretion (from 418 to 312 g/min, 27 per cent) in these patients. There was a marked decrease in urinary excretion rates of beta-2-microglobulin and creatinine (55 and 17 per cent, respectively) after insulin. — The decrease in albumin excretion after insulin in diabetics with albuminuria is most likely due to renal vasoconstriction. The absence of a rise in albumin excretion after insulin may be due to severe morphological changes in glomeruli in these patients.     

The variability of overnight urinary albumin excretion in insulin-dependent diabetic and normal subjects

The variability of overnight urinary albumin excretion rate (AER) and albumin to creatinine ratio was assessed in eight normal subjects and two groups of insulin-dependent diabetic patients divided on the basis of an initial overnight urinary albumin excretion rate below (n = 15) or above (n = 12) 30 micrograms/min. The latter group is known to be at risk of developing clinical diabetic nephropathy. An albumin to creatinine ratio of 2.6 and above identified all patients with an initial albumin excretion rate greater than 30 micrograms/min. The mean of the coefficients of variation, calculated from five successive overnight urine collections, for all subjects was 38% for albumin excretion rate and 37% for albumin to creatinine ratio. There was no significant difference in the variation of albumin excretion rate and albumin to creatinine ratio within or between the groups. Subsequent AERs from diabetics with an initial rate greater than 30 micrograms/min changed category more often (chi 2 = 11.9, p less than 0.001) than those from diabetics with lower initial rates and normal subjects. This was due to four subjects with initial values close to the cut-off level, whose subsequent values varied around it. Albumin excretion rates in normal subjects never exceeded 11 micrograms/min. Whether a patient's risk status is influenced by the degree of variation of albumin excretion rate around a risk level, or whether the classification of risk is improved by multiple collections, awaits testing in prospective subjects.     

Plasma lipids and urinary albumin excretion rate in Type 1 diabetes mellitus: the EURODIAB IDDM Complications Study.

AIMS: To examine the relationship between increased urinary albumin excretion rate and fasting plasma lipids among male and female respondents to the EURODIAB IDDM Complications Study, and attempt to explain inconsistencies in previous reports. METHODS: A cross-sectional study of 3250 randomly selected Type 1 diabetic patients from 31 diabetes clinics in 16 European countries was carried out between 1989 and 1990. Plasma lipids and urinary albumin were measured centrally. The present analysis was confined to the subgroup of 2205 patients attending after a 10-12 h overnight fast. Mean age was 33 years (SD 10) and mean duration of Type 1 diabetes mellitus was 15 years (SD 9). RESULTS: The prevalence of microalbuminuria (24-h urinary albumin excretion rate 20-200 microg/min) was 21.7% (95% confidence interval 19.9-23.5) and macroalbuminuria (24-h urinary albumin excretion rate > 200 microg/min) 7.8% (6.6-9.0). In comparison to patients with normal urinary albumin excretion rate (< 20 microg/min), and after controlling for age, sex, glycaemic control, duration of diabetes and current smoking, macroalbuminuria was associated with significantly (P<0.01) increased fasting plasma triglycerides, cholesterol, LDL-cholesterol, cholesterol:HDL-cholesterol ratio and, in women, reduced HDL-cholesterol. In men and women with microalbuminuria, the only significant association was with increased plasma triglycerides. CONCLUSIONS: These data confirm that there is an association between fasting plasma lipids and increasing urinary albumin excretion rate in European Type 1 diabetic patients. In microalbuminuric patients, however, the association was weaker than previously reported and partly explained by confounding factors.     

A comparison of urinary albumin excretion rate and microalbuminuria in various glucose tolerance subjects.

AIMS: To investigate the difference of urinary albumin excretion rate (UAER) and microalbuminuria (MAU) in various glucose tolerance subjects, especially between isolated-impaired glucose tolerance subjects and isolated-impaired fasting glycaemia subjects. METHODS: A total of 2934 subjects were divided into five groups with various glucose tolerances, based on a 75-g oral glucose tolerance test. Microalbuminuria was defined when urinary albumin excretion rate was between 20 and 200 microg/min. RESULTS: (i) The UAER in the newly diagnosed Type 2 diabetes mellitus group, impaired glucose tolerance/impaired fasting glycaemia group and isolated-impaired glucose tolerance group were all higher than that in the isolated-impaired fasting glycaemia group and normal glucose tolerance group, but it was comparable between isolated-impaired fasting glycemia group and normal glucose tolerance group. The prevalence of MAU and the odds ratio for MAU with adjustment for age and sex in various glucose tolerance groups showed the same trend as the UAER. (ii) After adjusting for age and sex, there is a significant association between logUAER and independent risk factors (partial correlation coefficients: r = 0.26 for 2-h post-challenge blood glucose, r = 0.26 for systolic blood pressure, r = 0.27 for diastolic blood pressure, r = 0.27 for body mass index and r = -0.13 for high density lipoprotein-cholesterol, all P < 0.001). The risks for MAU were 2-h post-challenge blood glucose, body mass index and diastolic blood pressure, while high density lipoprotein-cholesterol was protective. CONCLUSIONS: The urinary albumin excretion rate and prevalence of microalbuminuria were higher in isolated-impaired glucose tolerance subjects than those in isolated-impaired fasting glycaemia subjects. At early abnormal glucose tolerance stage, the increasing post-challenge glycaemia might be a more important risk factor for urinary albumin excretion rate and microalbuminuria than increasing fasting glycaemia.     

糖尿病患者心脏自主神经病变与尿白蛋白排泄的关系

目的探讨糖尿病患者尿白蛋白排出率（ＵＡＥ）与糖尿病自主神经病变之间的关系。方法对５６例糖尿病患者及５４例正常对照者进行了ＵＡＥ测定，并应用２４小时动态心电图心率变异性频谱分析技术测定了两组的心脏自主神经功能。结果糖尿病患者在不同ＵＡＥ阶段，其反映迷走神经功能的入睡后高频成分均显著低于对照组（Ｐ＝０．０００１）。随着ＵＡＥ的增加，心脏自主神经病变的各项指标均值呈明显的减低趋势，同时出现迷走－交感神经的联合损害。结论ＵＡＥ越高，心脏自主神经病变的各项指标越低，即自主神经病变越明显。     

Abnormalities in plasmas concentrations of lipoproteins and fibrinogen in Type 1 (insulin-dependent) diabetic patients with increased urinary albumin excretion

Summary Type 1 (insulin-dependent) diabetic patients with clinical nephropathy have a more than ten-fold increase in mortality of cardiovascular diseases compared with diabetic patients without nephropathy. The risk factors for cardiovascular disease, plasma concentrations of lipoproteins and fibrinogen, were investigated in 74 long-term diabetic patients: 37 with normal urinary albumin excretion, 20 with incipient nephropathy and 17 with overt clinical nephropathy based on urinary albumin excretion. The groups were matched according to sex, age and diabetes duration. The concentration of plasma cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride and fibrinogen rose with increasing urinary albumin excretion. The plasma concentrations of these lipoproteins and fibrinogen were 11–14% higher in the patients with incipient nephropathy and 26–87% higher in the patients with overt clinical ne phropathy compared with the patients without nephropathy. The plasma concentration of high density lipoprotein cholesterol was unaffected by albuminuria. Patients with normal urinary albumin excretion and HbA_1c>8.0% had significantly higher very low density lipoprotein- and lower high density lipoprotein cholesterol concentrations compared with patients with HbA_1c<8.0%. Simple addition of the described risk factors can only account for a minor part of the greatly increased cardiovascular mortality in patients with diabetic nephropathy. An additional and possibly more decisive factor might be a change in the arterial wall, a change which promotes lipid accumulation and/or facilitates thrombus formation.     

血压对NIDDM患者尿白蛋白排泄的影响

本文对１６４例非胰岛素依赖型糖尿病（ＮＩＤＤＭ）患者２４ｈ尿白蛋白排泄（２４ｈＵＡＥ）进行检测，结果显示：（１）在病程＜１０年的患者中，伴或不伴高血压者，２４ｈＵＡＥ无显著差异，但伴高血压者，微量白蛋白尿的发生率明显高于不伴高血压者，分别为３６．９％（１／１９）和７．９％（６／７６）；（２）在病程１０－２０年的患者中，伴高血压者，２４ｈＵＡＥ、微量及大量白蛋白尿的发生率均明显高于不伴高血压者；（３     

糖尿病肾病脂蛋白(a)质量浓度变化对尿白蛋白排泄率的影响

目的探讨血清脂蛋白(a)[Lp(a)]质量浓度变化与糖尿病肾病(DN)进展之间的关系以及降低血清Lp(a)质量浓度在防治DN进展中的意义。方法对广东省东莞市人民医院2002-04～2004-09门诊及住院270例糖尿病患者分为单纯糖尿病(SDM)组、早期糖尿病肾病(EDN)组和临床糖尿病肾病(CDN)组各90例,比较其与正常对照组的血清Lp(a)水平;两组DN患者在常规治疗基础上每晚服用氟伐他汀40mg。分析血清Lp(a)质量浓度变化与DN进展之间的关系。结果⑴SDM组血清Lp(a)质量浓度与正常对照组比较无显著性差异(P>0.05),EDN、CDN组血清Lp(a)质量浓度明显高于正常对照组和SDM组(P<0.01),CDN组血清Lp(a)质量浓度明显高于EDN组(P<0.01)。血清Lp(a)质量浓度与尿白蛋白排泄率(UAER)呈直线正相关(r=0.396,P<0.01)。⑵两组DN患者血清Lp(a)水平显著降低(P<0.01)。结论血清Lp(a)质量浓度升高与DN进展有关,降低血清Lp(a)质量浓度能有效减轻EDN患者的蛋白尿、改善肾功能,但对CDN患者无效。     

Normal urinary albumin excretion in recently diagnosed type 1 diabetic patients

The urinary excretion of albumin and retinol binding protein were measured in 51 recently diagnosed Type 1 diabetic patients and 48 control subjects, matched for age and sex. The diabetic patients, admitted consecutively to the Steno Memorial Hospital, were all studied 3 to 6 months after the onset of diabetes. Urinary albumin excretion (median and 95% confidence interval) was similar in the diabetic patients and normal control subjects (8 (6-11) vs 8 (6-11) mg 24-h-1, NS). Four diabetic patients had urinary albumin excretion in the microalbuminuric range of 30-300 mg 24-h-1. There was no significant difference between the two groups in urinary excretion of retinol binding protein. The distribution among the individuals of both urinary proteins was positively skewed and similar in the two groups. In conclusion, no significant differences in the urinary excretion of albumin and retinol binding protein were found between recently diagnosed Type 1 diabetic patients and normal subjects.     

The acute effect of insulin on heart rate,blood pressure,plasma noradrenaline and urinary albumin excretion

Summary The effect of intravenous insulin (7–8 U as a bolus injection) on renal haemodynamics and urinary excretion of albumin and beta-2-microglobulin was examined in five recent onset juvenile diabetics. Blood glucose concentration was maintained after insulin at unchanged or slightly increased levels by continuous intravenous glucose infusion (50 g/100 ml, 1.2 ml/min). Mean arterial blood pressure increased slightly but significantly from 94±8 mmHg to 99±10 (mean ± SD) after insulin. The rise in heart rate (16 versus 29 beats/min) and in plasma noradrenaline (from 0.16 to 0.32 ng/ml versus 0.20 to 0.49 ng/ml) was significantly greater in the tilted position after insulin. There was no decrease in glomerular filtration rate or renal plasma flow after insulin, in contrast to the findings after intravenous injection of insulin without maintenance of plasma glucose. Urinary albumin excretion was approximately doubled after insulin, from 6.8 to 12.5 g/min. Beta-2-microglobulin excretion decreased but this difference was not significant. — It is concluded that the rise in heart rate and plasma noradrenaline, and the increase in urinary albumin excretion, after insulin, are unrelated to changes in blood glucose concentration. It is suggested that increased albumin excretion after insulin is due to a direct effect of insulin on glomerular endothelial or epithelial cells.     

Urinary excretion of glycated albumin in insulin-dependent diabetic patients with normal urinary albumin excretion

Summary Glycation involves both circulating proteins, such as albumin, and structural proteins, such as the components of the glomerular basement membrane. A preferential excretion of glycated albumin (more anionic at physiological pH compared with unmodified plasma albumin) has been reported by some authors, but not by others. We therefore investigated the selectivity index (renal clearance of non-glycated albumin/clearance of glycated albumin) in 25 insulin-dependent diabetic patients with normal urinary albumin excretion and in 19 well-matched control subjects. The selectivity index was significantly higher in diabetic patients than in control subjects: 1.38±0.05 SEMvs 0.98±0.02, p<0.0001. This result is not consistent with a preferential urinary excretion of glycated albumin, at least in normoalbuminuric uncomplicated insulin-dependent diabetic patients.     

Reduction of urinary albumin excretion by thromboxane synthetase inhibitor, OKY-046, through modulating renal prostaglandins in patients with diabetic nephropathy

We evaluated the effects of thromboxane synthetase inhibitor, OKY-046, on urinary albumin and prostaglandin (PG) excretion in 14 patients with non-insulin-dependent diabetes mellitus (NIDDM).

Urinary excretion of 6-keto-PGF₁ (a stable metabolite of PGI₂), TXB₂ (a stable metabolite of TXA₂) and PGE₂ in NIDDM patients was comparable with that in control subjects. However, the urinary 6-keto-PGF₁/TXB₂ ratio in NIDDM patients with both micro- and macroalbuminuria was significantly (P < 0.001) lower than that in the controls.

By a single administration of OKY-046 (40 mg, i.v.) to the diabetic patients, urinary TXB₂ excretion significantly (P < 0.05) decreased from 169.7 ± 23.9 to 140.2 ± 17.9 ng/gCr, but urinary 6-keto-PGF₁ and PGE₂ excretion did not change significantly. The urinary 6-keto-PGF₁/TXB₂ ratio thus significantly (P < 0.01) increased from 1.02 ± 0.13 to 1.73 ± 0.41 as associated with significant increments in urine volume (P < 0.05), urinary sodium excretion (P < 0.01) and creatinine clearance (P < 0.05).

Of 14 diabetic patients, 7 with macroalbuminuria (albumin index exceeding 100 mg/gCr) were orally given OKY-046 (600 mg/day) for 8 weeks. After this period, the urinary albumin index significantly (P < 0.05) decreased from 524.9 ± 149.6 to 317.6 ± 90.6 mg/gCr. Urinary PG excretion did not change significantly, although the urinary 6-keto-PGF₁/TXB₂ ratio significantly (P < 0.01) increased from 1.33 ± 0.16 to 2.42 ± 0.65 and decreased to 1.09 ± 0.15 (P < 0.01) following termination of this drug. Similarly, creatinine clearance significantly (P < 0.01) increased, from 56.3 ± 14.1 to 69.4 ± 15.1 ml/min. During the period of 8 weeks, no significant alteration occurred in systemic blood pressure or glycemic control.

In conclusion, OKY-046 has a beneficial effect on albuminuria in diabetic nephropathy by modulating altered renal PGs synthesis, which leads to a change in renal hemodynamics.     

Serum sialic acid concentration is elevated in IDDM especially in early diabetic nephropathy

Abstract. Objectives. Elevated serum sialic acid concentration is a strong predictor of cardiovascular mortality in non-diabetic subjects. Because patients with insulin-dependent diabetes mellitus (IDDM) and albuminuria have a highly increased cardiovascular morbidity and mortality, we hypothesized that IDDM patients with albuminuria would have an increased concentration of serum sialic acid. Design. Cross-sectional study. Setting. Outpatient clinic at Steno Diabetes Centre, Gentofte, Denmark. Subjects. Twenty-six non-diabetic controls and 74 IDDM patients with normoalbuminuria (urinary albumin excretion [UAE] < 30 mg 24 h^?1; n = 37), incipient nephropathy (UAE 30–300 mg 24 h^?1; n = 20) and clinical nephropathy (UAE > 300 mg 24 h^?1; n = 17), matched for sex, age and body mass index (BMI). Main outcome measures. Serum sialic acid concentration, concurrent fasting blood glucose, glycated haemoglobin (HbA1c), serum creatinine, plasma fibrinogen and erythrocyte sedimentation rate. Results. Normoalbuminuric patients had a higher serum sialic acid concentration (mmol L^?1) than non-diabetic controls (1.83 ± 0.24 vs. 1.67 ± 0.26; P < 0.02). Serum sialic acid concentration was further increased in patients with incipient nephropathy (2.02 ± 0.37; P < 0.03) and in patients with clinical nephropathy (2.13 ± 0.33; P < 0.002) compared with normoalbuminuric IDDM patients. Serum sialic acid correlated strongly with plasma fibrinogen (r = 0.78; P < 0.0001) and erythrocyte sedimentation rate (r = 0.62; P < 0.0001). In a multiple regression analysis including UAE, retinopathy status, fasting blood glucose, HbA1c, mean blood pressure, serum creatinine, age, BMI, duration and smoking, UAE and fasting blood glucose were the independent variables which correlated significantly with serum sialic acid concentration (P < 0.0001 and P < 0.05, respectively). Conclusion. Serum sialic acid is elevated in IDDM especially in albuminuric patients. Whether elevated serum sialic acid is predictive for early diabetic nephropathy and cardiovascular disease in IDDM has to be shown in the future.     

Effect of troglitazone on urinary albumin excretion and serum type IV collagen concentrations in Type 2 diabetic patients with microalbuminuria or macroalbuminuria.

AIMS: Troglitazone, a newly developed thiazolidinedione derivative, has been shown to ameliorate microalbuminuria in diabetic animal model and in human diabetic nephropathy in short-term studies. The aim of the present study was to determine whether troglitazone or sulphonylurea affect micro- albuminuria, macroalbuminuria, or serum type IV collagen concentrations in patients with diabetic nephropathy. METHODS: We studied 32 normotensive patients with type 2 diabetes mellitus associated with microalbuminuria (n = 16) or macroalbuminuria (n = 16) and 20 healthy controls. The patients were randomly assigned to one of two groups: those treated with glibenclamide (5.0 mg/day) (n = 8) and those treated with troglitazone (400 mg/day) (n = 8). They received the drug regimen for 12 months. Serum type IV collagen was measured with sandwich enzyme immunoassay. RESULTS: Type IV collagen concentrations in macroalbuminuric patients were higher than those in microalbuminuric patients (P < 0.05) and healthy controls (P < 0.01). Troglitazone reduced urinary albumin excretion (UAE) in micro-albuminuric patients from 126 microg/min (range 58--180 microg/min) to 42 microg/min (range 14--80 microg/min) (P < 0.01) and also reduced serum type IV collagen levels gradually at 3, 6 and 12 months after treatment (P < 0.05). However, glibenclamide did not affect UAE and type IV collagen levels in micro- albuminuric diabetes patients. In addition, neither troglitazone nor gliben- clamide changed UAE and type IV collagen levels in macroalbuminuric patients. CONCLUSIONS: These data suggest that troglitazone is an effective treatment for renal injury in patients with early diabetic nephropathy.